Acetyl Coa Carboxylase 2 Sequences And Methods

Abstract

The present invention relates generally to novel nucleotide and amino acid sequences, and more particularly to novel human acetyl CoA carboxylase 2 (ACC2) and rat ACC2 sequences. The sequences provided herein can be expressed in a recombinant format. Methods of isolating the ACC2 sequence are also provided, which can be employed to isolate any ACC sequence. The ACC2 sequences can be employed in therapeutic applications to diagnose or treat a condition associated with ACC2. The invention also relates to the identification of modulators of ACC activity using the recombinant human ACC2 enzyme as the screening target.

Description

[0001] This application is a division of U.S. application Ser. No. 11/186,999, filed Jul. 21, 2005, which claims priority benefit to U.S. provisional application No. 60/590,948 filed Jul. 23, 2004. The entire teachings of the referenced application are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] Disclosed and claimed herein are novel polynucleotides encoding human and rat Acetyl CoA Carboxylase 2 ("ACC2") polypeptides, fragments and homologues thereof. Vectors, host cells, antibodies, and recombinant and synthetic methods for producing the ACC2 polypeptides are provided. Further described are diagnostic and therapeutic methods for applying the ACC2 polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders related to these polypeptides, including obesity. Further embodiments include screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.

BACKGROUND OF THE INVENTION

[0003] Acetyl CoA carboxylase (ACC) is the rate-determining enzyme of fatty acid biosynthesis in plants and animals. ACC is a biotin containing enzyme which catalyzes the carboxylation of acetyl CoA to form malonyl CoA in a two-step reaction (Beaty & Lane, (1982). J. Biol. Chem. 257:924-929). The first step is the ATP-dependent carboxylation of biotin covalently linked to the enzyme. In the second step, a carboxyltransferase step, the carboxyl group is transferred to the substrate, acetyl CoA, to form malonyl CoA. Citrate is a potent allosteric activator of ACC. Malonyl CoA is the C2 donor for de novo synthesis of long chain fatty acids.

[0004] In mammals, there are two subtypes of ACC, ACC1 and ACC2. ACC1 is mainly localized in lipogenic tissues such as adipose tissue and liver, where fatty acids are synthesized. ACC2 is found primarily in non-lipogenic tissues such as skeletal muscle and heart muscle, although some is also found in liver. Malonyl CoA allosterically inhibits carnitine palmitoyl transferase 1 (CPT1), which is a critical enzyme to transfer the long chain fatty acid into the mitochondria for .beta.-oxidation. Because ACC2 is co-localized with CPT-1, the primary role of malonyl CoA that is synthesized by ACC2 has been suggested to regulate the rate of .beta.-oxidation.

[0005] ACC is a potential target in metabolic diseases for the treatment of metabolic syndrome including obesity, insulin resistance and dyslipidemia. Increased rates of muscle fatty acid oxidation, a reduced fat content and a reduction in total body fat were observed in ACC-2 knock-out mice (Abu-Elheiga et al., (2001) Science 291:2613-2616; Abu-Elheiga et al., (2003) Proc. Natl. Acad. Sci. USA. 100:10207-10212). Harwood et al. reported that ACC inhibitors caused reduction in fatty acid synthesis, increase in fatty acid oxidation, and reduction of respiratory quotient in rats (Harwood et al., (2003) J. Biol. Chem. 278:37099-37111). Chronic dosing of these compounds resulted in the reduction of whole body fat mass and improvement of insulin sensitivity (Harwood et al., (2003) J. Biol. Chem. 278:37099-37111). These observations further validated the enzyme as a drug target.

[0006] Several human ACC2 and rat ACC2 nucleotide and amino acid sequences have been published (see, e.g., Human ACC2: GenBank Accession No. NM.sub.--001093 (SEQ ID NOs:1 and 2) and GenBank Accession No. AC007637 (SEQ ID NOs:3 and 4); Rat ACC2: GenBank Accession No. NM.sub.--053922 (SEQ ID NOs:7 and 8) and GenBank Accession No. AB004329 (SEQ ID NOs:9 and 10)). It was found, however, that for each species, each of the published amino acid and/or nucleotide sequences was different from one another by one or more residues. More specifically, it was found that the nucleotide sequences of human ACC2 and rat ACC2 contain non-silent mutations that introduce substitutions into several of the published encoded amino acid sequences of these enzymes.

[0007] In order to identify the most effective modulators of human ACC2 and rat ACC2, accurate nucleotide and amino acid sequences are required. Therefore, what is needed to advance research on human and rat ACC2 is an accurate amino acid sequence for these enzymes, as well as the encoding nucleotide sequences. The subject matter disclosed and claimed herein solves this and other problems.

SUMMARY OF THE INVENTION

[0008] Described and claimed herein is an isolated nucleic acid molecule encoding a human ACC2 polypeptide. In one embodiment the nucleic acid molecule comprises a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a polynucleotide encoding an ACC2 polypeptide comprising SEQ ID NO:12; (b) an isolated polynucleotide encoding a human ACC2 polypeptide comprising amino acids 2 to 2458 of SEQ ID NO:12 minus the start methionine; (c) an isolated polynucleotide encoding a human ACC2 polypeptide comprising amino acids 1 to 2458 of SEQ ID NO:12 including the start codon; (d) an isolated polynucleotide encoding the ACC2 polypeptide encoded by the cDNA clone contained in ATCC Deposit No: PTA-6054; and (e) a polynucleotide capable of hybridizing under stringent conditions to the polynucleotide specified in (a)-(d), wherein the polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues. The isolated nucleic acid molecule can comprise, for example, the nucleotide sequence of SEQ ID NO:11. In additional aspects, the present invention also relates to a polynucleotide that is complementary to the isolated nucleic acid molecule, a vector comprising the isolated nucleic acid molecule and a host cell, which can be a mammalian host cell, comprising the vector.

[0009] Also disclosed is a method of making an isolated human ACC2 polypeptide. In one embodiment the method comprises: (a) culturing the recombinant host cell under conditions such that the polypeptide is expressed; and (b) recovering the polypeptide.

[0010] Further described is an isolated human ACC2 polypeptide. In one embodiment the polypeptide comprises an amino acid sequence selected from the group consisting of: (a) a polypeptide comprising SEQ ID NO:12; (b) a polypeptide comprising amino acids 2 to 2458 of SEQ ID NO:12, wherein amino acids 2 to 2458 comprise a polypeptide of SEQ ID NO:12 minus the start methionine; and (c) a polypeptide comprising amino acids 1 to 2458 of SEQ ID NO:12. In another embodiment, the polypeptide comprises two or more sequential amino acid deletions from one or both of: (a) the COOH-terminus of the polypeptide; and (b) the NH.sub.2-terminus of the polypeptide.

[0011] Another embodiment disclosed herein is a method of identifying a compound that modulates the activity of a human ACC2 polypeptide. In one embodiment, the method comprises: (a) determining the activity of an ACC2 polypeptide in the absence of a test compound; (b) determining the activity of the polypeptide in the presence of a test compound; and (c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound relative to the activity of the polypeptide in the absence of the test compound indicates that the compound that modulates the activity of the polypeptide.

[0012] A further embodiment is an isolated antibody which specifically binds to a human ACC2 polypeptide. In various embodiments, the antibody is selected from the group consisting of a chimeric antibody, a single chain antibody, a Fab fragment, and a humanized antibody.

[0013] Further disclosed and claimed is an isolated nucleic acid molecule encoding a rat ACC2 polypeptide. In one embodiment the isolated nucleic acid molecule comprises a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a polynucleotide encoding an ACC2 polypeptide comprising SEQ ID NO:14; (b) an isolated polynucleotide encoding a rat ACC2 polypeptide comprising amino acids 2 to 2458 of SEQ ID NO:14 minus the start methionine; (c) an isolated polynucleotide encoding a rat ACC2 polypeptide comprising amino acids 1 to 2458 of SEQ ID NO:14 including the start codon; (d) the cDNA of ATCC Deposit No. PTA-6054; and (e) a polynucleotide capable of hybridizing under stringent conditions to the polynucleotide specified in (a)-(d), wherein the polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

[0014] In one embodiment, the isolated rat nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:13. In additional aspects, the present invention comprises a polynucleotide that is complementary to the isolated nucleic acid molecule, a vector comprising the isolated nucleic acid molecule and a host cell, which can be a mammalian host cell, comprising the vector.

[0015] Another embodiment relates to a method of making an isolated rat ACC2 polypeptide. In one embodiment the method comprises: (a) culturing a recombinant host cell under conditions such that the polypeptide is expressed; and (b) recovering the polypeptide.

[0016] Yet a further embodiment is an isolated rat ACC2 polypeptide. For example, the polypeptide comprises an amino acid sequence selected from the group consisting of: (a) a polypeptide comprising SEQ ID NO:14; (b) a polypeptide comprising amino acids 2 to 2455 of SEQ ID NO:14, wherein amino acids 2 to 2455 comprise a polypeptide of SEQ ID NO:14 minus the start methionine; and (c) a polypeptide comprising amino acids 1 to 2455 of SEQ ID NO:14. In another embodiment, the polypeptide comprises two or more sequential amino acid deletions from one or both of: (a) the COOH-terminus of the polypeptide; and (b) the NH.sub.2-terminus of the polypeptide.

[0017] Further disclosed is a method of identifying a compound that modulates the activity of a rat ACC2 polypeptide. In one embodiment, the method comprises: (a) determining the activity of a polypeptide in the absence of a test compound; (b) determining the activity of the polypeptide in the presence of a test compound; and (c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound relative to the activity of the polypeptide in the absence of the test compound indicates that the compound that modulates the activity of the polypeptide.

[0018] An isolated antibody that specifically binds to the rat ACC2 polypeptide is disclosed. In various embodiments, the antibody is selected from the group consisting of a chimeric antibody, a single chain antibody, a Fab fragment, and a humanized antibody.

[0019] A method of isolating a rat ACC polypeptide is additionally disclosed. In one embodiment, the method comprises: (a) contacting crude lysate derived from a cell or tissue expressing an ACC polypeptide with an antibody to form a complex comprising an antibody and an ACC; (b) washing the complex with a buffer comprising 0.5 M NaCl; and (c) contacting the complex with an eluting ligand. The antibody can comprise an IgG antibody, and in one embodiment, can be, for example, a c-Myc-5 IgG antibody and the eluting ligand can be a myc peptide. The myc peptide can comprise the amino acid sequence of SEQ ID NO:16. In another example, the IgG antibody is an anti-FLAG IgG antibody. Further, the antibody can be bound to a substrate. The method can be employed to isolate any ACC polypeptide, such as an ACC1 or ACC2 polypeptide.

[0020] Additionally, a polynucleotide capable of inhibiting the expression of an ACC2 gene comprising a polynucleotide sequence selected from the group consisting of SEQ ID NOs:11 and 13 by antisense inhibition is disclosed, as well as a method of inhibiting ACC2 gene expression comprising introducing an antisense polynucleotide into a cell or tissue that expresses an ACC2 gene, thereby inhibiting the expression of the gene in the cell or tissue by antisense inhibition.

[0021] A polynucleotide capable of inhibiting the expression of an ACC2 gene comprising a polynucleotide sequence selected from the group consisting of SEQ ID NOs:11 and 13 by RNA inhibition is disclosed, as well as a method of inhibiting ACC2 gene expression comprising introducing an RNAi polynucleotide into a cell or tissue that expresses an ACC2 gene, thereby inhibiting the expression of the gene in the cell or tissue by RNA inhibition.

[0022] Another embodiment is directed to an isolated polypeptide comprising an ACC2 polypeptide encoded by the cDNA deposited as ATCC Accession No. PTA-6054.

[0023] An additional embodiment is a method of increasing the activity of a human ACC2 polypeptide. In one embodiment, the method comprises generating an enhanced ACC2 polypeptide comprising: (a) a phenylalanine residue at position 254, (b) a glutamine residue at position 346, (c) a threonine residue at position 565, (d) an asparagine at position 841, (e) a valine residue at position 1103, (f) a cysteine residue at position 1259, (g) an alanine residue at position 1526, and (h) an isoleucine residue at position 1717, wherein the human ACC2 polypeptide does not comprise SEQ ID NO:12 and wherein the enhanced ACC2 polypeptide has an enzymatic activity level that is greater than the enzymatic activity level of an ACC2 polypeptide that does not contain the indicated residues at the indicated positions. In various aspects, the human ACC2 polypeptide sequence is selected from the group consisting of SEQ ID NOs:2, 4 and 6.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIGS. 1A-1K depicts a polynucleotide (SEQ ID NO:11) and encoded ACC2 amino acid sequence (SEQ ID NO:12) of a human ACC2.

[0025] FIGS. 2A-2K depicts a polynucleotide (SEQ ID NO:13) and encoded ACC2 amino acid sequence (SEQ ID NO:14) of a rat ACC2 identified as described herein.

[0026] FIGS. 3A-3I is an alignment of a published rat nucleotide ACC2 sequence (SEQ ID NO:9) with a rat ACC2-encoding sequence consensus sequence described herein (SEQ ID NO:13). In the figure, "AB004329" represents the nucleic aside sequence of GenBank Accession No. AB004329 and "BMS" represents a rat ACC2 sequence.

[0027] FIGS. 4A-4C is an alignment of a published rat amino acid ACC2 sequence (SEQ ID NO:10) with a rat ACC2-encoding sequence consensus sequence described herein (SEQ ID NO:14). In the figure, "AB004329" represents the amino acid sequence of GenBank Accession No. AB004329 and "BMS_ratACC2" represents the amino acid sequence of a rat ACC2 sequence described herein.

[0028] FIGS. 5A-5I is an alignment of a cloned rat ACC2 nucleotide sequence (SEQ ID NO:13) with a sequence derived from PCR products generated in consensus sequencing (SEQ ID NO:15). In the figure, "ratACC2_C7" represents the cloned rat ACC2 nucleotide sequence and "RatACC2" represents the nucleotide sequence derived from PCR products generated in consensus sequencing.

[0029] FIG. 6A is a schematic drawing for comparison of the primary structure of human ACC1 versus ACC2 and the final version construct of human ACC2 which was used for expression in the work described herein; BC represents the biotin carboxylase domain, BCCP represents the biotin carboxyl carrier protein domain, CT represents the carboxyltransferase domain, filled circles denote the biotin group, open circles denote the discrepancies of amino acids between pYES-human-ACC2 (designated as Mt) versus the wild type human ACC2 (designated as WT), V5, Myc, 6His represent three tags fused in frame to the human ACC2 sequence at the COOH-terminus and the numbers presented below the bar denote the amino acid numbers predicted by the full length human ACC2 cDNA.

[0030] FIG. 6B is an autoradiograph depicting the results of blot analyses of total cell extracts from Sf9 cells that are infected with either wild type baculovirus as Mock control, or with ACC2Mt and ACC2WT recombinant virus respectively; the blots were probed with anti-V5 IgG (left panel) or with Streptavidin-HRP-conjugated (right panel) respectively.

[0031] FIG. 7 is an autoradiograph depicting the results of a chromatographic separation of recombinant human ACC2 on monomeric avidin column.

[0032] FIG. 8 is a photograph (left panel) and an autoradiograph (right panel) depicting the results of a chromatographic separation of total Sf9 cell lysates and recombinant human ACC2 on TALON resin assayed by coomassie stain (left panel) or by anti-V5 immunoblot analysis (right panel).

[0033] FIG. 9A is a photograph depicting the results of a chromatographic separation of a recombinant human ACC2 of the present invention on a c-Myc-5 affinity column; fractions eluted from the column by myc peptide (SEQ ID NO:16) were assayed with coomassie stain.

[0034] FIG. 9B is a bar graph depicting the results of a chromatographic separation of a recombinant human ACC2 of the present invention on a c-Myc-5 affinity column; fractions eluted from the column by myc peptide (SEQ ID NO:16) were assayed with ACC activity measurement.

[0035] FIG. 10 is a series of four plots depicting the concentration dependence of a recombinant human ACC2 described herein, on the substrates acetyl CoA, bicarbonate, ATP and its effector citrate; each plot is labeled according to substrate.

[0036] FIG. 11 is a series of two plots depicting the concentration dependent inhibition of a recombinant human ACC2 described herein by the known inhibitors of ACC enzymes palmitoyl CoA and malonyl CoA; each plot is labeled according to inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The subject matter disclosed and claimed herein relates to novel nucleotide sequences encoding human and rat ACC2 proteins and to the novel proteins themselves. Several embodiments are described and include uses of the novel sequences for identifying modulators of ACC and for treating conditions associated with undesired ACC activity. The novel sequences disclosed herein are consensus sequences that were identified, cloned and sequenced based on published versions of the human and rat ACC2 sequences.

[0038] A human ACC2 polynucleotide sequence of the present invention is set forth in FIG. 1 (SEQ ID NO:11), and a rat ACC2 polynucleotide of the present invention is set forth in FIG. 2 (SEQ ID NO:13). The human sequence was deposited with ATCC on Jun. 8, 2004 and has been assigned Deposit Number PTA-6054. A human ACC2 polypeptide sequence of the present invention is set forth in FIG. 1 (SEQ ID NO:12), and a rat ACC2 polypeptide of the present invention is set forth in FIG. 2 (SEQ ID NO:14). Based on the established physiological function of ACC2, these novel sequences represent an important target for the treatment of obesity, diabetes and related disease states.

I. Definitions

[0039] All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.

[0040] Following long-standing patent law convention, the terms "a" and "an" mean "one or more" when used in this application, including the claims.

[0041] As used herein, the term "about," when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of .+-.20% or less (e.g., .+-.15%, .+-.10%, .+-.7%, .+-.5%, .+-.4%, .+-.3%, .+-.2%, .+-.1%, or .+-.0.1%) from the specified amount, as such variations are appropriate.

[0042] As used herein, unless clearly specified otherwise explicitly or by context, the terms "ACC2" and "ACC2 of the present invention" are used interchangeably and mean an acetyl CoA carboxylase polypeptide comprising SEQ ID NOs:12 or 14, which can be encoded by a polynucleotide sequence comprising the nucleic acid sequence of SEQ ID NO:11 (human ACC2) or SEQ ID NO:13 (rat ACC2). The terms also encompass variants, such as, but not limited to, polynucleotides that are not identical to SEQ ID NOs:11 and 13, due to degeneracy in the genetic code, but still code for an ACC2 polypeptide.

[0043] The terms "ACC2" and "ACC2 of the present invention" whether referring to a rat or a human sequence, encompasses sequences comprising one or more conservative substitutions in the ACC2 amino acid sequences of SEQ ID NOs:12 and 14. The substitution can be naturally occurring or introduced by man. In a conservative substitution, the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. A table disclosing some representative, but non-limiting properties that can be used as a guide when identifying or generating a conservative mutation follows: TABLE-US-00001 Representative Conservative Amino Acid Substitutions Amino Acid Property Amino Acid Basic: arginine lysine histidine Acidic: glutamic acid aspartic acid Polar: glutamine asparagine Hydrophobic: leucine isoleucine valine Aromatic: phenylalanine tryptophan tyrosine Small: glycine alanine serine threonine methionine

[0044] Conservative substitutions typically include the substitution of one amino acid for another with similar characteristics, e.g., substitutions within the following groups: valine, glycine; glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Other conservative amino acid substitutions are shown in the following table: TABLE-US-00002 For Amino Acid Code Replace with any of: Alanine A D-Ala, Gly, beta-Ala, L-Cys, D-Cys Arginine R D-Arg, Lys, D-Lys, homo-Arg, D-homo-Arg, Met, Ile, D-Met, D-Ile, Orn, D-Orn Asparagine N D-Asn, Asp, D-Asp, Glu, D-Glu, Gln, D-Gln Aspartic D D-Asp, D-Asn, Asn, Glu, D-Glu, Acid Gln, D-Gln Cysteine C D-Cys, S-Me-Cys, Met, D-Met, Thr, D-Thr Glutamine Q D-Gln, Asn, D-Asn, Glu, D-Glu, Asp, D-Asp Glutamic E D-Glu, D-Asp, Asp, Asn, D-Asn, Acid Gln, D-Gln Glycine G Ala, D-Ala, Pro, D-Pro, .beta.- Ala, Acp Isoleucine I D-Ile, Val, D-Val, Leu, D-Leu, Met, D-Met Leucine L D-Leu, Val, D-Val, Met, D-Met Lysine K D-Lys, Arg, D-Arg, homo-Arg, D-homo-Arg, Met, D-Met, Ile, D-Ile, Orn, D-Orn Methionine M D-Met, S-Me-Cys, Ile, D-Ile, Leu, D-Leu, Val, D-Val Phenylal- F D-Phe, Tyr, D-Thr, L-Dopa, His, anine D-His, Trp, D-Trp, Trans-3,4, or 5-phenylproline, cis-3,4, or 5-phenylproline Proline P D-Pro, L-1-thioazolidine-4- carboxylic acid, D- or L-1-oxazo- lidine-4-carboxylic acid Serine S D-Ser, Thr, D-Thr, allo-Thr, Met, D-Met, Met(O), D-Met(O), L-Cys, D-Cys Threonine T D-Thr, Ser, D-Ser, allo-Thr, Met, D-Met, Met(O), D-Met(O), Val, D-Val Tyrosine Y D-Tyr, Phe, D-Phe, L-Dopa, His, D-His Valine V D-Val, Leu, D-Leu, Ile, D-Ile, Met, D-Met

[0045] As used herein, the term "agonist," and grammatical derivations thereof, refer to an agent that initiates, supplements or potentiates the bioactivity of a functional ACC2 gene or protein, or that supplements or potentiates the bioactivity of a naturally occurring or engineered functional ACC2 gene or protein. An agonist can be a ligand. Further, an agonist can act by preventing an antagonist from acting on a given protein.

[0046] As used herein, the terms "amino acid," "amino acid residue" and "residue" are used interchangeably and mean any of the twenty naturally occurring amino acids. An amino acid is formed upon chemical digestion (hydrolysis) of a polypeptide at its peptide linkages. The amino acid residues described herein are preferably in the "L" isomeric form. However, residues in the "D" isomeric form can be substituted for any L-amino acid residue, as long as the desired functional property is retained by the polypeptide (e.g., enzymatic activity). NH.sub.2 refers to the free amino group present at the amino terminus of a polypeptide. COOH refers to the free carboxy group present at the carboxy terminus of a polypeptide. In addition, the phrases "amino acid" and "amino acid residue" are broadly defined to include modified and unusual amino acids.

[0047] As used herein, the term "antagonist," and grammatical derivations thereof, means an agent that decreases or inhibits the bioactivity of a functional ACC2 gene or protein, or that decreases or inhibits the bioactivity of a naturally occurring or engineered ACC2 gene or protein. An antagonist can be a ligand. Further, an antagonist can act by preventing an agonist from acting on a given protein.

[0048] As used herein, the term "antibody" means polyclonal, monoclonal, antibody fragments (e.g. a Fab fragment) and antibody derivatives. The term encompasses antibodies prepared by recombinant techniques, such as chimeric or humanized antibodies, as well as single chain or bispecific antibodies. The term specifically encompasses antibodies that bind to an epitope, or a portion thereof, of a polypeptide that is described in the present disclosure.

[0049] As used herein, the terms "antigen" and "epitope," which are well understood in the art, mean all or a portion of a macromolecule that is specifically recognized by a component of the immune system, e.g. an antibody or a T-cell antigen receptor. An epitope is a region of an antigen. As used herein, the term "antigen" encompasses antigenic epitopes, e.g., fragments of an antigen that are antigenic epitopes.

[0050] As used herein, the term "associates specifically," and grammatical derivations thereof, means an interaction between a first moiety (e.g. a modulator, such as an agonist or an antagonist) and a second moiety (e.g., an ACC2 polypeptide or fragment thereof) that occurs preferentially to an interaction the first or second moiety and any other moieties present. For example, an antibody is presented with a variety of antigens, but only binds to a particular antigen. In this example, the antibody "specifically associates" with the particular antigen.

[0051] As used herein, the term "biological activity" means any activity that a biological molecule normally exhibits in vivo. For example, when the biological molecule is ACC2, representative biological activities can include the catalytic carboxylation of biotin covalently bound to ACC2 polypeptide in an ATP-dependent manner, the catalytic formation of malonyl CoA as a result of transfer of carboxyl group to acetyl CoA, and the binding of citrate.

[0052] As used herein, the term "biological sample" means any biological sample obtained from an organism, body fluids, cell line, tissue culture. A biological sample can be a body fluid (for example, sputum, amniotic fluid, urine, saliva, breast milk, secretions, interstitial fluid, blood, serum, spinal fluid, etc.) or other tissue source. Methods for obtaining tissue biopsies and body fluids from organisms are known to those of ordinary skill in the art. Where the biological sample is to include mRNA, a tissue biopsy is a preferred source.

[0053] As used herein the term "complementary" means a nucleic acid sequence that is base paired, or is capable of base-pairing, according to the standard Watson-Crick complementarity rules. These rules generally hold that guanine pairs with cytosine (G:C) and adenine pairs with either thymine (A:T) in the case of DNA, or adenine pairs with uracil (A:U) in the case of RNA.

[0054] As used herein, the term "hybridize" means the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity.

[0055] As used herein, the terms "isolated" and "purified" are used interchangeably and refer to material (e.g., a nucleic acid or a polypeptide) removed from its original environment (e.g., the natural environment, if it is naturally occurring), and thus is altered "by the hand of man" from its natural state. The term "isolated" does not refer to genomic or cDNA libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide and/or protein sequences of the present invention; such sequences are excluded from the scope of the present invention.

[0056] As used herein the term "modulate," and grammatical derivations thereof, refer to an increase, decrease, or other alteration of any and/or all chemical and/or biological activities or properties mediated by a given DNA sequence, RNA sequence, polypeptide, peptide or molecule. The definition of "modulator" as used herein encompasses agonists and/or antagonists of a particular activity or protein. The term "modulate" refers to both upregulation (i.e., activation or stimulation) and downregulation (i.e. inhibition or suppression).

[0057] As used herein, the term "stringent hybridization conditions," in the context of nucleic acid hybridization experiments such as southern and northern blot analysis, means a set of conditions under which single stranded nucleic acid sequences are unlikely to hybridize to one another unless there is substantial complementarity between the sequences. Stringent hybridization conditions can be both sequence- and environment-dependent. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found, for example, in Tijssen, (1993) Laboratory Techniques in Biochemistry and Molecular Biology--Hybridization with Nucleic Acid Probes, part I, chapter 2, Elsevier, N.Y. Generally, highly stringent hybridization and wash conditions are selected to be about 5.degree. C. lower than the thermal melting point (T.sub.m) for the specific sequence at a defined ionic strength and pH. Typically, under "stringent conditions" a probe will hybridize specifically to its target subsequence, but to no other sequences.

[0058] Examples of stringency conditions are shown in the table below: highly stringent conditions are those that are at least as stringent as, for example, conditions A-F; stringent conditions are at least as stringent as, for example, conditions G-L; and reduced stringency conditions are at least as stringent as, for example, conditions M-R. TABLE-US-00003 Stringency Conditions Hybridization Wash Stringency Polynucleotide Hybrid Length Temperature Temperature Condition Hybrid.+-. (bp) .dagger-dbl. and Buffer.dagger. and Buffer.dagger. A DNA:DNA > or equal to 50 65.degree. C.; 1xSSC - 65.degree. C.; 0.3xSSC or- 42.degree. C.; 1xSSC, 50% formamide B DNA:DNA <50 Tb*; 1xSSC Tb*; 1xSSC C DNA:RNA > or equal to 50 67.degree. C.; 1xSSC - 67.degree. C.; 0.3xSSC or- 45.degree. C.; 1xSSC, 50% formamide D DNA:RNA <50 Td*; 1xSSC Td*; 1xSSC E RNA:RNA > or equal to 50 70.degree. C.; 1xSSC - 70.degree. C.; 0.3xSSC or- 50.degree. C.; 1xSSC, 50% formamide F RNA:RNA <50 Tf*; 1xSSC Tf*; 1xSSC G DNA:DNA > or equal to 50 65.degree. C.; 4xSSC - 65.degree. C.; 1xSSC or- 45.degree. C.; 4xSSC, 50% formamide H DNA:DNA <50 Th*; 4xSSC Th*; 4xSSC I DNA:RNA > or equal to 50 67.degree. C.; 4xSSC - 67.degree. C.; 1xSSC or- 45.degree. C.; 4xSSC, 50% formamide J DNA:RNA <50 Tj*; 4xSSC Tj*; 4xSSC K RNA:RNA > or equal to 50 70.degree. C.; 4xSSC - 67.degree. C.; 1xSSC or- 40.degree. C.; 6xSSC, 50% formamide L RNA:RNA <50 Tl*; 2xSSC Tl*; 2xSSC M DNA:DNA > or equal to 50 50.degree. C.; 4xSSC - 50.degree. C.; 2xSSC or- 40.degree. C. 6xSSC, 50% formamide N DNA:DNA <50 Tn*; 6xSSC Tn*; 6xSSC O DNA:RNA > or equal to 50 55.degree. C.; 4xSSC - 55.degree. C.; 2xSSC or- 42.degree. C.; 6xSSC, 50% formamide P DNA:RNA <50 Tp*; 6xSSC Tp*; 6xSSC Q RNA:RNA > or equal to 50 60.degree. C.; 4xSSC - 60.degree. C.; 2xSSC or- 45.degree. C.; 6xSSC, 50% formamide R RNA:RNA <50 Tr*; 4xSSC Tr*; 4xSSC .dagger-dbl. The "hybrid length" is the anticipated length for the hybridized region(s) of the hybridizing polynucleotides. When hybridizing a polynucleotide of unknown sequence, the hybrid is assumed to be that of the hybridizing polynucleotide of the present invention. When polynucleotides of known sequence are hybridized, the hybrid length can be determined by # aligning the sequences of the polynucleotides and identifying the region or regions of optimal sequence complementarity. Methods of aligning two or more polynucleotide sequences and/or determining the percent identity between two polynucleotide sequences are well known in the art (e.g., MEGALIGN program of the DNA*Star suite of programs, etc). .dagger.SSPE (1xSSPE is 0.15M NaCl, 10 mM NaH2PO4, and 1.25 mM EDTA, pH 7.4) can be substituted for SSC (1xSSC is 0.15M NaCl and 15 mM sodium citrate) in the hybridization and wash buffers; washes are performed for 15 minutes after hybridization is complete. The hybridizations and washes may additionally include 5.times. Denhardt's reagent, 0.5-1.0% SDS, 100 .mu.g/ml # denatured, fragmented salmon sperm DNA, 0.5% sodium pyrophosphate, and up to 50% formamide. *Tb - Tr: The hybridization temperature for hybrids anticipated to be less than 50 base pairs in length should be 5-10.degree. C. less than the melting temperature Tm of the hybrids there Tm is determined according to the following equations. For hybrids less than 18 base pairs in length, Tm(.degree. C.) = 2(# of A + T bases) + 4(# of G + C bases). # For hybrids between 18 and 49 base pairs in length, Tm(.degree. C.) = 81.5 + 16.6(log.sub.10[Na.sup.+]) + 0.41(% G + C) - (600/N), where N is the number of bases in the hybrid, and [Na.sup.+] is the concentration of sodium ions in the hybridization buffer ([Na.sup.+] for 1xSSC = .165 M).

[0059] .+-.--The present invention encompasses the substitution of any one, or more DNA or RNA hybrid partners with either a PNA, or a modified polynucleotide. Such modified polynucleotides are known in the art and are more particularly described elsewhere herein.

[0060] Additional examples of stringency conditions for polynucleotide hybridization are provided, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, 3.sup.rd ed., Cold Spring Harbor Press, Cold Spring Harbor (2001), and Current Protocols in Molecular Biology, 1995, F. M., Ausubel et al., eds, John Wiley and Sons, Inc., which are hereby incorporated by reference herein.

[0061] As used herein, the term "vector" means a replicon, such as plasmid, phage or cosmid, to which another DNA segment may be attached so as to bring about the replication of the attached segment.

II. ACC2 Polypeptides

[0062] ACC2 polypeptides that form aspects of the present invention are presented in FIGS. 1 and 2 and in SEQ ID NOs:12 and 14. These sequences represent human and rat genomic ACC2 polypeptide sequences. Although several human and rat ACC2 sequences have been published (see, e.g., Human ACC2: GenBank Accession No. NM.sub.--001093 (SEQ ID NOs:1 and 2), GenBank Accession No. AC007637 (SEQ ID NOs:3 and 4) and the sequence of pYES-human ACC2, (SEQ ID NOs:5 and 6); Rat ACC2: GenBank Accession No. NM.sub.--053922 (SEQ ID NOs:7 and 8) and GenBank Accession No. AB004329 (SEQ ID NOs:9 and 10)), there are discrepancies between these sequences. Consequently, the present inventors re-evaluated the published human and rat ACC2 sequences, which lead to the identification of the ACC2 sequences of the present invention.

[0063] Based on the identified discrepancies in the published sequences, it was speculated that these discrepancies may represent inadvertent mutations introduced during a cloning or sequencing process. The positions at which residues differ between the published human and rat sequences were also identified. In the human ACC2 amino acid consensus sequence of the present invention, these positions are occupied by R at position 9, P at position 111, A at position 127, F at position 254, Q at position 345, V at position 347, AGWG at positions of 349-352, P at position 450, T at position 565, H at position 614, E at position 656, E at position 671, ET at position 742-743, E at position 799, N at position 841, V at position 1025, V at position 1064, V at position 1103, C at position 1259, R at position 1480, A at position 1526, R at position 1547, I at position 1717, G at position 1821, I at position 2141, PPYA at position 2194-2197, and K at position 2242. In the rat ACC2 amino acid consensus sequence of the present invention, these positions in the sequence are occupied by residues C at position 9, K at position 30, S at position 42, S at position 50, S at position 91, H at position 153, A at position 178, S at position 179, A at position 191, L at position 196, C at position 272, I at position 308, QYV at position 313-315, E at position 365, PSEA at position 372-375, WA at position 377-378, KI at position 382-383, P at position 422, R at position 463, ML at position 472-473, T at position 534, G at position 556, E at position 563, G at position 658, AD at position 693-694, R at position 707, F at position 742, C at position 774, M at position 788, L at position 849, K at position 940, L at position 1025, G at position 1048, M at position 1062, Y at position 1065, Y at position 1122, P at position 1159, IFLSAIDMY at position 1243-1251, R at position 1467, A at position 1493, PT at position 1596-1597, E at position 1629, PK at position 1737-1738, RM at position 1832-1833, RYV at position 1890-1892, T at position 1932, A at position 2079, D at position 2111, P at position 2150, Y at position 2168, F at position 2185, A at position 2203, GQL at position 2260-2262, TA at position 2264-2265, E at position 2309, I at position 2403, and DCVA at position 2428-2431. Details regarding the analysis of the published ACC2 sequences and the generation of the human and rat ACC2 polypeptide sequences of the present invention are provided in the accompanying Examples. Methods of isolating and using the polypeptides are also provided.

[0064] Although the ACC2 polypeptide sequences of SEQ ID NOs:12 and 14 form an aspect of the present invention, the polypeptides of the present invention are not limited to the precise sequences provided in the Sequence Listing. In other aspects of the present invention, variant polypeptides, and polypeptides comprising non-standard amino acids, can be generated using techniques known to those of ordinary skill in the art.

[0065] The polypeptides of the present invention can comprise non-standard amino acids, namely amino acids other than the 20 gene-encoded amino acids. Such polypeptides can be generated by natural processes, such as by posttranslational processing, or by chemical modification techniques which are well known in the art. Such modifications are described in basic texts and in more detailed monographs, as well as in the pertinent research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini.

[0066] A given polypeptide can contain many types of modifications. Polypeptides can be branched, for example, as a result of ubiquitination, and they can be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides can result from posttranslation natural processes or can be made by employing synthetic methods known to those of ordinary skill in the art. Representative modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. Tags to facilitate purification can also be added (see, e.g. Creighton, Proteins--Structures and Molecular Properties, 2nd ed., W.H. Freeman, New York (1992); Posttranslational Covalent Modification of Proteins, (Johnson, ed.), Academic Press, New York, (1984); Seifter & Englard, Method Enzymol. 182:626-646 (1990)).

[0067] The ACC2 polypeptides of the present invention, and variants, fragments and serial deletions thereof, can be produced by any method known in the art for the synthesis of polypeptides, for example, by chemical synthesis, by the recombinant expression techniques described herein or by purification from a biological source, such as tissue, as described herein. For example, methods that are well known to those skilled in the art can be used to construct expression vectors containing a partial or the entire native or mutated ACC2 polypeptide coding sequence and appropriate transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques, as described herein, synthetic techniques and in vivo recombination/genetic recombination.

III. Polynucleotides

[0068] ACC2 polynucleotides that form aspects of the present invention are presented in FIGS. 1 and 2 and in SEQ ID NOs:11 and 13. In the case of human ACC2, the present inventors have found discrepancies between the published sequences and the sequences of the present invention and have reconciled these differences in the ACC2 nucleotide and polypeptide sequences of the present invention.

[0069] The present inventors have identified discrepancies between the published ACC2 sequences. These residue may comprise inadvertent mutations introduced by the cloning process. In the human ACC2 sequence of the present invention, these positions in the sequence are occupied by R at position 9, P at position 111, A at position 127, F at position 254, Q at position 345, V at position 347, AGWG at positions of 349-352, P at position 450, T at position 565, H at position 614, E at position 656, E at position 671, ET at position 742-743, E at position 799, N at position 841, V at position 1025, V at position 1064, V at position 1103, C at position 1259, R at position 1480, A at position 1526, R at position 1547, I at position 1717, G at position 1821, I at position 2141, PPYA at position 2194-2197, and K at position 2242. In the rat ACC2 sequence of the present invention, these positions in the sequence are occupied by C at position 9, K at position 30, S at position 42, S at position 50, S at position 91, H at position 153, A at position 178, S at position 179, A at position 191, L at position 196, C at position 272, I at position 308, QYV at position 313-315, E at position 365, PSEA at position 372-375, WA at position 377-378, KI at position 382-383, P at position 422, R at position 463, ML at position 472-473, T at position 534, G at position 556, E at position 563, G at position 658, AD at position 693-694, R at position 707, F at position 742, C at position 774, M at position 788, L at position 849, K at position 940, L at position 1025, G at position 1048, M at position 1062, Y at position 1065, Y at position 1122, P at position 1159, IFLSAIDMY at position 1243-1251, R at position 1467, A at position 1493, PT at position 1596-1597, E at position 1629, PK at position 1737-1738, RM at position 1832-1833, RYV at position 1890-1892, T at position 1932, A at position 2079, D at position 2111, P at position 2150, Y at position 2168, F at position 2185, A at position 2203, GQL at position 2260-2262, TA at position 2264-2265, E at position 2309, I at position 2403, and DCVA at position 2428-2431. Details regarding the generation of the human and rat ACC2 sequences of the present invention are provided in the accompanying Examples.

[0070] In one aspect of the present invention, isolated polynucleotides encoding a polypeptide comprising the amino acid sequence of human ACC2 (SEQ ID NO:12) and rat ACC2 (SEQ ID NO:14) is disclosed. Examples of such polynucleotides are presented in FIGS. 1 and 2 and in SEQ ID NOs:11 and 13, which encode human and rat ACC2 proteins, respectively. In another aspect of the present invention, the nucleotide sequence of the cDNA insert of the plasmid deposited with the ATCC as Accession Number PTA-6054 on Jun. 8, 2004, and complements thereof, are disclosed.

[0071] The present invention encompasses complements of the ACC2-encoding polynucleotides of the present invention. As explained herein, a complementary sequence is a nucleotide sequence that it can hybridize to a polynucleotide sequence of the present invention to form a stable duplex. Sequences that are complementary to an ACC2 polynucleotide sequence of the present invention can be readily identified using the sequences provided in SEQ ID NOs:11 and 13 as templates. Thus, the present invention encompasses not only polynucleotide sequences encoding the ACC2 proteins of the present invention, but complements of these sequences as well.

[0072] As used herein, a "polynucleotide" of the present invention includes the polynucleotides disclosed herein and in the Sequence Listing, as well as those polynucleotides capable of hybridizing, under stringent hybridization conditions, to the polynucleotide sequences of SEQ ID NOs:11 and 13, the complement thereof, or the cDNA within the clone deposited with the ATCC. "Stringent hybridization conditions" are described herein.

[0073] A polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, is not included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., almost any double-stranded cDNA clone generated using oligo dT as a primer).

[0074] The polynucleotides of the present invention can comprise any polyribonucleotide or polydeoxyribonucleotide, which can be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can comprise single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, the polynucleotide can comprise triple-stranded regions comprising RNA, DNA or both RNA and DNA. A polynucleotide can also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.

[0075] The polynucleotides of the present invention are useful as probes for the identification and isolation of full-length cDNAs and/or genomic DNA which correspond to the polynucleotides of the present invention, as probes to hybridize to and discover novel, related DNA sequences, as probes for positional cloning of a sequence of the present invention or a related sequence, as probe to "subtract-out" known sequences in the process of discovering other novel polynucleotides, as probes to quantify polynucleotide expression, and as probes for microarrays.

[0076] The present invention further provides for other experimental methods and procedures currently available to derive functional assignments. These procedures include but are not limited to spotting of clones on arrays, micro-array technology, PCR based methods (e.g., quantitative PCR), anti-sense methodology, gene knockout experiments, and other procedures that could use sequence information from clones to build a primer or a hybrid partner.

[0077] Details regarding the generation of the human and rat ACC2 sequences of the present invention are provided herein and in the accompanying Examples.

IV. Fragments

[0078] The present invention encompasses fragments of the polynucleotides encoding ACC2 proteins of the present invention. As used herein, the term "fragment" means a polynucleotide sequence that is shorter than an ACC2-encoding polynucleotide sequence of the present invention (e.g., SEQ ID NOs:11 and 13), but retains a region comprising the contiguous sequence of the polynucleotide from which the fragment is derived. A fragment of an ACC2 nucleotide sequence can encode a biologically active portion of an ACC2 protein, or it can be a fragment that can be used as a hybridization probe or as a primer. Nucleic acid molecules that are fragments of an ACC2-encoding polynucleotide can comprise any number of nucleotides up to the number of nucleotides present in a full-length ACC2-encoding polynucleotide sequence of the present invention.

[0079] The term "fragment," therefore, includes any contiguous sequence not disclosed prior to the present invention, but excludes sequences known prior to the present invention. More particularly, if an isolated fragment is disclosed prior to the present invention, that fragment is not encompassed by the present invention.

[0080] A fragment of an ACC2-encoding polynucleotide sequence can, but need not, encode a biologically active ACC2. For example a fragment of an ACC2-encoding polynucleotide sequence of the present invention can be employed as a probe or as a primer, in which case, these fragments will not encode a biologically active protein. On the other hand, a truncated form of an ACC2-encoding polynucleotide sequence of the present invention may encode a biologically active protein, yet be referred to as a fragment. Both biologically active and non-biologically active sequences are within the scope of the claims of the present invention.

[0081] Polypeptide fragments also form aspects of the present invention. A polypeptide fragment of the present invention can comprise any number of amino acids up to the full length of an ACC2 amino acid sequence of the present invention. Polypeptide fragments of the present invention include truncations of any length up to, but excluding, a full length ACC2 polypeptide of the present invention. As discussed herein, a polypeptide fragment of the present invention excludes sequences known prior to the present invention. Thus, an isolated fragment that was described prior to the present invention, is not encompassed by the present invention.

[0082] A polypeptide fragment can be, for example, an epitope, which can be employed to raise antibodies against an ACC2 polypeptide of the present invention, as described herein and as generally known to those of ordinary skill in the art. Fragments can, but need not, include a biologically active segment of an ACC2 protein of the present invention. Other applications for the polypeptide fragments of the present invention will be apparent to those of ordinary skill in the art.

[0083] A polypeptide fragment of the present invention can comprise an ACC2 sequence of the present invention from which serial deletions from the NH.sub.2- or COOH-terminus, or both the NH.sub.2- and COOH-terminus have been made. Such a fragment will comprise a variable number of contiguous amino acids of an ACC2 polypeptide of the present invention, but will be shorter in sequence than a full-length ACC2 polypeptide of the present invention.

V. Variants

[0084] In a further aspect of the present invention, the polypeptides and polynucleotides of the present invention encompass sequences that are variants of the ACC2 polypeptide and ACC2-encoding polynucleotide sequences disclosed herein. As used herein, a "variant polynucleotide" is a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention, but retaining essential properties thereof. Generally, variants are similar, and, over many regions, identical to the polynucleotide or polypeptide of the present invention. "Variants" of the polynucleotide sequences of the present invention include sequences that encode an ACC2 protein of the present invention, but differ conservatively because of the degeneracy of the genetic code. These naturally occurring variants can be identified using standard methodology, such as polymerase chain reaction (PCR), hybridization and sequencing techniques.

[0085] A variant can comprise alterations in the coding regions, non-coding regions, or both regions of an ACC2-encoding polynucleotide sequence For example, a variant can comprise alterations that produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. As noted, nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are within the scope of the claims. Moreover, a variant can comprise any number of amino acid substitutions, for example 1, 2, 3, 4, 5, 7, 8, 10, or more amino acids can be substituted, deleted, or added in any combination are also within the scope of the claims. Preferably, a variant of the present invention retains the amino acids identified as different from published ACC2 sequences (i.e., R at position 9, P at position 111, A at position 127, F at position 254, Q at position 345, V at position 347, AGWG at positions of 349-352, P at position 450, T at position 565, H at position 614, E at position 656, E at position 671, ET at position 742-743, E at position 799, N at position 841, V at position 1025, V at position 1064, V at position 1103, C at position 1259, R at position 1480, A at position 1526, R at position 1547, I at position 1717, G at position 1821, I at position 2141, PPYA at position 2194-2197, and K at position 2242 in the human sequence and C at position 9, K at position 30, S at position 42, S at position 50, S at position 91, H at position 153, A at position 178, S at position 179, A at position 191, L at position 196, C at position 272, I at position 308, QYV at position 313-315, E at position 365, PSEA at position 372-375, WA at position 377-378, KI at position 382-383, P at position 422, R at position 463, ML at position 472-473, T at position 534, G at position 556, E at position 563, G at position 658, AD at position 693-694, R at position 707, F at position 742, C at position 774, M at position 788, L at position 849, K at position 940, L at position 1025, G at position 1048, M at position 1062, Y at position 1065, Y at position 1122, P at position 1159, IFLSAIDMY at position 1243-1251, Rat position 1467, A at position 1493, PT at position 1596-1597, E at position 1629, PK at position 1737-1738, RM at position 1832-1833, RYV at position 1890-1892, T at position 1932, A at position 2079, D at position 2111, P at position 2150, Y at position 2168, F at position 2185, A at position 2203, GQL at position 2260-2262, TA at position 2264-2265, E at position 2309, I at position 2403, and DCVA at position 2428-2431).

[0086] Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. These allelic variants can vary at either the polynucleotide and/or polypeptide level and are within the scope of the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis. Nucleic acid molecules corresponding to natural allelic variants and homologues of the ACC2 cDNA of the present invention can be isolated based on their identity to the polynucleotides disclosed herein using the cDNA, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions as described herein.

[0087] Using known methods of protein engineering and recombinant DNA technology, variants can be generated to alter a characteristic of the polypeptides of the present invention, such as molecular weight or antigenic response. For example, a variant can have one or more altered characteristics while retaining other characteristics. For example, one or more amino acids can be deleted from the NH.sub.2-terminus or COOH-terminus of the protein (as described herein), which will alter the molecular weight of the protein, and might alter the immunologic response profile of the variant and/or the preferred purification protocol for the variant, but might not substantially alter the enzymatic activity of the variant.

[0088] Even if deleting one or more amino acids from the NH.sub.2-terminus or COOH-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities might still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the protein will likely be retained when less than the majority of the residues of the protein are removed from the NH.sub.2-terminus or COOH-terminus. Whether a particular polypeptide lacking NH.sub.2- or COOH-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.

[0089] Thus, the present invention encompasses polypeptide variants that show varying degrees of biological activity. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity.

[0090] Various methods for making phenotypically silent amino acid substitutions are known. For example, by comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.

[0091] In another example, standard mutagenesis methods can be employed to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be employed. The resulting mutant molecules can then be tested for biological activity.

[0092] Thus, the present invention encompasses, but is not limited to, conservative amino acid substitutions introduced into the ACC2 polypeptides of the present invention. Particular examples of conservative amino acid substitutions are presented herein.

[0093] In addition to conservative amino acid substitution, variants of the present invention include, but are not limited to: (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitution with one or more amino acid residues having a substituent group, (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as, for example, an IgG Fc fusion region peptide, a leader or secretory sequence, or a sequence facilitating purification.

[0094] Methods of introducing coding and non-coding mutations into a sequence are known in the art and can be readily employed in the present invention to generate polypeptide and polynucleotide variants (see, e.g. Sambrook et al. and Creighton).

VI. Recombinant Expression of ACC2 Sequences

[0095] In one aspect of the present invention, the ACC2 enzymes of the present invention can be expressed recombinantly. Thus, in accordance with the present invention, conventional molecular biology, microbiology, recombinant DNA and protein chemistry techniques known to those of ordinary skill of the art can be employed to produce a DNA sequence encoding an ACC2 polypeptide, in addition to the guidance provided herein. Such techniques are explained fully in the relevant literature (see, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3.sup.rd ed., Cold Spring Harbor Press, Cold Spring Harbor (2001); Glover, DNA Cloning: A Practical Approach, (2.sup.nd ed.) IRL Press, New York, USA (1995); Gait, Oligonucleotide Synthesis: A Practical Approach, IRL Press, New York, USA (1984); Hames & Higgins, Protein Expression: A Practical Approach, Oxford University Press, New York, USA, (1999); Bickerstaff, Immobilization of Cells And Enzymes, Humana Press, Totowa, N.J., USA (1997); Perbal, A Practical Guide To Molecular Cloning (2.sup.nd ed.) Wiley, New York, N.Y., USA (1988); Current Protocols in Molecular Biology, (Ausubel et al., eds.), Greene Publishing Associates and Wiley-Interscience, New York (2002); Ausubel, Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, (4.sup.th ed.) John Wiley & Sons, New York, N.Y., USA (1999)). A DNA sequence encoding an ACC2 polypeptide of the present invention (including variants, analogs, and functional equivalents), can be prepared by various molecular biology methods known in the art.

[0096] Recombinant expression of an ACC2 polypeptide of the present invention, or a fragment, variant or analog thereof, (e.g. a human or a rat ACC2 polypeptide), requires the construction of an expression vector comprising a polynucleotide that encodes the protein of interest. Once a polynucleotide encoding an ACC2 protein of the present invention has been obtained, a vector for the production of the ACC2 polypeptide can be produced by recombinant DNA technology using techniques known in the art. Methods for preparing a protein by expressing a polynucleotide containing an ACC2-encoding nucleotide sequence are known in the art and described herein.

[0097] Methods known to those of ordinary skill in the art can be used to construct an expression vector comprising an ACC2 coding sequence and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The present invention, thus, encompasses replicable vectors comprising an ACC2-encoding nucleotide sequence of the present invention, which may be operably linked to a promoter.

[0098] The expression vector can then be transferred to a host cell by conventional techniques and the transfected cells are then cultured under appropriate conditions to produce an ACC2 polypeptide of the present invention. Thus, the present invention also comprises host cells containing a polynucleotide encoding an ACC2 polypeptide of the present invention operably linked to a heterologous promoter.

[0099] A variety of host-expression vector systems can be employed to express an ACC2 polypeptide of the present invention. Such host-expression systems represent vehicles by which a coding sequence of interest can be produced and subsequently purified, but also represent cells that may, when transformed or transfected with the appropriate nucleotide coding sequences, express an ACC2 polypeptide of the present invention in situ. These include but are not limited to microorganisms such as bacteria (e.g. E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing ACC2 coding sequences; yeast (e.g. Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing ACC2 coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing ACC2 coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, (CaMV); tobacco mosaic virus, (TMV)) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing ACC2 coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Under some conditions it might be desirable that bacterial cells such as Escherichia coli, or eukaryotic cells be used for the expression of a recombinant ACC2 polypeptide.

[0100] In bacterial systems, a number of expression vectors can be advantageously employed, depending upon the use intended for the ACC2 polypeptide being expressed. For example, when a large quantity of such a protein is to be produced, for example for the generation of a pharmaceutical composition comprising an ACC2 polypeptide, vectors that direct the expression of high levels of fusion protein products that are readily purified can be desirable. pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or Factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0101] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) can be used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The ACC2 polypeptide coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

[0102] In mammalian host cells, a number of viral-based expression systems can be utilized. In cases where an adenovirus is used as an expression vector, the ACC2 polypeptide coding sequence of interest can be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the ACC2 protein in infected hosts (see, e.g. Logan & Shenk, (1984) Proc. Natl. Acad. Sci. U.S.A. 81:355-359). Specific initiation signals may also be required for efficient translation of inserted ACC2 coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be from a variety of origins, both natural and synthetic. The efficiency of expression can be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., (1987) Method Enzymol. 153:51-544).

[0103] In addition, a host cell strain can be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products can be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be employed.

[0104] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines that stably express the ACC2 polypeptide can be engineered. Rather than using expression vectors that contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells can be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines that express an ACC2 polypeptide. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the ACC2 polypeptide.

[0105] A number of selection systems can be employed in the recombinant expression of an ACC2 polypeptide of the present invention. For example, the herpes simplex virus thymidine kinase (Wigler et al., (1977) Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, (1992) Proc. Natl. Acad. Sci. U.S.A. 48:202), and adenine phosphoribosyltransferase (Lowy et al., (1980) Cell 22:817) genes can be employed in tk-, hgprt- or aprt- cells, respectively. Additionally, anti-metabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., (1980) Proc. Natl. Acad. Sci. U.S.A. 77:357; O'Hare et al., (1981) Proc. Natl. Acad. Sci. U.S.A. 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, (1981) Proc. Natl. Acad. Sci. U.S.A. 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Clinical Pharmacy 12:488-505; Wu & Wu, (1991) Biotherapy 3:87-95; Tolstoshev, (1993) Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, (1993) Science 260:926-932; and Morgan & Anderson, (1993) Ann. Rev. Biochem. 62:191-217; TIB TECH 11(5):155-215, May, 1993); and hygro, which confers resistance to hygromycin (Santerre et al., (1984) Gene 30:147), to provide just a few examples.

[0106] Methods known in the art of recombinant DNA technology can be applied to select the desired recombinant clone, and such methods are described, for example, in Current Protocols in Molecular Biology, (Ausubel et al., eds.), Greene Publishing Associates and Wiley-Interscience, New York (2002); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, New York, N.Y., USA (1990); Current Protocols in Human Genetics, (Dracopoli et al., eds.), John Wiley & Sons, New York, N.Y., USA (1994), Chapters 12 and 13; and Colberre-Garapin et al., (1981) J. Mol. Biol. 150:1.

[0107] The expression levels of an ACC2 polypeptide can be increased in several different ways, for example by vector amplification (for a review of this technique, see e.g. Bebbington & Hentschel, in DNA Cloning, vol. 3, Academic Press, New York (1987)). When a marker in the vector system expressing an ACC2 polypeptide is amplifiable, an increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the ACC2 gene, production of ACC2 protein will also increase.

[0108] Once an ACC2 polypeptide of the present invention has been produced by a cell, tissue, animal, or has been chemically synthesized, or recombinantly expressed, it can be purified by any method known in the art for purification of a polypeptide, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the ACC2 polypeptides of the present invention, or fragments thereof, can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification (e.g., a His tag). Another aspect of the present invention relates to the purification of ACC polypeptides, which is not limited to ACC2 polypeptides, is described herein and can be employed to generate an isolated ACC2 polypeptide.

VII. Isolation of ACC Polypeptides

[0109] The ACC2 polypeptides of the present invention can be isolated from any suitable source, for example from cells recombinantly or endogenously expressing the protein or from tissues such as rat livers and/or rat heart muscle. ACC2 can be isolated from a biological sample using standard protein purification methodology known to those of the art (see, e.g., Janson, Protein Purification: Principles, High Resolution Methods, and Applications, (2.sup.nd ed.) Wiley, New York, (1997); Rosenberg, Protein Analysis and Purification: Benchtop Techniques, Birkhauser, Boston, (1996); Walker, The Protein Protocols Handbook, Humana Press, Totowa, N.J., (1996); Doonan, Protein Purification Protocols, Humana Press, Totowa, N.J., (1996); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York, (1994); Harris, Protein Purification Methods: A Practical Approach, IRL Press, New York, (1989)). Guidance in the isolation of an ACC and/or FAS is provided herein, for example in the Examples (see, e.g. Example 9). Other methods of purifying active ACC will be known to those of skill in the art and any such methods can be employed in the present invention.

[0110] In one aspect of the present invention, a method of isolating an ACC polypeptide is provided. This purification method is exemplified in the context of ACC2, but the method can be employed to isolate any ACC (e.g., ACC1 or ACC2) polypeptide. In one embodiment, the method comprises a single step IgG mediated affinity column. The IgG mediated affinity column can comprise an anti-myc IgG. Anti-Myc-IgG, especially c-Myc-5 IgG, has been characterized (Hillman et al., (2001) Protein Expression and Purification 23, 359-368) and can be readily prepared as described by Hillman et al. (Hillman et al. (2001) Protein Expression and Purification 23, 359-368).

[0111] In one embodiment of the method, total crude homogenized tissue or cell cytosolic lysates, for example lysates derived from ACC virus infected Sf9 cells or any other transfected cell, are loaded on a c-Myc-5 IgG column. The loading can be accomplished by overnight incubation, although the precise loading procedure employed can depend on a variety of factors, such as volume of lysate and whether any other pre-column purification procedures were performed (e.g., a preliminary precipitation, etc.). Such considerations will be known to those of ordinary skill in the art upon considering the present disclosure.

[0112] The bound protein can then extensive washed with high salt buffer. A buffer comprising 0.5 M NaCl, for example can be employed. One purpose of this high salt wash is to remove a fraction of the proteins present in the crude lysate; accordingly, the concentration and composition of salt employed in the wash can vary.

[0113] Following the salt wash, the proteins that remain bound to the column can be eluted with an elution ligand. For example, when an anti-myc IgG antibody is employed, the elution ligand can be a peptide comprising a myc peptide (EQKLISEEDL; SEQ ID NO:16), which can comprise various modifications, such capping of the NH.sub.2- or COOH-terminal, which eliminate charges. The elution of the ACC protein from the column can be performed stepwise, for example in a series of steps (e.g., 1, 2, 5, 7, 10 or more steps). Additional suitable elution ligands can be employed and can depend, in part, on the nature of the IgG employed in the method. In another example, when an anti-FLAG IgG is employed the elution ligand can comprise a FLAG peptide, which comprises the core sequence DYKD (SEQ ID NO:33) and is commercially available as a peptide having the sequence DYKDDDDK (SEQ ID NO:34).

[0114] The presence of ACC in the eluent of each step can be confirmed by immunological techniques and/or by simply running the eluent on an SDS PAGE gel and identifying the molecular weight of the eluted protein. Additionally, the identity of the eluted protein can be confirmed by an enzymatic assay, such as that described herein (see also U.S. Patent Application Ser. No. 60/558,015, incorporated herein by reference in its entirety) or an assay known in the art (see, e.g., Waite & Wakil (1962) J. Biol. Chem. 237:2750-2757, Tanabe et al., (1981) Methods Enzymol. 71 Pt C, 5-16; Wakil et al., (1959) Biochim. Biophys. Acta 34:227-233, also incorporated herein by reference). The eluent from each step can be evaluated separately and the active fractions can subsequently be pooled. Pooled protein can be stored in buffer or in a lyophilized form.

VIII. Methods of Assaying for ACC2 Catalytic Activity

[0115] The activity of the ACC2 polypeptides of the present invention can be determined using a variety of ACC2 activity assays. Some representative assays are described herein below.

[0116] A CO.sub.2-fixation assay is an ACC assay that can be employed in the present invention. In this assay, [.sup.14C]--NaHCO.sub.3, acetyl CoA, Mg-ATP, citrate and ACC are incubated at 37.degree. C.; the reaction mixture is quenched with acid at the end of the reaction, and subsequently heated to remove bicarbonate as .sup.14CO.sub.2. Scintillant is then added and the acid-stable malonyl CoA remaining in the vial is counted in a scintillation counter (see Waite & Wakil (1962) J. Biol. Chem. 237:2750-2757 and Tanabe et al. (1981) Methods Enzymol. 71 Pt C, 5-16).

[0117] The continuous ATP regeneration-coupled spectrophotometric assay is another ACC2 assay that can be employed in the present invention. In this assay, the ADP generated in the ACC enzyme reaction is converted to ATP by a pyruvate kinase/lactate dehydrogenase coupled enzyme system, and NADH disappearance is followed at 340 nm spectrophotometrically or fluorometrically (see Tanabe et al., (1981) Methods Enzymol. 71 Pt C, 5-16). The ATP-regeneration system is very sensitive to the presence of ATPases.

[0118] Yet another form of ACC assay is an ACC/FAS coupled assay. In the ACC reaction, malonyl CoA is formed from acetyl CoA. Malonyl CoA can then be used as a substrate for FAS with NADPH as the cofactor. The reaction can be monitored by the rate of utilization of NADPH spectrophotometrically (see Wakil et al., (1959) Biochim. Biophys. Acta 34:227-233).

[0119] Another method of assaying ACC2 enzymatic activity that can be employed in the present invention is described in U.S. Patent Application Ser. No. 60/558,015. In one embodiment of this assay, the method comprises: (a) contacting an enzyme mix comprising ACC and FAS, optionally comprising one or more of bicarbonate, Mg, ATP, NADPH and an ACC effector, with a solid support comprising a scintillant and a linking moiety; (b) incubating the enzyme mix with an acetyl CoA mix comprising radiolabeled acetyl CoA, optionally comprising one or more of bicarbonate, Mg, ATP, NADPH and an ACC effector, under suitable reaction conditions, for a desired incubation time; and (c) detecting scintillation signal, wherein scintillation signal is indicative of ACC catalytic activity.

IX. Transgenic Animals

[0120] The preparation of a transgenic non-human animal that expresses an ACC2-encoding sequence of the present invention is within the scope of the present invention. A preferred transgenic animal is a mouse.

[0121] Techniques for the preparation of transgenic animals are known in the art. Representative techniques are described in the literature and will be known to those of ordinary skill in the art. Some representative techniques are described, for example, in U.S. Pat. No. 5,489,742 (transgenic rats); U.S. Pat. Nos. 4,736,866, 5,550,316, 5,614,396, 5,625,125 and 5,648,061 (transgenic mice); U.S. Pat. No. 5,573,933 (transgenic pigs); U.S. Pat. No. 5,162,215 (transgenic avian species) and U.S. Pat. No. 5,741,957 (transgenic bovine species).

[0122] In one method for the preparation of a transgenic mouse, cloned recombinant or synthetic DNA sequences or DNA segments encoding a human ACC2 gene product are injected into fertilized mouse eggs. The injected eggs are implanted in pseudo pregnant females and are grown to term to provide transgenic mice whose cells express a human or rat ACC2 gene product.

X. Antibodies

[0123] In another aspect, the present invention relates to antibodies that specifically recognize the ACC2 proteins of the present invention. Such antibodies can be employed in a range of applications. By way of non-limiting example, antibodies of the present invention can be used to purify, detect, and/or target the polypeptides of the present invention, including both in vitro and in vivo diagnostic and therapeutic methods. For example, antibodies can be employed in immunoassays for qualitatively and/or quantitatively measuring levels of the polypeptides of the present invention in biological samples (see, e.g., Harlow & Lane., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed. (1988), incorporated by reference herein in its entirety).

[0124] Antibodies of the present invention include, but are not limited to, polyclonal, monoclonal, monovalent, bispecific, heteroconjugate, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above. The term "antibody," as used herein, encompasses immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.

[0125] The terms "antibody" (Ab) and "monoclonal antibody" (Mab) encompasses intact molecules, as well as, antibody fragments (such as, for example, Fab and F(ab')2 fragments) which are capable of specifically binding to a given protein. Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, often clear more rapidly from the circulation of the animal or plant, and may have less non-specific tissue binding than an intact antibody. Thus, in some situations these fragments are preferred, as well as the products of a Fab or other immunoglobulin expression library.

[0126] Antibodies of the present invention include chimeric, single chain, and humanized antibodies. For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g. Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; Boulianne et al., Nature 312:643 (1984); and Neuberger et al., Nature 314:268 (1985), which are incorporated herein by reference in their entirety.

[0127] A humanized antibody, which is a form of chimeric antibody, comprises a portion of an antibody molecule from non-human species that binds the desired antigen, and can comprise one or more complementarity determining regions (CDRs) from the non-human species, and a framework region from a human immunoglobulin molecule. Often, framework residues in the human framework region(s) will be substituted with the corresponding residue from the CDR donor antibody to alter, and often improve, antigen binding. These framework substitutions can be identified by methods well known in the art, e.g. by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions (see, e.g. Riechmann et al., Nature 332:323 (1988)). Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (Padlan, Mol. Immunol. 28(4/5):489-498 (1991); Studnicka et al., Prot. Engineering 7(6):805-814 (1994); Roguska. et al., Proc. Natl. Acad. Sci. U.S.A. 91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332). In some cases, a humanized antibody comprises one or more amino acid residues introduced from a source that is non-human. Methods of humanizing antibodies are known in the art; for example, humanization can be performed essentially as described in Jones et al., Nature 321:522-525 (1986); Reichmann et al., Nature 332:323-327 (1988); and Verhoeyen et al., Science 239:1534-1536 (1988), namely by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies.

[0128] In general, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., Nature 321:522-525 (1986); Reichmann et al., Nature 332:323-327 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0129] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art, including phage display methods using antibody libraries derived from human immunoglobulin sequences. The techniques of Cole et al., and Boerder et al., are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, New York (1985); and Boerner et al., J. Immunol. 147(1):86-95 (1991)).

[0130] Human antibodies can be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes can be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. The modified embryonic stem cells are then expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies.

[0131] The transgenic mice can be immunized in the normal fashion with a selected antigen, e.g., all or a portion of an ACC2 polypeptide of the present invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see, e.g., Lonberg & Huszar, Int. Rev. Immunol. 13:65-93 (1995).

[0132] Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and creation of an antibody repertoire. This approach is described, for example, in Marks et al., Biotechnol. 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Fishwild et al., Nature Biotechnol. 14:845-51 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg & Huszer, Intern. Rev. Immunol. 13:65-93 (1995).

[0133] In general, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0134] The antibodies of the present invention can comprise monoclonal antibodies. Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler & Milstein, Nature, 256:495 (1975) and Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2.sup.nd ed. (1988); additional methods are known to those of ordinary skill in the art. Other examples of methods which may be employed for producing monoclonal antibodies includes, but are not limited to, the human B-cell hybridoma technique (Cole et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:2026-2030 (1983)), and the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, New York, pp. 77-96 (1985)). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing a mAb of this invention can be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this a preferred method of production in some situations.

[0135] It is generally desirable that immortalized cell lines fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Generally, methods of preparing antibodies are known in the art and can be employed in the present invention to raise antibodies against an ACC2 polypeptide of the present invention.

XI. Antisense and RNAi Methods

[0136] The present invention encompasses antisense nucleic acid molecules, i.e., molecules that are complementary to a coding strand of a double-stranded cDNA molecule (i.e., a sense strand) encoding an ACC2 protein of the present invention or a sequence that is complementary to an mRNA sequence. An antisense nucleic acid of the invention comprises a sequence that is complementary to at least a portion of an RNA transcript of a gene of interest. Absolute complementarity is not required. The ability to hybridize depends on both the degree of complementarity and the length of the antisense nucleic acid Generally, the larger the hybridizing nucleic acid, the more base mismatches with a polynucleotide sequence of the present invention it can contain and still form a stable multiplex structure (e.g., a duplex or triplex). One of ordinary skill in the art can readily ascertain a tolerable degree of mismatch by employing standard procedures to determine the melting point of the hybridized complex. Antisense nucleic acids are preferably at least six nucleotides in length, and more preferably 6 to about 50 nucleotides in length. In specific embodiments, an antisense oligonucleotide comprises at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides.

[0137] Antisense sequences of the invention can be chemically synthesized by standard methods known in the art (see, e.g. Stein et al., Nucl. Acids Res. 16:3209 (1988) and Sarin et al., Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451 (1988), or by employing an automated DNA synthesizer, many of which are commercially available. An antisense sequence of the present invention can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the multiplex formed between the antisense and sense nucleic acids, including, but not limited to, phosphorothioate derivatives and acridine substituted nucleotides.

[0138] Antisense sequences can also be prepared in vivo, again by employing techniques known to those of ordinary skill in the art. For example, an antisense sequence can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

[0139] An antisense nucleic acid can be complementary to an entire coding strand of the present invention, or to only a portion thereof, e.g., all or part of the protein coding region. An antisense sequence can also be complementary to a noncoding region of the coding strand of a nucleotide sequence encoding an ACC2 polypeptide. For example, an antisense sequence can be complementary to the region surrounding the translation start site of ACC2 mRNA. By employing the polynucleotide sequences encoding the ACC2 polypeptides provided herein, an antisense sequence of the present invention can be readily designed based on standard base pairing rules.

[0140] The antisense sequences of the present invention can also be used in therapeutic applications to reduce or eliminate ACC2 activity in vivo. When used therapeutically, antisense sequences of the present invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a GPCR-like protein to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. In other examples, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, antisense molecules can be linked to peptides or antibodies to form a complex that specifically binds to receptors or antigens expressed on a selected cell surface.

[0141] An antisense sequence of the present invention can comprise DNA or RNA and can be used to control gene expression via the formation of multiplexes or via traditional antisense methodology. Antisense techniques are discussed, for example, in Okano, J. Neurochem. 56:560 (1991) and in Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton (1988). Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both methods have previously been demonstrated to be effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat or prevent disease.

[0142] RNA interference (RNAi) reagents form another aspect of the present invention. RNAi is a process by which a target gene can be specifically silenced. The RNAi process is activated when a double-stranded RNA molecule of greater than about 19 duplex nucleotides (referred to herein interchangeably as dsRNA and "RNAi reagent") enters a cell, which causes the degradation of not only the invading dsRNA molecule itself, but also single-stranded RNAs of identical sequences, including endogenous mRNAs. As such, RNAi is a powerful tool in the development of highly specific RNA-based gene-silencing therapeutics, an aspect of the present invention. Thus, in one aspect of the present invention, RNA interference (RNAi) methodologies can be employed to selective inhibit the expression of a target gene in a vertebrate, which can form an element of a therapeutic regimen.

[0143] RNAi reagents of the present invention can be obtained using any of a number of techniques known to those of ordinary skill in the art. Generally, production of RNAi reagents can be carried out by chemical synthetic methods or by recombinant nucleic acid techniques. Methods of preparing a dsRNA are described, for example, in Ausubel et al., Current Protocols in Molecular Biology (Supplement 56), John Wiley & Sons, New York (2001); Sambrook et al., Molecular Cloning: A Laboratory Manual, 3.sup.rd ed., Cold Spring Harbor Press, Cold Spring Harbor (2001); and can be employed in the present invention. For example, RNA can be transcribed from PCR products, followed by gel purification. Standard procedures known in the art for in vitro transcription of RNA from PCR templates. For example, dsRNA can be synthesized using a PCR template and the Ambion T7 MEGASCRIPT, or other similar, kit (Austin, Tex.); the RNA can be subsequently precipitated with LiCl and resuspended in a buffer solution.

[0144] An RNAi reagent of the present invention can be both partially or completely double-stranded. Generally, an RNAi reagent of the present invention encompasses fragments of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 30, at least 35, at least 40, at least 45, and at least 50 or more nucleotides per strand. An RNAi reagent can also comprise 3' overhangs of at least 1, at least 2, at least 3, or at least 4 nucleotides. Broadly, an RNAi reagent of the present invention can be of any length desired by the user as long as the ability to inhibit target gene expression is preserved.

[0145] An RNAi reagent of the present invention can include modifications to the phosphate-sugar backbone or the nucleoside, e.g., to reduce susceptibility to cellular nucleases, improve bioavailability, improve formulation characteristics, and/or change other pharmacokinetic properties. For example, the phosphodiester linkages of natural RNA can be modified to include at least one of an nitrogen or sulfur heteroatom. Other modifications that can be desirable under certain conditions will be known to those of ordinary skill in the art. Modifications in RNA structure can be tailored to allow specific genetic inhibition while avoiding a general response to dsRNA.

[0146] An RNAi reagent of the present invention, can also be synthesized in vitro (see, e.g., Fire et al., Nature 391:806-811 (1998); Montgomery et al., Proc. Natl. Acad Sci U.S.A. 95:15502-15507; Tabara et al., Science 282:430-431 (1998)). Additionally, commercially available polynucleotide synthesizers can be employed to prepare an RNAi reagent.

[0147] At least two ways can be employed to achieve siRNA-mediated gene silencing. First, siRNAs can be synthesized in vitro and introduced into cells to transiently suppress gene expression, for example as a component of a therapeutic regimen. Synthetic RNAi reagents provide an easy and efficient way to achieve RNAi. Using synthetic 21 base pair duplexes, sequence specific gene silencing can be achieved in mammalian cells. These RNAi reagents can specifically suppress targeted gene translation in mammalian cells without activation of DNA-dependent protein kinase (PKR) by longer dsRNA, which may result in non-specific repression of translation of many proteins.

[0148] Additionally, RNAi reagents can be expressed in vivo from vectors. This approach can be used to stably express RNAi reagents in cells or transgenic animals. In one embodiment, RNAi reagent expression vectors are engineered to drive transcription from polymerase III (pol III) transcription units. The Pol III expression vectors can also be used to create transgenic mice that express siRNA.

[0149] In another embodiment, siRNAs can be expressed in a tissue-specific manner. In this approach, long double-stranded RNAs (dsRNAs) are first expressed from a promoter (such as CMV (pol II)) in the nuclei of selected cell lines or transgenic mice. The long dsRNAs are processed into siRNAs in the nuclei (e.g., by Dicer). The siRNAs exit from the nuclei and mediate gene-specific silencing. A similar approach can be used in conjunction with tissue-specific (pol II) promoters to create tissue-specific knockdown mice.

[0150] An antisense sequence or RNAi reagent of the present invention can be administered as part of a therapeutic regimen in which repression of ACC2 expression is desired. In this application, the antisense sequence or RNAi reagent can be administered as a component of a buffered solution, or it can be administered as a component of a pharmaceutical composition, as described herein.

XII. ACC2 Modulators and Screening Methods

[0151] The present invention broadly encompasses modulators of ACC2 and methods of identifying such modulators. As used herein, the term "modulator" means a compound that can act as an agonist or an antagonist. An ACC2 modulator can be employed in the various methods of the present invention, for example as a component of a therapeutic regimen. Such modulators can comprise for example, one, or a combination of, a polypeptide of variable length (including antibodies and fusion proteins) or a small molecule.

[0152] A modulator of the present invention can comprise any type of chemical entity, such as a protein of any size, a small molecule or an antibody. Just as there is no limitation on whether a modulator augments or inhibits ACC2 or ACC2-mediated activity, there is no limitation on the mechanism by which a modulator of ACC2 achieves such an effect. For example, a modulator might block a ligand from associating with an ACC2 polypeptide. In another case, a modulator might inhibit an ACC2 polypeptide from associating with another polypeptide. In yet another case, a modulator might facilitate the association of an ACC2 polypeptide with another polypeptide expressed.

[0153] General methods of identifying modulators are known in the art and can be employed in the present invention. Such methods will employ a polypeptide or polynucleotide sequence of the present invention (e.g., SEQ ID NOs:11-14) as a target.

[0154] The ACC2 polypeptides and/or peptides of the present invention, or immunogenic fragments or oligopeptides thereof, can be used for screening therapeutic drugs or test compounds in a variety of drug screening techniques. The fragment employed in such a screening assay can be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The reduction or abolition of the formation of binding complexes between an ACC2 protein of the present invention and a test agent can be measured. Thus, the present invention provides a method for screening or assessing one or a plurality of test compounds for their ability to specifically bind an ACC2 polypeptide, or a bindable peptide fragment thereof, of the present invention, comprising providing a plurality of compounds, combining an ACC2 polypeptide, or a bindable peptide fragment thereof, with each of a plurality of test compounds for a time sufficient to allow binding under suitable conditions and detecting binding of the ACC2 polypeptide or peptide to each of the plurality of test compounds, thereby identifying the compounds that specifically bind to the ACC2 polypeptide or peptide.

[0155] Methods of identifying compounds that modulate the activity of the ACC2 polypeptides and/or peptides are provided in an aspect of the present invention and, in one embodiment, comprise combining a potential or candidate compound or drug modulator of ACC2 biological activity with an ACC2 polypeptide or peptide, for example, an ACC2 amino acid sequence as set forth in SEQ ID NOs:12 and 14, and measuring an effect of the candidate compound or drug modulator on the biological activity of the ACC2 polypeptide or peptide. Such measurable effects include, for example, physical binding interaction; the ability to cleave a suitable substrate; effects on native and cloned ACC2-expressing cell line; and effects of modulators or other ACC2-mediated physiological measures.

[0156] Another method of identifying compounds that modulate the biological activity of an ACC2 polypeptide of the present invention comprises combining a potential or test compound or drug modulator of ACC2 biological activity with a host cell that expresses an ACC2 polypeptide and measuring an effect of the test compound or drug modulator on the biological activity of the ACC2 polypeptide. The host cell can also be capable of being induced to express the ACC2 polypeptide, e.g., via inducible expression.

[0157] The physiological effects of a given test compound on an ACC2 polypeptide can also be measured. Thus, cellular assays for particular ACC2 modulators can comprise either direct measurement or quantification of the physical biological activity of the ACC2 polypeptide, or they can be measurement or quantification of a physiological effect. Such methods preferably employ an ACC2 polypeptide as described herein, or an overexpressed recombinant ACC2 polypeptide in suitable host cells comprising an expression vector as described herein, wherein the ACC2 polypeptide is expressed, overexpressed, or undergoes upregulated expression.

[0158] Another aspect of the present invention encompasses a method of screening for a compound that is capable of modulating the biological activity of an ACC2 polypeptide and comprises providing a host cell containing an expression vector harboring a nucleic acid sequence encoding a ACC2 polypeptide, or a functional peptide or portion thereof, determining the biological activity of the expressed ACC2 polypeptide in the absence of a test compound; contacting the cell with the test compound and determining the biological activity of the expressed ACC2 polypeptide in the presence of the test compound. In such a method, a difference between the activity of the ACC2 polypeptide in the presence of the test compound and in the absence of the test compound indicates a modulating effect of the compound.

[0159] Any chemical compound can be employed as a test compound in the assays of the present invention. Compounds tested as ACC2 modulators can be any small chemical compound, or biological entity (e.g., protein, sugar, nucleic acid, lipid). Test compounds will typically be small chemical molecules. Generally, compounds employed as potential modulators can be capable of dissolution in aqueous or organic (e.g., DMSO-based) solutions. The assays of the present invention can be employed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source. Assays can be run in parallel, for example, in microtiter formats on microtiter plates in robotic assays. Test compounds can be purchased from a supplier or synthesized by appropriate methods known to those of ordinary skill in the art.

[0160] High throughput screening methodologies are suitable for the detection of modulators of the ACC2 polynucleotides and polypeptides described herein. Such high throughput screening methods can involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds (e.g., ligand or modulator compounds). Such combinatorial chemical libraries or ligand libraries are then screened in one or more assays to identify those library members (e.g., particular chemical species or subclasses) that display a desired characteristic activity. The compounds so identified can serve as lead compounds, or can themselves be used as potential or actual therapeutics.

[0161] The present invention, therefore, provides methods of screening for drugs or any other agents which affect activities mediated by the ACC2 polypeptides of the present invention. In one embodiment, these methods comprise contacting a test compound with a polypeptide of the present invention, or a fragment thereof, and assaying for the presence of a complex between the agent and the polypeptide or a fragment thereof, the presence of which can be determined using methods well known to those of ordinary skill in the art.

[0162] Thus, the use of the ACC2 polypeptides of the present invention, or the polynucleotides encoding these polypeptides, to screen for molecules which modify the activities of the ACC2 polypeptides of the present invention form an aspect of the present invention. One embodiment of such a method comprises contacting an ACC2 polypeptide of the present invention with a test compound(s) suspected of having modulatory (e.g., antagonist or agonist) activity, and then assaying the activity of the polypeptide following binding.

[0163] In another aspect of the present invention, therapeutic compounds can be screened by employing the an ACC2 polypeptide of the present invention, or binding fragments thereof, in any of a variety of drug screening techniques. The polypeptide or fragment employed in such a test can be affixed to a solid support, expressed on a cell surface, free in solution, or located intracellularly. One method of drug screening employs eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. One can measure, for example, the formation of complexes between the agent being tested and a polypeptide of the present invention.

XIII. Diagnostic/Prognostic Assays and Kits

[0164] The present invention encompasses diagnostic/prognostic assays and kits. Such assays and kits can be employed to detect the presence, absence and/or expression level of an ACC2 polypeptide of the present invention. The assays and kits of the present invention can also be employed to identify or predict the presence of an adverse condition associated with ACC2, such as obesity or diabetes, or the likelihood that a subject will acquire such a condition. Non-limiting examples diagnostic methods and kits that can be employed in the present invention are provided.

[0165] Increased or decreased expression of an ACC2 gene in a subject affected with a certain condition, such as obesity or diabetes, both of which are known to be associated with ACC2, as compared to unaffected organisms can be assessed using the ACC2-encoding polynucleotides of the present invention. For example, altered expression, chromosomal rearrangement, or the presence of a mutation can be used as a diagnostic or prognostic marker for the presence of or predisposition to diabetes or obesity. These diagnostic applications can employ an ACC2 polynucleotide of the present invention.

[0166] Thus, the present invention provides a diagnostic method useful for the diagnosis of a disorder or condition. In one embodiment, the method involves measuring the expression level of an ACC2 polynucleotide of the present invention in cells, tissue or body fluid from an organism and comparing the measured gene expression level with a standard level of ACC2 polynucleotide expression, whereby an increase or decrease in the gene expression level compared to the standard is indicative of a disorder.

[0167] As used herein, the phrase "measuring the expression level of a polynucleotide of the present invention" means making qualitative, quantitative and estimated measurements of (a) the degree to which an ACC2 polypeptide of the present invention is expressed, or (b) the level of the mRNA encoding an ACC2 polypeptide in a first biological sample, either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing the polypeptide level in the first biological sample to the polypeptide level or mRNA level in a second biological sample). In one embodiment, the polypeptide level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, wherein the standard is taken from a second biological sample obtained from an individual not having the disorder or determined not to have the disorder by averaging levels from a population of organisms not having a disorder. Once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.

[0168] The method(s) provided herein can be applied in a diagnostic method and/or kits in which polynucleotides and/or polypeptides are attached to a solid support. In one exemplary method, the support may be a "gene chip" or a "biological chip" as described in U.S. Pat. Nos. 5,837,832, 5,874,219, and 5,856,174. Further, a gene chip comprising an ACC2 polynucleotide of the present invention can be employed to identify polymorphisms between reference ACC2 polynucleotide sequences, and ACC2 polynucleotides isolated from a test subject. The knowledge of such polymorphisms (i.e. their location, as well as, their existence) can be beneficial in identifying disease loci for an ACC2-associated disorder.

[0169] In addition to various detection and purification applications, the anti-ACC2 antibodies of the present invention can also be employed in diagnostic and prognostic applications. For example, such antibodies can be employed to monitor protein levels in tissue as part of a clinical testing procedure, e.g. to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance.

[0170] Continuing, labeled antibodies, and derivatives and analogs thereof, that specifically bind to an ACC2 polypeptide of the present invention can be used to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of an ACC2 polypeptide of the present invention. Antibodies of the invention can be used to assay ACC2 levels in a biological sample using classical immunohistological methods known to those of ordinary skill in the art. Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA).

[0171] Examples of detectable labels include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of enzymes suitable for use as a label include horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase, or acetylcholinesterase; examples of prosthetic group complexes suitable for use as a label include streptavidin/biotin and avidin/biotin; examples of fluorescent materials suitable for use as a label include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material suitable for use as a label includes luminol; examples of bioluminescent materials suitable for use as a label include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include .sup.125I, .sup.131I, .sup.35S, or .sup.3H.

[0172] In one aspect, the present invention provides for the detection of aberrant expression of an ACC2 polypeptide of the present invention, comprising (a) assaying the expression of the ACC2 polypeptide in cells or body fluid of an individual using one or more antibodies specific to the ACC2 polypeptide; and (b) comparing the level of gene expression with a standard gene expression level, wherein an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of aberrant expression.

[0173] The present invention also provides a diagnostic assay for diagnosing a disorder. In one embodiment the assay comprises (a) assaying the expression of an ACC2 polypeptide of the present invention in cells or body fluid of an individual using one or more antibodies specific to the ACC2 polypeptide; and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed ACC2 polypeptide gene expression level compared to the standard expression level is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.

[0174] The methods described herein can furthermore be utilized as diagnostic or prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with an ACC2 protein, ACC2 nucleic acid expression, or ACC2 activity. Prognostic assays can be used for prognostic or predictive purposes to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with an ACC2 protein, ACC2 nucleic acid expression, or ACC2 activity.

[0175] In another aspect, the present invention provides a diagnostic method in which a test sample is obtained from a subject, and an ACC2 protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of an ACC2 protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant ACC2 expression or activity.

[0176] The present invention also provides a method of detecting genetic lesions or mutations in an ACC2 gene, thereby determining if a subject with the lesioned gene is at risk for an ACC2-related disorder. In one embodiment, the method comprises detecting, in a biological sample obtained from a subject, the presence or absence of a genetic mutation characterized by an alteration affecting the integrity of a gene encoding an ACC2-protein, or the misexpression of an ACC2 gene. For example, such genetic mutations can be detected by determining the presence or absence of at least one of: (1) a deletion of one or more nucleotides from an ACC2 gene; (2) an addition of one or more nucleotides to an ACC2 gene; (3) a substitution of one or more nucleotides in an ACC2 gene; (4) a chromosomal rearrangement of an ACC2 gene; (5) an alteration in the level of a messenger RNA transcript of an ACC2 gene; (6) an aberrant modification of an ACC2 gene, such as of the methylation pattern of the genomic DNA; (7) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of an ACC2 gene; (8) an undesirable level of an ACC2 protein; (9) an allelic loss of an ACC2-like gene; and (10) an inappropriate post-translational modification of a GPCR-like-protein. There are a large number of assay techniques known in the art that can be used for detecting mutations in an ACC2 gene

[0177] The present invention also encompasses kits for detecting the presence of ACC2 proteins in a biological sample (a test sample). Such kits can be used to determine if a subject is suffering from or is at increased risk of developing a disorder associated with aberrant expression of ACC2 protein (e.g., diabetes). For example, a kit can comprise a labeled compound or agent capable of detecting an ACC2 protein or mRNA in a biological sample and means for determining the amount of an ACC2 protein in the sample (e.g., an anti-ACC2 antibody or an oligonucleotide probe that binds to DNA encoding an ACC2 protein, e.g. SEQ ID NOs:12 and 14). A kit can also include instructions for interpreting observed results and/or steps for performing the assay.

[0178] For antibody-based kits, a kit can comprise, for example: (1) a first antibody, optionally attached to a solid support, that binds an ACC2 polypeptide of the present invention; and, optionally, (2) a second, different antibody that binds an ACC2 polypeptide of the present invention or the first antibody and is conjugated to a detectable label. For oligonucleotide-based kits, a kit can comprise, for example: (1) an oligonucleotide, optionally a detectably labeled oligonucleotide, that hybridizes to an ACC2 polynucleotide sequence of the present invention, or (2) a pair of primers useful for amplifying an ACC2 polynucleotide.

[0179] Depending on the nature of the kit, a kit of the present invention can also comprise other components, such as a buffering agent, a preservative, or a protein stabilizing agent. The kit can also comprise components that facilitate the detection of the label. The kit can also contain a control sample or a series of control samples that can be assayed and compared to the test sample contained. A diagnostic kit of the present invention can also comprise instructions to assist the user in performing the diagnostic test and/or interpreting the results of the diagnostic test.

XIV. Pharmaceutical Compositions

[0180] An ACC2 polypeptide of the present invention, with or without a therapeutic agent conjugated to it, can be administered alone or in combination with a another biologically active moiety, including a small molecule, and can be used as a therapeutic. Additionally, modulators of the ACC2 polypeptides of the present invention form another aspect of the invention.

[0181] The present invention provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an ACC2 polypeptide or an ACC2 modulator of the present invention, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and water-based formulations are desirable carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, (Gennaro, ed.) 20th ed., Mack Publishing, Easton, Pa., USA (2000). Such compositions will contain a therapeutically effective amount of the modulator, for example in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration.

[0182] In one embodiment, a composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where a composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where a composition is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0183] The amount of ACC2 polypeptide or ACC2 modulator that will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of an ACC2 polypeptide of the present invention can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and can be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0184] A pharmaceutical composition can be administered in conjunction with a pharmaceutically acceptable carrier, diluent, or excipient, to achieve any of the above-described therapeutic uses and effects. Such pharmaceutical compositions can comprise agonists, antagonists, activators or inhibitors. The compositions can be administered alone, or in combination with at least one other agent or reagent, such as a stabilizing compound, which can be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water. The compositions can be administered to a patient alone, or in combination with other agents, drugs, hormones, or biological response modifiers.

[0185] The pharmaceutical compositions for use in the present invention can be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, or rectal means.

[0186] In addition to the active ingredients, the pharmaceutical compositions can contain pharmaceutically acceptable/physiologically suitable carriers or excipients comprising auxiliaries which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Further details on techniques for formulation and administration are provided in Remington's Pharmaceutical Sciences, (Gennaro, ed.) 20th ed., Mack Publishing, Easton, Pa., USA (2000).

[0187] The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. Optionally a notice can be associated with such container(s) in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Such a notice can also provide guidance on how to use the pack or kit.

XV. Method of Increasing ACC2 Enzymatic Activity

[0188] In yet another aspect of the present invention, a method of increasing the activity of a human ACC2 polypeptide is disclosed. In one embodiment, the method comprises generating an enhanced ACC2 polypeptide comprising (a) a phenylalanine residue at position 254, (b) a glutamine residue at position 346, (c) a threonine residue at position 565, (d) an asparagine at position 841, (e) a valine residue at position 1103, (f) a cysteine residue at position 1259, (g) an alanine residue at position 1526, and (h) an isoleucine residue at position 1717, wherein the human ACC2 polypeptide does not comprise SEQ ID NO:12 and wherein the enhanced ACC2 polypeptide has an enzymatic activity level that is greater than the enzymatic activity level of an ACC2 polypeptide that does not contain the indicated residues at the indicated positions.

[0189] The present inventors have identified eight amino acids which, when mutated to the residues described herein, impart increased activity to ACC2. Although the ACC2 sequences of the present invention include point mutations differentiating the ACC2 sequences of the present invention from the published sequences, this group of mutations includes a core group of eight mutations, which are believed to affect the activity of the mutated enzyme. More particularly, when the noted residues of an ACC2 sequence other than that of SEQ ID NO:12 are replaced with (a) F at position 254, (b) Q at position 346, (c) T at position 565, (d) N at position 841, (e) V at position 1103, (f) C at position 1259, (g) A at position 1526, and (h) I at position 1717, a concurrent >200-fold increase in activity is observed.

[0190] Consistent with the observations disclosed herein (see, e.g., Example 9), a method of increasing ACC2 enzymatic activity is provided. In one embodiment the method comprises introducing eight point mutations into an ACC2 sequence other than the sequence of SEQ ID NO:12. The mutations introduced are (a) F at position 254, (b) Q at position 346, (c) T at position 565, (d) N at position 841, (e) V at position 1103, (f) C at position 1259, (g) A at position 1526, and (h) I at position 1717. Additional mutations can, but need not, be introduced.

[0191] It is possible that one or more residues may be present in a published ACC2 sequence at the noted position(s). In this case, less than the eight mutations can be introduced, with the proviso that the final form of the mutated ACC2 sequence comprises the noted eight mutations. After mutations have been made, the activity of the resultant mutant can be determined as described herein and can be compared to an activity measurement made before any mutations were introduced.

[0192] The ACC2 sequence can comprise any known ACC2 sequence, such as the ACC2 sequences of SEQ ID NOs:2, 4 or 6. When there is a residue other than one of the specified eight residues at the corresponding position in the ACC2 sequence, a point mutation can be introduced into the ACC2 sequence to conform the residues and positions with the eight residue/position combinations indicated herein. Such mutations can be introduced using standard methodology, such as that provided herein.

EXAMPLES

[0193] The following Examples have been included to illustrate preferred modes of the invention. Certain aspects of the following Examples are described in terms of techniques and procedures found or contemplated by the present inventors to work well in the practice of the invention. These Examples are exemplified through the use of standard laboratory practices of the inventors. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the invention.

Example 1

Identification of Human ACC2 Amino Acid Sequence

[0194] To identify the wild type human ACC2 amino acid sequences, the following three amino acid sequences were compared: 1) the sequence of pYES-human-ACC2 (purchased from Dr. Ki-Han Kim, Purdue University), 2) the coding region of human ACC2 predicted by human genomic contig AC007637 (defined by 12q24 BAC RCPI11-443D10; Roswell Park Cancer Institute Human BAC Library, complete sequence), and 3) Genbank ACC2 sequence (NM.sub.--001093; Ha et al., (1996) Proc. Natl. Acad. Sci. USA 93:11466-11470). The multiple sequence alignment was performed with ClustalW algorithm in VectorNTI program. The result of the comparison revealed that there are multiple discrepancies among these three sequences. Specifically, in amino acid sequences predicted by genomic contig AC007637, the discrepancies are C at position 9, G at position 347, G at positions of 349-352, V at position 2141; in amino acid sequences described in Genbank Accession No. NM.sub.--001093, the discrepancies are H at position 111, V at position 127, S at position 450, R at position 614, K at position 656, V at position 671, KI at position 742-743, K at position 799, A at position 1025, A at position 1064, A at position 1480, G at position 1547, A at position 1821, RPMR at position 2194-2197, E at position 2242; in amino acid sequences as predicted by pYES-human-ACC2, the discrepancies are Y at position 254, R at position 345, A at position 565, Y at position 841, A at position 1103, R at position 1259, V at position 1526, V at position 1717. The consensus of amino acid sequences among pYES-human-ACC2, Genbank Accession No. NM.sub.--001093 and human genome contig AC007637 is defined as the wild type human ACC2 amino acid sequence (SEQ ID NO:12). Specifically the amino acids need to be R at position 9, P at position 111, A at position 127, F at position 254, Q at position 345, V at position 347, AGWG at positions of 349-352, P at position 450, T at position 565, H at position 614, E at position 656, E at position 671, ET at position 742-743, E at position 799, N at position 841, V at position 1025, V at position 1064, V at position 1103, C at position 1259, R at position 1480, A at position 1526, R at position 1547, I at position 1717, G at position 1821, I at position 2141, PPYA at position 2194-2197, K at position 2242.

Example 2

Identification of Rat ACC2 Amino Acid Sequence

[0195] Initially the published sequences for both genes were used to design primers to amplify overlapping fragments. Two different clones for each fragment were sequenced and aligned using ClustalW algorithm in VectorNTI program with the published sequences (SEQ ID NOs:7 and 9; GenBank Accession Nos. NM.sub.--053922 and AB004329, respectively). Using a consensus sequence built from this comparison, the consensus translation was then aligned with the published rat ACC2 sequence (SEQ ID NO: 9, FIGS. 3 and 4) and the sequence of human ACC2 (SEQ ID NO: 2) was employed to guide decisions surrounding ambiguous regions, providing a refined consensus sequence. This refined consensus sequence was then compared to the rat genomic ACC2 region and provided an identical match (FIG. 5).

Materials for Examples 3 to 5

[0196] Expression vectors pBlueBac4.5/V5-His, pcDNA4/V5-His a Bac-N-Blue Transfection kit, and monoclonal anti-V5 antibody was obtained from Invitrogen; goat anti-mouse horseradish peroxidase (HRP)-conjugated antibody was obtained from BioRad; streptavidin conjugated with HRP was obtained from Pierce; COMPLETE.RTM. protease inhibitor cocktail tablets and FuGene 6 transfection reagent was obtained from Roche Molecular Biochemicals; TALON.TM. resin was obtained from BD Biosciences; oligonucleotide primers were obtained from Sigma-Genosys; a LA-PCR kit and a ligation kit was obtained from Panvera Corporation; a QUIKCHANGE.RTM. multi site-directed mutagenesis kit was obtained from Stratagene; human embryonic kidney (HEK) 293 cells and insect Sf9 cells were obtained from ATCC; [.sup.14C]--NaHCO.sub.3 (45 mCi/mmol, 1 mCi/m) was obtained from NEN Life Science Products, Inc. C-Myc peptide (Ac-EQKLISEEDL-OH; SEQ ID NO:16) was synthesized.

Example 3

Construction of Human ACC2 Expression Vectors

[0197] To construct pBlueBac-human-ACC2, a .about.7.5 kb fragment of a Kpn I/Xho I double digestion of pYES-human-ACC2 (purchased from Dr. Ki-Han Kim, Purdue University; SEQ ID NO: 5) was ligated with a pBlueBac4.5 vector digested with same set of restriction enzymes.

[0198] To create a V5-His tag at human ACC2 COOH-terminus, a PCR reaction was carried out using the following set of primers: forward: 5'-TCCTGTATTGGCGTCTGCGCCGC-3' (SEQ ID NO:17), reverse: 5'-CGAATTCACGGTGGAGGCCGGGCTGTC-3' (SEQ ID NO:18), and with pYES-human-ACC2 as the template. The resultant .about.490 bp product was digested with Esp3 I and EcoR I which is ligated with pBlueBac4.5/V5-His that was digested with Esp3 I and EcoR I. The resultant plasmid was designated pBlueBac-human-ACC2-V5-His.

[0199] To construct mammalian expression construct, pBlueBac-human-ACC2-V5-His was digested with Kpn I and Age I. The resultant .about.7.5 kb fragment was ligated with pcDNA4/V5-His that was digested with the same set of enzymes. The resulting plasmid was designated pcDNA-human-ACC2-V5-His.

[0200] To delete the NH.sub.2-terminus 148 amino acid of human ACC2, a PCR reaction was carried out using the following set of primers: forward: 5'-GGCCGAAGCCGGTACCGCCATGGGCAAAGAAGACAAGAAGCAGGCAAACATCAAGAGGCAGCTG-3', (SEQ ID NO:19), reverse: 5'-CGTCTGGGCGACAACGGTGGA-3' (SEQ ID NO:20), and with pcDNA-human-ACC2-V5-His as the template. The PCR product was digested with ACC65 I and Sfi I and ligated with the .about.12.5 kb digestion product of pcDNA-human-ACC2-V5-His with the same set of enzymes. The resultant plasmid was designated pcDNA-human-ACC2-Delta148-V5-His.

[0201] To insert myc tag between V5- and His-tags at the COOH terminus, a PCR reaction was carried out using the following set of primers: forward: 5'-TCCTGTATTGGCGTCTGCGCCGC-3' (SEQ ID NO:21), reverse: 5'-GGCCGAAGCCACCGGTGCCCAGATCCTCTTCTGAGATGAGTTTTTGTTCGCCCGTAGAATCGAGACCGAG- GAGAG-3' (SEQ ID NO:22), and with pcDNA-human-ACC2-Delta-V5-His as the template. The PCR product was digested with Esp3 I and with Age I, which was ligated with the .about.14 kb digestion product of pcDNA-human-ACC2-Delta148-V5-His generated by digestion with the same set of enzymes. The resultant plasmid was designated pcDNA-human-ACC2-Delta148-V5-Myc-His.

[0202] To conduct site-directed mutagenesis in order to create a version that contains all the amino acids as predicted by wild type sequence (SEQ ID NO:12), two intermediate plasmids were constructed. First, pBlueScrip-ACC2-N and pBlueScript-ACC2-C were constructed. pBlueScrip-ACC2-N was constructed by ligation of 3.4 kb ACC65 I/Sac II digestion product of pcDNA-human-ACC2-Delta148-V5-Myc-His with .about.3.0 kb ACC65 I/Sac II digestion product of pBlueScript II. pBlueScript-ACC2-C was constructed by ligation of the .about.4.0 kb Sac II/Pme I digestion product of pcDNA-human-ACC2-Delta148-V5-Myc-His with .about.3.0 kb Sac II/Pme I digestion product of pBlueScript II.

[0203] In order to change the discrepancies found in pYes-human-ACC2 that reside in the 5'-3.4 kb portion, mutagenesis was conducted using pBlueScript-ACC2-N as the template, using the following primers: TABLE-US-00004 (SEQ ID NO:23) 5'-CGATCCCCCCCAAAGCGTGTGACAAA-3', (SEQ ID NO:24) 5'-CCACACCGCCTGCACGGGGATTC-3', (SEQ ID NO:25) 5'-GAGGTATTCCACTGTCCCTGCACTCAC-3'v, (SEQ ID NO:26) 5'-CGATGTGGCAGCCATTCATGATGAGAACG-3', and (SEQ ID NO:27) 5'-TGTTGATGAAGAAGACCTCTCGATCAGCCT-3',

using a QUIKCHANGE multi site-directed mutagenesis kit according to the manufacturer's instructions. Sequencing experiments were conducted to identify clones that bear all the desired changes without introducing undesired changes. The resulting clone was designated pBlueScript-ACC2-N-WT.

[0204] In order to change the discrepancies found in pYes-human-ACC2 that resides in the 3'-4.0 kb portion, mutagenesis was conducted using pBlueScript-ACC2-C as the template, using the following primers:

5'-GTTCTCGGGGCAGAACTGGTGGC-3' (SEQ ID NO:28),

5'-CCTTCACCTTGGCAGCACCCAGGTAAAG-3' (SEQ ID NO:29), and

5'-GGGAAGTCATAGATGTAGGTGGTTCCC-3' (SEQ ID NO:30),

[0205] using QUIKCHANGE multi site-directed mutagenesis kit according to the manufacturer's instructions. Sequencing experiments were conducted to identify clones that bear all the desired changes without introducing undesired changes. The resulting clone was designated pBlueScript-ACC2-C-WT.

[0206] To reconstruct the expression vector containing all the wild type amino acid sequences, a ligation was conducted to join the following three components: the ACC65 I/Age I digestion product of pcDNA4/V5-His, the .about.3.4 kb ACC65 I/Sac II digestion product of pBlueScript-ACC2-N-WT, and the .about.4.0 kb Sac I/Age I digestion product of pBlueScript-ACC2-C-WT. The resulting plasmid was designated pcDNA-human-ACC2-Delta 148-V5-Myc-His-WT.

[0207] To construct a baculoviral vector comprising the final version human ACC2, the Kpn I/Age I digestion product of pBlueBac4.5/V5-His and the Kpn I/Age I digestion product of pcDNA-human-ACC2-Delta148-V5-Myc-His-WT were ligated. The resultant plasmid was designated as pBlueBac-human-ACC2-Delta148-V5-Myc-His-WT.

Example 4

Purification of Recombinant Human ACC2 by Anti-myc Affinity Column

[0208] Affinity chromatography using c-Myc-5 monoclonal IgG column and was carried out essentially according to Hillman et al (Hillman et al., (2001) Protein Expression and Purification 23:359-368), with several modifications. Pellets of HEK-293 cells or Sf9 cells that were either transiently transfected with a human ACC2 expression vector or infected with a recombinant human ACC2 baculovirus were lysed in 5.times. cell pellet volume of Buffer A (225 mM mannitol, 75 mM sucrose, 10 mM Tris/HCl. pH 7.5, 0.05 mM EDTA, 1.times. complete protease inhibitor cocktail, 0.5 mM PMSF) with sonication for 10 seconds. The broken cells were centrifuged for 10 minutes at 2000.times.g. NaCl concentration of supernatant was raised to .about.500 mM with addition of 1/10 volume of 5 M NaCl. The cell lysates were then further centrifuged for 30 minutes at 10,000.times.g at 4.degree. C. The supernatants of the second centrifugation were incubated with 3 ml resin coupled with c-Myc-5 IgG (density: 3 mg IgG/ml resin), which was pre-equilibrated with Buffer B (100 mM Tris/HCl, pH 7.5, 0.5 M NaCl, 1 mM EDTA, 10% glycerol) overnight at 4.degree. C. The incubated resin was then packed in a column and washed with Buffer B extensively (.about.200 ml) until O.D.280 reached baseline. After the wash, an aliquot of 1 ml Buffer C (Buffer B containing 1 mM myc peptide) was carefully applied to the column. Once Buffer C completely entered the column bed, column was plugged and incubated for 15 minutes at 4.degree. C. After the incubation, the eluate was collected via gravity. This elution procedure was repeated twelve times. The elution fractions were then subjected to analyses by coomassie stain, immunoblot and ACC enzymatic assays. Peak fractions were pooled and stored at -80.degree. C. for further study.

Example 5

ACC Enzyme Activity Assay

[0209] ACC enzymatic assays were carried out essentially according to Tanabe et al. (Tanabe et al. (1981) Methods Enzymol. 71 Pt C, 5-16) with modifications. In 7 ml glass scintillation vials, either fractions of recombinant human ACC2 eluted from the affinity column or .about.0.25 .mu.g of pooled purified ACC2 were mixed with 120 .mu.l Buffer D (50 mM Hepes, pH 7.5, 10 mM MgCl2, 10 mM tripotassium citrate, 0.1 mM DTT, 100 .mu.g/ml BSA) that contains either 4 mM ATP, 250 .mu.M acetyl CoA or at various concentrations as indicated in the figures. Aliquots of 30 .mu.l of 25 mM KH[.sup.14C]O.sub.3 (specific activity 1.3 .mu.Ci/.mu.mol, final KH[.sup.14C]O.sub.3, concentration 5 mM) was then added to the mixture to initiate the reaction which was carried out for 10 min at 37.degree. C. At the end, the reactions were quenched with 50 .mu.l 2 N HCl and the vials were heated for 2 hours at 80.degree. C. to remove excess bicarbonate as .sup.14CO.sub.2. Scintillant was then added and the acid-stable malonyl CoA remaining in the vial was counted in a scintillation counter. ACC specific activities were expressed as nmol/min/mg protein.

Example 6

Immunoblot Analyses of Insect Sf9 Cells Expressing Human ACC2

[0210] FIG. 1A is a schematic diagram depicting the primary structure of the form of human ACC2 that is expressed in one aspect of the present invention. In order to increase the solubility of recombinant human ACC2, the first 27 hydrophobic amino acids and the following stretch of amino acids (from 27 to 148) were deleted. This stretch of sequence has been shown to facilitate the attachment of ACC2 with mitochondria (Abu-Elheiga et al., (2000) Proc. Nat. Acad. Sci. USA 97:1444) Since these sequences are not present in ACC1 enzyme (Ha et al., (1996) Proc. Natl. Acad. Sc. USA 93:11466-11470), it was deemed plausible that they are not essential for the catalytic activity. It was also predicted that deleting the mitochondria attachment sequence would also minimize docking too much over-expressed recombinant protein to the mitochondria and thereby prevent a potential detriment to the host cells.

[0211] In order to facilitate the identification and purification of the recombinant enzyme, three consecutive tags were fused to the COOH-terminus end of the enzyme, namely V5 and myc epitope-tags, and a 6.times.His tag.

[0212] To ensure the fidelity of coding sequence in the recombinant human ACC2, the amino acid sequences of pYES-human-ACC2, the coding region of human ACC2 predicted by human genomic contig AC007637 and Genbank ACC2 sequence (NM.sub.--001093) (Ha et al. (1996) Proc. Natl. Acad. Sci. USA 93:11466-11470) were compared. The result of the comparison revealed that there are multiple discrepancies among these three sequences. Specifically, in amino acid sequences predicted by genomic contig AC007637, the discrepancies are C at position 9, G at position 347, G at positions of 349-352, V at position 2141; in amino acid sequences described in Genbank Accession No. NM.sub.--001093, the discrepancies are H at position 111, V at position 127, S at position 450, R at position 614, K at position 656, V at position 671, KI at position 742-743, K at position 799, A at position 1025, A at position 1064, A at position 1480, G at position 1547, A at position 1821, RPMR at position 2194-2197, E at position 2242; in amino acid sequences as predicted by pYES-human-ACC2, the discrepancies are Y at position 254, R at position 345, A at position 565, Y at position 841, A at position 1103, R at position 1259, V at position 1526, V at position 1717. The consensus of amino acid sequences among pYES-human-ACC2, Genbank Accession No. NM.sub.--001093 and human genome contig AC007637 is defined as the wild type human ACC2 amino acid sequence (SEQ ID NO:12). Specifically the amino acids need to be R at position 9, P at position 111, A at position 127, F at position 254, Q at position 345, V at position 347, AGWG at positions of 349-352, P at position 450, T at position 565, H at position 614, E at position 656, E at position 671, ET at position 742-743, E at position 799, N at position 841, V at position 1025, V at position 1064, V at position 1103, C at position 1259, R at position 1480, A at position 1526, R at position 1547, I at position 1717, G at position 1821, I at position 2141, PPYA at position 2194-2197, K at position 2242. The discrepancies in the human Genomic contig were attributed to the presence of a sequencing error or polymorphism, and the discrepancies in pYES-human-ACC2 and Genbank Accession No. NM.sub.--001093 were attributed to the mutations possibly introduced by a PCR reaction during the cloning (Ha et al. (1996) Proc. Natl. Acad. Sci. USA 93:11466-11470).

[0213] In pYES-human-ACC2, there were eight single amino acid discrepancies identified, as compared to the designated wild type human ACC2 sequence. The discrepancies are distributed throughout the entire coding region and correspond to the following mutations: F254Y, Q345R, T565A, N841Y, V1103A, C1259R, V1526A, I1711V At the nucleotide level, in all cases, single nucleotide changes were identified. In order to test the possibility that these eight point mutations might change the protein's stability or, alternatively, might change ACC enzyme activity, these amino acids were systematically changed to the wild type sequence. FIG. 6A depicts the number and location of the identified discrepancies.

[0214] Activity assays indicated that these eight point mutations decrease the activity of the protein.

[0215] FIG. 6B demonstrates ACC2 protein expression levels, which were generated using immunoblot analyses. Probed with anti-V5 IgG antibodies (V5 is a common epitope present in both ACC2Mt (containing the original eight mutations found in pYES-human-ACC2) and ACC2WT)), it was found that ACC2WT is more stable than ACC2Mt. This result was reproduced when lysates were probed with Streptavidin-conjugated-with-HRP, which detects the biotin group on ACC. Further, there is a detectable signal in Mock-infected Sf9 cells at the same molecular mass, indicating there is substantial endogenous insect cell ACC enzyme present (FIG. 6B).

Example 7

Performance of Recombinant Human ACC2 on Monomeric Avidin Column

[0216] Biotinylation of ACC is an indispensable protein modification for its enzymatic function. To investigate the level of biotinylation of the recombinant human ACC2, lysates derived from cells expressing human ACC2 were loaded on monomeric avidin column. The column was washed and was then eluted with 0.2 mM biotin for 3 hours (Elu1, lane 3), which was followed by another overnight elution (Elu2, lane 4). Aliquots from the flow-through from the loading step (FT), two steps of elution, and materials remained in the column after two steps of biotin-elution (eluted by boiling in SDS loading buffer) were quantitatively loaded on SDS-PAGE and blot-analyzed with anti-V5 IgG. Almost no recombinant human ACC2 was detected in the flow-through fraction, whereas there was a quantitative recovery for human ACC2 bound to the avidin column. This indicates that nearly all the recombinant human ACC2 is properly biotinylated (FIG. 7).

Example 8

Performance of Human ACC2 on TALON Resin

[0217] The observation that the recombinant human ACC2 cannot be eluted from a monomeric avidin column via competition with a high concentration of biotin suggests that in some situations this may not be a preferred method of purifying the recombinant human ACC2 of the present invention. Additionally, multiple attempts to purify that recombinant ACC2 enzyme using conventional protein purification methods (including ammonium sulfate precipitation, gel-filtration, ion-exchange chromatography) did not provide the desired level of separation of these two types of ACC enzymes. Lastly, the observation that there is endogenous insect ACC enzyme in the host cells (FIG. 6B, lane 4), suggested that it might be advantageous to employ an affinity tag that is capable of differentiating the recombinant enzyme from the endogenous ACC.

[0218] The first affinity tag that was employed was TALON resin (Clontech, Palo Alto, Calif.), which can be used to purify recombinant poly-His-tagged proteins (Bush et al., (1991) J. Biol. Chem. 266:13811-13814). FIG. 8 depicts a comparison of binding for the total lysates and recombinant human ACC2. The results suggest that there is an amount of non-specific binding of host cell proteins to the TALON resin, particularly those proteins with high molecular mass (FIG. 8, lanes 1 to 4). Probing specifically for human ACC2 indicates a loss of signal in the Eluate fraction as compared with the Load fraction (FIG. 8, lanes 6 and 8). ACC activity measurement revealed that there is a small increase in ACC specific activity before and after the sample was applied to the TALON column. These results indicated that a 6.times.His-tag might not be desirable in all situations for the isolation of recombinant human ACC2 from the host cell lysates.

Example 9

Purification of Recombinant Human ACC2 with Anti-Myc-IgG

[0219] It was hypothesized that a preferred affinity column for purifying human recombinant human ACC2 would have a high enough affinity to absorb the protein (e.g., higher than Kd .about.10.sup.-3 M, the affinity reported by the manufacturer for the TALON-PolyHis resin) and to allow stringent washing condition, yet have a low enough affinity for the protein to be eluted (e.g., smaller than Kd of .about.10.sup.-15 M, the avidin-biotin affinity; Hiller et al. (1987) Biochem. J. 248:167-171). Antibody-antigen interactions, for example, fall into this category. An anti-Myc-IgG antibody was therefore selected for investigation. c-Myc-5 IgG has been extensively characterized (see, e.g. Hillman et al., (2001) Protein Expres. Purif. 23:359-368).

[0220] FIGS. 9A and 9B depict the purification of human ACC2 using a c-Myc-5 IgG column. Total crude cell cytosolic lysates derived from 1 liter of human ACC2 virus infected Sf9 cells were loaded on a 3-ml c-Myc-5 IgG column by overnight incubation. The bound protein was then extensive washed with high salt buffer (0.5 M NaCl). The most tightly bound proteins were then eluted with 1 mM myc peptide (Ac-EQKLISEEDL-OH; SEQ ID NO:16) in 10 steps. The protein peak of the eluate resided at fraction 4 and 5 as a single .about.250 kDa protein band (FIG. 9A). This protein was recognized by anti-V5 and Streptavidin-conjugated-with-HRP in blot analyses, indicating that the purified band is recombinant human ACC2. In a parallel ACC enzymatic measurement, ACC activity peaks were found in the same fractions as those identified in the coomassie stain assay (compare FIGS. 9A and 9B).

[0221] The active fractions were then pooled. A quantitative ACC enzyme assay indicated that the pooled enzyme has a specific activity of 500 nmol/min/mg. The yield from 1 liter Sf9 cell culture was .about.2 mg protein. The recovery of total activity was 80%.

[0222] In order to address whether human-ACC2-Mt is different at enzymatic level as compared with human-ACC2-WT, human-ACC2-Mt was purified in the same way as described above. In addition to the lower yield, in ACC enzyme assays human-ACC2-Mt was not observed to contain measurable activity, indicating that one or several amino acids that were identified as discrepant between pYES-human-ACC2 and the wild type ACC2 sequence is critical for ACC enzyme activity.

Example 10

Determination of Kinetic Parameters for Recombinant Human ACC2

[0223] In order to detect recombinant human ACC2 activity in one in vitro assay (see, e.g. U.S. Patent Application Ser. No. 60/558,015, incorporated herein by reference), acetyl CoA, ATP, bicarbonate are preferably present. It was found that in the absence of any one of these compounds, no activity was detected. In addition, the presence of the known effector citrate was found to be required for the detection of ACC2 activity in the assay employed. The K.sub.m for the substrates, acetyl CoA, ATP and bicarbonate and the K.sub.act for the effector citrate were determined by assaying ACC activity at various concentrations of one reagent and saturating concentrations of all the others at 37.degree. C.

[0224] FIG. 10 comprises plots depicting the concentration dependence of acetyl CoA, ATP, bicarbonate and citrate. Table 1 summarizes the K.sub.m and K.sub.act value for the recombinant human ACC2 as compared with literature values of rat ACC enzymes. TABLE-US-00005 TABLE 1 Kinetic Parameters of Recombinant Human ACC2 Recombinant Literature Values* Human ACC2 Rat ACC1 Rat ACC2 Km Acetyl CoA (uM) 23 22 32 ATP (uM) 270 110 58 HCO.sub.3.sup.-(mM) 5 2.7 2.3 Kact Citrate (mM) 1.8 3 2.1 (*literature value from Trumble et al., (1995) Eur. J. Biochem. 231: 192-198)

Example 11

Effect of Known Inhibitors for Recombinant Human ACC2

[0225] FIG. 11 comprises two plots depicting the concentration dependent inhibition of recombinant human ACC2 by known inhibitors such as palmitoyl CoA and malonyl CoA. The IC.sub.50 for these two agents was determined to be 4.4 .mu.M and 26.7 .mu.M for palmitoyl CoA and malonyl CoA, respectively. For comparison, the literature IC.sub.50 values of palmitoyl CoA and malonyl CoA for rat ACC2 enzyme are 2.2 .mu.M and 10.6 .mu.M (Trumble et al., (1995) Eur. J. Biochem. 231, 192-198).

REFERENCES

[0226] The references cited herein are incorporated herein by reference to the extent that they supplement, explain, provide a background for or teach methodology, techniques and/or compositions employed herein. All cited patents, including patent applications, and publications referred to in this application are herein expressly incorporated by reference. Also expressly incorporated herein by reference are the contents of all citations of GenBank accession numbers, LocusID, and other computer database listings, as well as the contents of any Sequence Listing associated herewith.

[0227] While the invention has been described in connection with specific embodiments, it will be understood that the invention encompasses further modifications including variations, uses, and adaptations of the invention that follow the principles of the invention. Furthermore, the foregoing description is for purposes of illustration.

Sequence CWU 1

1

33 1 7452 DNA Homo sapiens CDS (1)..(7452) 1 atg gtc ttg ctt ctt tgt cta tct tgt ctg att ttc tcc tgt ctg acc 48 Met Val Leu Leu Leu Cys Leu Ser Cys Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 ttt tcc tgg tta aaa atc tgg gag aaa atg acg gac tcc aag ccg atc 96 Phe Ser Trp Leu Lys Ile Trp Glu Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 acc aag agt aaa tca gaa gca aac ctc atc ccg agc cag gag ccc ttt 144 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 cca gcc tct gat aac tca ggg gag aca ccg cag aga aat ggg gag ggc 192 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 cac act ctg cac aaa gac acc cag cca ggc cga gcc cag cct ccc aca 240 His Thr Leu His Lys Asp Thr Gln Pro Gly Arg Ala Gln Pro Pro Thr 65 70 75 80 aag gcc caa aga tcc ggt cgg cgg aga aac tcc cta cca ccc tcc cgc 288 Lys Ala Gln Arg Ser Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser Arg 85 90 95 cag aag ccc cca aga aac ccc ctt tct tcc agt gac gca gca ccc tcc 336 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 cca gag ctt caa gcc aac ggg act ggg aca caa ggt ctg gag gcc aca 384 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 gat acc aat ggc ctg tcc tcc tca gcc agg ccc cag ggc agc aag ctg 432 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Ser Lys Leu 130 135 140 gtc ccc tcc aaa gaa gac aag aag cag gca aac atc aag agg cag ctg 480 Val Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln Leu 145 150 155 160 atg acc aac ttc atc ctg ggc tct ttt gat gac tac tcc tcc gac gag 528 Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp Glu 165 170 175 gac tct gtt gct ggc tca tct cgt gag tct acc cgg aag ggc agc cgg 576 Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser Arg 180 185 190 gcc agc ttg ggg gcc ctg tcc ctg gag gct tat ctg acc aca ggt gaa 624 Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly Glu 195 200 205 gct gag acc cgc gtc ccc act atg agg ccg agc atg tcg gga ctc cac 672 Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu His 210 215 220 ctg gtg aag agg gga cgg gaa cac aag aag ctg gac ctg cac aga gac 720 Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp 225 230 235 240 ttt acc gtg gct tct ccc gct gag ttt gtc aca cgc ttt ggg ggg gat 768 Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asp 245 250 255 cgg gtc atc gag aag gtg ctt att gcc aac aac ggg att gcc gct gtg 816 Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val 260 265 270 aag tgc atg cgc tcc atc cgc agg tgg gcc tat gag atg ttc cgc aac 864 Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn 275 280 285 gag cgg gcc atc cgg ttt gtt cgc atg gtg acc ccc gag gac ctt aag 912 Glu Arg Ala Ile Arg Phe Val Arg Met Val Thr Pro Glu Asp Leu Lys 290 295 300 gcc aac gca gag tac atc aag atg gcg gat cat tac ggg ccc gcc cca 960 Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Gly Pro Ala Pro 305 310 315 320 gga ggg ccc aat aac aac aac tat gcc aac gtg gag ctg att gtg gac 1008 Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val Asp 325 330 335 att gcc aag aga atc ccg ttg cag gcg gtg tgg gct ggc tgg ggc cat 1056 Ile Ala Lys Arg Ile Pro Leu Gln Ala Val Trp Ala Gly Trp Gly His 340 345 350 gct tta gaa aac cct aaa ctt ccg gag ctg ctg tgc aag aat gga gtt 1104 Ala Leu Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly Val 355 360 365 gct ttc tta ggc cct ccc agg ttg agg cca atg gtg ggt cta gga gat 1152 Ala Phe Leu Gly Pro Pro Arg Leu Arg Pro Met Val Gly Leu Gly Asp 370 375 380 aag atc gcc tcc acc gtt gtc gcc cag acg cta cag gtc cca acc ctg 1200 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 ccc agg agt gga agc gcc ctg aca gtg gag tgg aca gaa gat gat ctg 1248 Pro Arg Ser Gly Ser Ala Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 cag cag gga aaa aga atc agt gtc cca gaa gat gtt tat gac aag ggt 1296 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 tgc gtg aaa gac gta gat gag ggc ttg gag gca gca gaa aga att ggt 1344 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 ttt cca ttg atg atc aaa gct tct gaa ggt ggc gga ggg aag gga atc 1392 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 cgg gaa act gag agt gcg gag gac ttc ccg atc ctt ttc aga caa gta 1440 Arg Glu Thr Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 cag agt gag atc cca ggc tcg ccc atc ttt ctc atg aag ctg gcc cag 1488 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 cac gcc cgt cac ctg gaa gtt cag atc ctc gct gac cag tat ggg aat 1536 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 gct gtg tct ctg ttt ggt cgc gac tgc tcc atc cag cgg cgg cat cag 1584 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 aag atc gtt gag gaa gca ccg gcc acc atc gcg ccg ctg gcc ata ttc 1632 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 gag ttc atg gag cag tgt gcc att cgc ctg gcc aag acc gtg ggc tat 1680 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 gtg agt gca ggg aca gtg gaa tac ctc tat agt cag gat ggt agc ttc 1728 Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 cac ttc ttg gag ctg aat cct cgc ttg cag gtg gaa cat ccc tgc aca 1776 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 gaa atg att gct gac gtt aat ctg ccg gcc gcc cag cta cag atc gcc 1824 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 atg ggt gcc cca ctg cac cgg ctg aaa gat atc cgg ctt ctg tat gga 1872 Met Gly Ala Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 gag tca ccc tgg gga gac tcc cca att tct ttt gaa aac tca gct cat 1920 Glu Ser Pro Trp Gly Asp Ser Pro Ile Ser Phe Glu Asn Ser Ala His 625 630 635 640 ctc ccc tgc ccc cga ggc cac gtc att gcc acc aga atc acc agc gaa 1968 Leu Pro Cys Pro Arg Gly His Val Ile Ala Thr Arg Ile Thr Ser Glu 645 650 655 aac cca gac gag ggt ttt aag ccg agc tcc ggg act gtc cag gaa ctg 2016 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 aat ttc cgg agc agc aag aac gtc tgg ggt tac ttc acg gtg gcc gct 2064 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Thr Val Ala Ala 675 680 685 act gga ggc ctg cac gag ttt gcg att tcc cag ttt ggg cac tgc ttc 2112 Thr Gly Gly Leu His Glu Phe Ala Ile Ser Gln Phe Gly His Cys Phe 690 695 700 tcc tgg gga gag aac cgg aaa gag gcc att tcg aac atg gtg gtg gct 2160 Ser Trp Gly Glu Asn Arg Lys Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 ttg aag gaa ctg tcc ctc cga ggc gac ttt agg act acc gtg gaa tac 2208 Leu Lys Glu Leu Ser Leu Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 ctc att aac ctc ctg gag acc gag agc ttc cag aac aac tac atc gac 2256 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Tyr Ile Asp 740 745 750 acc ggg tgg ttg gac tac ctc att gct gag aaa gtg caa aag aaa ccg 2304 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Lys Lys Pro 755 760 765 aat atc atg ctt ggg gtg gta tgc ggg gcc ctt gaa cgt gga gat gcg 2352 Asn Ile Met Leu Gly Val Val Cys Gly Ala Leu Glu Arg Gly Asp Ala 770 775 780 atg ttc aga acg tgc atg aca gat ttc tta cac tcc ctg gaa agg ggc 2400 Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg Gly 785 790 795 800 cag gtc ctc cca gcg gat tca cta ctg aac ctc gta gat gtg gaa tta 2448 Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu Leu 805 810 815 att tac gag ggt gta aag tac att cta aag gtg acc cgg cag tct ctg 2496 Ile Tyr Glu Gly Val Lys Tyr Ile Leu Lys Val Thr Arg Gln Ser Leu 820 825 830 acc atg ttc gtt ctc atc atg aat ggc tgc cac atc gag att gat gcc 2544 Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala 835 840 845 cac cgg ctg aat gat ggg ggg ctc ctg ctc tcc tac aat ggg aac agc 2592 His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn Ser 850 855 860 tac acc acc tac atg aag gaa gag gtt gac agt tac cgt acc atc ggc 2640 Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Thr Ile Gly 865 870 875 880 aat aag acg tgt gtt ttt gag aag gag aac gat cct aca gtc ctg aga 2688 Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg 885 890 895 tcc ccc tcg gct ggg aag ctg aca cag atc aca gtg gag gat ggg ggc 2736 Ser Pro Ser Ala Gly Lys Leu Thr Gln Ile Thr Val Glu Asp Gly Gly 900 905 910 cac gtt gag gct ggg aga cgc tac gct gag atg gag gtg atg aag atg 2784 His Val Glu Ala Gly Arg Arg Tyr Ala Glu Met Glu Val Met Lys Met 915 920 925 atc atg acc ctg aac gtt cag gaa aga ggc cgg gtg aag tac atc aag 2832 Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr Ile Lys 930 935 940 cgt cca ggt gcg gtg ctg gaa gca ggc tgc gtg gtg gcc agg ctg gag 2880 Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg Leu Glu 945 950 955 960 ctc gat gac cct tct aaa gtc cac ccg gct gaa ccg ttc aca gga gaa 2928 Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr Gly Glu 965 970 975 ctc cct gcc cag cag aac act gcc gac ctc gga aag aaa ctg cac agg 2976 Leu Pro Ala Gln Gln Asn Thr Ala Asp Leu Gly Lys Lys Leu His Arg 980 985 990 gtc ttc cac agc gtc ctg gga agc ctc acc aac gtc atg agt ggc ttt 3024 Val Phe His Ser Val Leu Gly Ser Leu Thr Asn Val Met Ser Gly Phe 995 1000 1005 tgt ctg cca gag ccg ttt ttt agc ata aag ctg aag gag tgg gtg 3069 Cys Leu Pro Glu Pro Phe Phe Ser Ile Lys Leu Lys Glu Trp Val 1010 1015 1020 cag aag ctc atg atg acc ctc cgg cac ccg tca ctg ctg ctg gac 3114 Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Leu Leu Asp 1025 1030 1035 gtg cag gag atc atg acc agt cgt gca ggc cgc atc ccc ccc cct 3159 Val Gln Glu Ile Met Thr Ser Arg Ala Gly Arg Ile Pro Pro Pro 1040 1045 1050 gtt gag aag tct gtc cgc aag gtg atg gcc cag tat gcc agc aac 3204 Val Glu Lys Ser Val Arg Lys Val Met Ala Gln Tyr Ala Ser Asn 1055 1060 1065 atc acc tcg gtg ctg tgc cag ttc ccc agc cag cag ata gcc acc 3249 Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr 1070 1075 1080 atc ctg gac tgc cat gca gcc acc ctg cag cgg aag gct gat cga 3294 Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Ala Asp Arg 1085 1090 1095 gag gtc ttc ttc atc aac acc cag agc atg gtg cag ttg gtc cag 3339 Glu Val Phe Phe Ile Asn Thr Gln Ser Met Val Gln Leu Val Gln 1100 1105 1110 agg tac cga agt gga atc cgc ggt cat atg aaa aca gtg gtg atc 3384 Arg Tyr Arg Ser Gly Ile Arg Gly His Met Lys Thr Val Val Ile 1115 1120 1125 gat ctc ttg aga aga tac ttg cgt gtt gag acc att ttc ggc aag 3429 Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu Thr Ile Phe Gly Lys 1130 1135 1140 gca aga gat gct gat gcc aac tcc agt ggg atg gtg ggg ggc gtg 3474 Ala Arg Asp Ala Asp Ala Asn Ser Ser Gly Met Val Gly Gly Val 1145 1150 1155 agg agc ctg agc ttt acc tct gtg tgg gtg gtt ttg tct ccc cca 3519 Arg Ser Leu Ser Phe Thr Ser Val Trp Val Val Leu Ser Pro Pro 1160 1165 1170 gcc cac tac gac aag tgt gtg ata aac ctc agg gaa cag ttc aag 3564 Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys 1175 1180 1185 cca gac atg tcc cag gtg ctg gac tgc atc ttc tcc cac gca cag 3609 Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser His Ala Gln 1190 1195 1200 gtg acc aag aag aac cag ctg gtg atc atg ttg atc gat gag ctg 3654 Val Thr Lys Lys Asn Gln Leu Val Ile Met Leu Ile Asp Glu Leu 1205 1210 1215 tgt ggc cca gac cct tcc ctg tcg gac gag ctg atc tcc atc ctc 3699 Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile Ser Ile Leu 1220 1225 1230 aac gag ctc act cag ctg agc aaa agc gag cac tgc aaa gtg gcc 3744 Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys Lys Val Ala 1235 1240 1245 ctc aga gcc cgg cag atc ctg atc gcc tcc ccc tcc tac gag ctg 3789 Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser Pro Ser Tyr Glu Leu 1250 1255 1260 cgg cat aac cag gtg gag tcc att ttc ctg tct gcc att gac atg 3834 Arg His Asn Gln Val Glu Ser Ile Phe Leu Ser Ala Ile Asp Met 1265 1270 1275 tac ggc cac cag ttc tgc ccc gag aac ctc cag aaa tta ata ctt 3879 Tyr Gly His Gln Phe Cys Pro Glu Asn Leu Gln Lys Leu Ile Leu 1280 1285 1290 tcg gaa aca acc atc ttc gac gtc ctg aat act ttc ttc tat cac 3924 Ser Glu Thr Thr Ile Phe Asp Val Leu Asn Thr Phe Phe Tyr His 1295 1300 1305 gca aac aaa gtc gtg tgc atg gcg tcc ttg gag gtt tac gtg ggg 3969 Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val Gly 1310 1315 1320 ggg gct tac atc gcc tat gtg tta aac agc ctg cag cac cgg cag 4014 Gly Ala Tyr Ile Ala Tyr Val Leu Asn Ser Leu Gln His Arg Gln 1325 1330 1335 ctc ccg gac ggc acc tgc gtg gta gaa ttc cag ttc atg ctg ccg 4059 Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu Pro 1340 1345 1350 tcc tcc cac cca aac cgg atg acc gtg ccc atc agc atc acc aac 4104 Ser Ser His Pro Asn Arg Met Thr Val Pro Ile Ser Ile Thr Asn 1355 1360 1365 cct gac ctg ctg agg cac acg aca gag ctc ttc atg gac agc ggc 4149 Pro Asp Leu Leu Arg His Thr Thr Glu Leu Phe Met Asp Ser Gly 1370 1375 1380 ttc tcc cca ctg tgc cag cgc atg gga gcc atg gta gcc ttc agg 4194 Phe Ser Pro Leu Cys Gln Arg Met Gly Ala Met Val Ala Phe Arg 1385 1390 1395 aga ttc gag gac ttc acc aga aat ttt gat gaa gtc atc tct tgc 4239 Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp Glu Val Ile Ser Cys 1400 1405 1410 ttc gcc aac gtg ccg aaa gac ccc ccc ctc ttc agc gag gcc cgc 4284 Phe Ala Asn Val Pro Lys Asp Pro Pro Leu Phe Ser Glu Ala Arg 1415 1420 1425 acc tcc cta tac tcc gag gat gac tgc aag agc ctc aga gaa gag 4329 Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys Ser Leu Arg Glu Glu 1430 1435 1440 ccc atc cac att ctg aat gtg tcc atc cag tgt gcg gac cac ctg 4374 Pro Ile His Ile Leu Asn Val Ser Ile Gln Cys Ala Asp His Leu 1445 1450 1455 gag gat gag gca ctg gtg ccg att tta cgt aca ttc gta cag tcc 4419 Glu Asp Glu Ala Leu Val Pro Ile Leu Arg Thr Phe Val Gln Ser 1460 1465 1470 aag aaa aat atc ctt gtg gat tat gga ctc cga cga atc cca ttc 4464 Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile Pro Phe 1475 1480 1485 ttg att gcc caa gag aaa gaa ttt ccc aag ttt ttc aca ttc aga 4509 Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe

Phe Thr Phe Arg 1490 1495 1500 gca aga gat gag ttt gca gaa gat cgc att tac cgt cac ttg gaa 4554 Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His Leu Glu 1505 1510 1515 cct gcc ctg gct ttc cag ctg gaa ctc aac cgg atg cgt aac ttc 4599 Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn Arg Met Arg Asn Phe 1520 1525 1530 gat ctg acc gcc gtg ccc tgt gcc aac cac aag atg cac ctt tac 4644 Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His Leu Tyr 1535 1540 1545 ctg ggt gct gcc aag gtg gaa gga agg tat gaa gtg acg gac cat 4689 Leu Gly Ala Ala Lys Val Glu Gly Arg Tyr Glu Val Thr Asp His 1550 1555 1560 agg ttc ttc atc cgt gcc atc atc agg cac tct gac ctg atc aca 4734 Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu Ile Thr 1565 1570 1575 aag gaa gcc tcc ttc gaa tac ctg cag aac gag ggt gag cgg ctg 4779 Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu Arg Leu 1580 1585 1590 ctc ctg gag gcc atg gac gag ctg gag gtg gcg ttc aat aac acc 4824 Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn Asn Thr 1595 1600 1605 aac gtg cgc acc gac tgc aac cac atc ttc ctc aac ttc gtg ccc 4869 Asn Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe Val Pro 1610 1615 1620 act gtc atc atg gac ccc aac aag atc gag gag tcc gtg cgc tac 4914 Thr Val Ile Met Asp Pro Asn Lys Ile Glu Glu Ser Val Arg Tyr 1625 1630 1635 atg gtt atg cgc tac ggc agc cgg ctg tgg aaa ctc cgt gtg cta 4959 Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg Val Leu 1640 1645 1650 cag gct gag gtc aag atc aac atc cgc cag acc acc acc ggc agt 5004 Gln Ala Glu Val Lys Ile Asn Ile Arg Gln Thr Thr Thr Gly Ser 1655 1660 1665 gcc gtt ccc atc cgc ctg ttc atc acc aat gag tcg ggc tac tac 5049 Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly Tyr Tyr 1670 1675 1680 ctg gac atc agc ctc tac aaa gaa gtg act gac tcc aga tct gga 5094 Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg Ser Gly 1685 1690 1695 aat atc atg ttt cac tcc ttc ggc aac aag caa ggg ccc cag cac 5139 Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Pro Gln His 1700 1705 1710 ggg atg ctg atc aat act ccc tac gtc acc aag gat ctg ctc cag 5184 Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu Leu Gln 1715 1720 1725 gcc aag cga ttc cag gcc cag acc ctg gga acc acc tac atc tat 5229 Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly Thr Thr Tyr Ile Tyr 1730 1735 1740 gac ttc ccg gaa atg ttc agg cag gct ctc ttt aaa ctg tgg ggc 5274 Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu Trp Gly 1745 1750 1755 tcc cca gac aag tat ccc aaa gac atc ctg aca tac act gaa tta 5319 Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu Thr Tyr Thr Glu Leu 1760 1765 1770 gtg ttg gac tct cag ggc cag ctg gtg gag atg aac cga ctt cct 5364 Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg Leu Pro 1775 1780 1785 ggt gga aat gag gtg ggc atg gtg gcc ttc aaa atg agg ttt aag 5409 Gly Gly Asn Glu Val Gly Met Val Ala Phe Lys Met Arg Phe Lys 1790 1795 1800 acc cag gag tac ccg gaa gga cgg gat gtg atc gtc atc ggc aat 5454 Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val Ile Val Ile Gly Asn 1805 1810 1815 gac atc acc ttt cgc att gga tcc ttt ggc cct gga gag gac ctt 5499 Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly Pro Gly Glu Asp Leu 1820 1825 1830 ctg tac ctg cgg gca tcc gag atg gcc cgg gca gag gcg att ccc 5544 Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Ala Glu Ala Ile Pro 1835 1840 1845 aaa att tac gtg gca gcc aac agt ggc gcc cgt att ggc atg gca 5589 Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala Arg Ile Gly Met Ala 1850 1855 1860 gag gag atc aaa cac atg ttc cac gtg gct tgg gtg gac cca gaa 5634 Glu Glu Ile Lys His Met Phe His Val Ala Trp Val Asp Pro Glu 1865 1870 1875 gac ccc cac aaa gga ttt aaa tac ctg tac ctg act ccc caa gac 5679 Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr Leu Thr Pro Gln Asp 1880 1885 1890 tac acc aga atc agc tcc ctg aac tcc gtc cac tgt aaa cac atc 5724 Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val His Cys Lys His Ile 1895 1900 1905 gag gaa gga gga gag tcc aga tac atg atc acg gat atc atc ggg 5769 Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile Thr Asp Ile Ile Gly 1910 1915 1920 aag gat gat ggc ttg ggc gtg gag aat ctg agg ggc tca ggc atg 5814 Lys Asp Asp Gly Leu Gly Val Glu Asn Leu Arg Gly Ser Gly Met 1925 1930 1935 att gct ggg gag tcc tct ctg gct tac gaa gag atc gtc acc att 5859 Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu Glu Ile Val Thr Ile 1940 1945 1950 agc ttg gtg acc tgc cga gcc att ggg att ggg gcc tac ttg gtg 5904 Ser Leu Val Thr Cys Arg Ala Ile Gly Ile Gly Ala Tyr Leu Val 1955 1960 1965 agg ctg ggc cag cga gtg atc cag gtg gag aat tcc cac atc atc 5949 Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser His Ile Ile 1970 1975 1980 ctc aca gga gca agt gct ctc aac aag gtc ctg gga aga gag gtc 5994 Leu Thr Gly Ala Ser Ala Leu Asn Lys Val Leu Gly Arg Glu Val 1985 1990 1995 tac aca tcc aac aac cag ctg ggt ggc gtt cag atc atg cat tac 6039 Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile Met His Tyr 2000 2005 2010 aat ggt gtc tcc cac atc acc gtg cca gat gac ttt gag ggg gtt 6084 Asn Gly Val Ser His Ile Thr Val Pro Asp Asp Phe Glu Gly Val 2015 2020 2025 tat acc atc ctg gag tgg ctg tcc tat atg cca aag gat aat cac 6129 Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met Pro Lys Asp Asn His 2030 2035 2040 agc cct gtc cct atc atc aca ccc act gac ccc att gac aga gaa 6174 Ser Pro Val Pro Ile Ile Thr Pro Thr Asp Pro Ile Asp Arg Glu 2045 2050 2055 att gaa ttc ctc cca tcc aga gct ccc tac gac ccc cgg tgg atg 6219 Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr Asp Pro Arg Trp Met 2060 2065 2070 ctt gca gga agg cct cac cca act ctg aag gga acg tgg cag agc 6264 Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr Trp Gln Ser 2075 2080 2085 gga ttc ttt gac cac ggc agt ttc aag gaa atc atg gca ccc tgg 6309 Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met Ala Pro Trp 2090 2095 2100 gcg cag acc gtg gtg aca gga cga gca agg ctt ggg ggg att ccc 6354 Ala Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly Gly Ile Pro 2105 2110 2115 gtg gga gtg att gct gtg gag aca cgg act gtg gag gtg gca gtc 6399 Val Gly Val Ile Ala Val Glu Thr Arg Thr Val Glu Val Ala Val 2120 2125 2130 cct gca gac cct gcc aac ctg gat tct gag gcc aag ata att cag 6444 Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu Ala Lys Ile Ile Gln 2135 2140 2145 cag gca gga cag gtg tgg ttc cca gac tca gcc tac aaa acc gcc 6489 Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Tyr Lys Thr Ala 2150 2155 2160 cag gcc atc aag gac ttc aac cgg gag aag ttg ccc ctg atg atc 6534 Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys Leu Pro Leu Met Ile 2165 2170 2175 ttt gcc aac tgg agg ggg ttc tcc ggt ggc atg aaa gac atg tat 6579 Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys Asp Met Tyr 2180 2185 2190 gac cag gtg ctg aag ttt gga gcc tac atc gtg gac ggc ctt aga 6624 Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile Val Asp Gly Leu Arg 2195 2200 2205 caa tac aaa cag ccc atc ctg atc tat atc cgc cct atg cgg gag 6669 Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile Arg Pro Met Arg Glu 2210 2215 2220 ctc cgg gga ggc tcc tgg gtg gtc ata gat gcc acc atc aac ccg 6714 Leu Arg Gly Gly Ser Trp Val Val Ile Asp Ala Thr Ile Asn Pro 2225 2230 2235 ctg tgc ata gaa atg tat gca gac aaa gag agc agg ggt ggt gtt 6759 Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg Gly Gly Val 2240 2245 2250 ctg gaa cca gag ggg aca gtg gag att aag ttc cga aag gaa gat 6804 Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg Lys Glu Asp 2255 2260 2265 ctg ata aag tcc atg aga agg atc gat cca gct tac aag aag ctc 6849 Leu Ile Lys Ser Met Arg Arg Ile Asp Pro Ala Tyr Lys Lys Leu 2270 2275 2280 atg gaa cag cta ggg gaa cct gat ctc tcc gac aag gac cga aag 6894 Met Glu Gln Leu Gly Glu Pro Asp Leu Ser Asp Lys Asp Arg Lys 2285 2290 2295 gac ctg gag ggc cgg cta aag gct cgc gag gac ctg ctg ctc ccc 6939 Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu Asp Leu Leu Leu Pro 2300 2305 2310 atc tac cac cag gtg gcg gtg cag ttc gcc gac ttc cat gac aca 6984 Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Phe His Asp Thr 2315 2320 2325 ccc ggc cgg atg ctg gag aag ggc gtc ata tct gac atc ctg gag 7029 Pro Gly Arg Met Leu Glu Lys Gly Val Ile Ser Asp Ile Leu Glu 2330 2335 2340 tgg aag acc gca cgc acc ttc ctg tat tgg cgt ctg cgc cgc ctc 7074 Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp Arg Leu Arg Arg Leu 2345 2350 2355 ctc ctg gag gac cag gtc aag cag gag atc ctg cag gcc agc ggg 7119 Leu Leu Glu Asp Gln Val Lys Gln Glu Ile Leu Gln Ala Ser Gly 2360 2365 2370 gag ctg agt cac gtg cat atc cag tcc atg ctg cgt cgc tgg ttc 7164 Glu Leu Ser His Val His Ile Gln Ser Met Leu Arg Arg Trp Phe 2375 2380 2385 gtg gag acg gag ggg gct gtc aag gcc tac ttg tgg gac aac aac 7209 Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp Asp Asn Asn 2390 2395 2400 cag gtg gtt gtg cag tgg ctg gaa cag cac tgg cag gca ggg gat 7254 Gln Val Val Val Gln Trp Leu Glu Gln His Trp Gln Ala Gly Asp 2405 2410 2415 ggc ccg cgc tcc acc atc cgt gag aac atc acg tac ctg aag cac 7299 Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile Thr Tyr Leu Lys His 2420 2425 2430 gac tct gtc ctc aag acc atc cga ggc ctg gtt gaa gaa aac ccc 7344 Asp Ser Val Leu Lys Thr Ile Arg Gly Leu Val Glu Glu Asn Pro 2435 2440 2445 gag gtg gcc gtg gac tgt gtg ata tac ctg agc cag cac atc agc 7389 Glu Val Ala Val Asp Cys Val Ile Tyr Leu Ser Gln His Ile Ser 2450 2455 2460 cca gct gag cgg gcg cag gtc gtt cac ctg ctg tct acc atg gac 7434 Pro Ala Glu Arg Ala Gln Val Val His Leu Leu Ser Thr Met Asp 2465 2470 2475 agc ccg gcc tcc acc tga 7452 Ser Pro Ala Ser Thr 2480 2 2483 PRT Homo sapiens 2 Met Val Leu Leu Leu Cys Leu Ser Cys Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 Phe Ser Trp Leu Lys Ile Trp Glu Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 His Thr Leu His Lys Asp Thr Gln Pro Gly Arg Ala Gln Pro Pro Thr 65 70 75 80 Lys Ala Gln Arg Ser Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser Arg 85 90 95 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Ser Lys Leu 130 135 140 Val Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln Leu 145 150 155 160 Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp Glu 165 170 175 Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser Arg 180 185 190 Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly Glu 195 200 205 Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu His 210 215 220 Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp 225 230 235 240 Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asp 245 250 255 Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val 260 265 270 Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn 275 280 285 Glu Arg Ala Ile Arg Phe Val Arg Met Val Thr Pro Glu Asp Leu Lys 290 295 300 Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Gly Pro Ala Pro 305 310 315 320 Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val Asp 325 330 335 Ile Ala Lys Arg Ile Pro Leu Gln Ala Val Trp Ala Gly Trp Gly His 340 345 350 Ala Leu Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly Val 355 360 365 Ala Phe Leu Gly Pro Pro Arg Leu Arg Pro Met Val Gly Leu Gly Asp 370 375 380 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 Pro Arg Ser Gly Ser Ala Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 Arg Glu Thr Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 Met Gly Ala Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 Glu Ser Pro Trp Gly Asp Ser Pro Ile Ser Phe Glu Asn Ser Ala His 625 630 635 640 Leu Pro Cys Pro Arg Gly His Val Ile Ala Thr Arg Ile Thr Ser Glu 645 650 655 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Thr Val Ala Ala 675 680 685 Thr Gly Gly Leu His Glu Phe Ala Ile Ser Gln Phe Gly His Cys Phe 690 695 700 Ser Trp Gly Glu Asn Arg Lys Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 Leu Lys Glu Leu Ser Leu Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Tyr Ile Asp 740 745 750 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Lys Lys Pro 755 760 765 Asn Ile Met Leu Gly Val Val Cys Gly Ala Leu Glu Arg Gly Asp Ala 770 775 780 Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg Gly 785

790 795 800 Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu Leu 805 810 815 Ile Tyr Glu Gly Val Lys Tyr Ile Leu Lys Val Thr Arg Gln Ser Leu 820 825 830 Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala 835 840 845 His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn Ser 850 855 860 Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Thr Ile Gly 865 870 875 880 Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg 885 890 895 Ser Pro Ser Ala Gly Lys Leu Thr Gln Ile Thr Val Glu Asp Gly Gly 900 905 910 His Val Glu Ala Gly Arg Arg Tyr Ala Glu Met Glu Val Met Lys Met 915 920 925 Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr Ile Lys 930 935 940 Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg Leu Glu 945 950 955 960 Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr Gly Glu 965 970 975 Leu Pro Ala Gln Gln Asn Thr Ala Asp Leu Gly Lys Lys Leu His Arg 980 985 990 Val Phe His Ser Val Leu Gly Ser Leu Thr Asn Val Met Ser Gly Phe 995 1000 1005 Cys Leu Pro Glu Pro Phe Phe Ser Ile Lys Leu Lys Glu Trp Val 1010 1015 1020 Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Leu Leu Asp 1025 1030 1035 Val Gln Glu Ile Met Thr Ser Arg Ala Gly Arg Ile Pro Pro Pro 1040 1045 1050 Val Glu Lys Ser Val Arg Lys Val Met Ala Gln Tyr Ala Ser Asn 1055 1060 1065 Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr 1070 1075 1080 Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Ala Asp Arg 1085 1090 1095 Glu Val Phe Phe Ile Asn Thr Gln Ser Met Val Gln Leu Val Gln 1100 1105 1110 Arg Tyr Arg Ser Gly Ile Arg Gly His Met Lys Thr Val Val Ile 1115 1120 1125 Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu Thr Ile Phe Gly Lys 1130 1135 1140 Ala Arg Asp Ala Asp Ala Asn Ser Ser Gly Met Val Gly Gly Val 1145 1150 1155 Arg Ser Leu Ser Phe Thr Ser Val Trp Val Val Leu Ser Pro Pro 1160 1165 1170 Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys 1175 1180 1185 Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser His Ala Gln 1190 1195 1200 Val Thr Lys Lys Asn Gln Leu Val Ile Met Leu Ile Asp Glu Leu 1205 1210 1215 Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile Ser Ile Leu 1220 1225 1230 Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys Lys Val Ala 1235 1240 1245 Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser Pro Ser Tyr Glu Leu 1250 1255 1260 Arg His Asn Gln Val Glu Ser Ile Phe Leu Ser Ala Ile Asp Met 1265 1270 1275 Tyr Gly His Gln Phe Cys Pro Glu Asn Leu Gln Lys Leu Ile Leu 1280 1285 1290 Ser Glu Thr Thr Ile Phe Asp Val Leu Asn Thr Phe Phe Tyr His 1295 1300 1305 Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val Gly 1310 1315 1320 Gly Ala Tyr Ile Ala Tyr Val Leu Asn Ser Leu Gln His Arg Gln 1325 1330 1335 Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu Pro 1340 1345 1350 Ser Ser His Pro Asn Arg Met Thr Val Pro Ile Ser Ile Thr Asn 1355 1360 1365 Pro Asp Leu Leu Arg His Thr Thr Glu Leu Phe Met Asp Ser Gly 1370 1375 1380 Phe Ser Pro Leu Cys Gln Arg Met Gly Ala Met Val Ala Phe Arg 1385 1390 1395 Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp Glu Val Ile Ser Cys 1400 1405 1410 Phe Ala Asn Val Pro Lys Asp Pro Pro Leu Phe Ser Glu Ala Arg 1415 1420 1425 Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys Ser Leu Arg Glu Glu 1430 1435 1440 Pro Ile His Ile Leu Asn Val Ser Ile Gln Cys Ala Asp His Leu 1445 1450 1455 Glu Asp Glu Ala Leu Val Pro Ile Leu Arg Thr Phe Val Gln Ser 1460 1465 1470 Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile Pro Phe 1475 1480 1485 Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr Phe Arg 1490 1495 1500 Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His Leu Glu 1505 1510 1515 Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn Arg Met Arg Asn Phe 1520 1525 1530 Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His Leu Tyr 1535 1540 1545 Leu Gly Ala Ala Lys Val Glu Gly Arg Tyr Glu Val Thr Asp His 1550 1555 1560 Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu Ile Thr 1565 1570 1575 Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu Arg Leu 1580 1585 1590 Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn Asn Thr 1595 1600 1605 Asn Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe Val Pro 1610 1615 1620 Thr Val Ile Met Asp Pro Asn Lys Ile Glu Glu Ser Val Arg Tyr 1625 1630 1635 Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg Val Leu 1640 1645 1650 Gln Ala Glu Val Lys Ile Asn Ile Arg Gln Thr Thr Thr Gly Ser 1655 1660 1665 Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly Tyr Tyr 1670 1675 1680 Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg Ser Gly 1685 1690 1695 Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Pro Gln His 1700 1705 1710 Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu Leu Gln 1715 1720 1725 Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly Thr Thr Tyr Ile Tyr 1730 1735 1740 Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu Trp Gly 1745 1750 1755 Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu Thr Tyr Thr Glu Leu 1760 1765 1770 Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg Leu Pro 1775 1780 1785 Gly Gly Asn Glu Val Gly Met Val Ala Phe Lys Met Arg Phe Lys 1790 1795 1800 Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val Ile Val Ile Gly Asn 1805 1810 1815 Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly Pro Gly Glu Asp Leu 1820 1825 1830 Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Ala Glu Ala Ile Pro 1835 1840 1845 Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala Arg Ile Gly Met Ala 1850 1855 1860 Glu Glu Ile Lys His Met Phe His Val Ala Trp Val Asp Pro Glu 1865 1870 1875 Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr Leu Thr Pro Gln Asp 1880 1885 1890 Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val His Cys Lys His Ile 1895 1900 1905 Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile Thr Asp Ile Ile Gly 1910 1915 1920 Lys Asp Asp Gly Leu Gly Val Glu Asn Leu Arg Gly Ser Gly Met 1925 1930 1935 Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu Glu Ile Val Thr Ile 1940 1945 1950 Ser Leu Val Thr Cys Arg Ala Ile Gly Ile Gly Ala Tyr Leu Val 1955 1960 1965 Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser His Ile Ile 1970 1975 1980 Leu Thr Gly Ala Ser Ala Leu Asn Lys Val Leu Gly Arg Glu Val 1985 1990 1995 Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile Met His Tyr 2000 2005 2010 Asn Gly Val Ser His Ile Thr Val Pro Asp Asp Phe Glu Gly Val 2015 2020 2025 Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met Pro Lys Asp Asn His 2030 2035 2040 Ser Pro Val Pro Ile Ile Thr Pro Thr Asp Pro Ile Asp Arg Glu 2045 2050 2055 Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr Asp Pro Arg Trp Met 2060 2065 2070 Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr Trp Gln Ser 2075 2080 2085 Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met Ala Pro Trp 2090 2095 2100 Ala Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly Gly Ile Pro 2105 2110 2115 Val Gly Val Ile Ala Val Glu Thr Arg Thr Val Glu Val Ala Val 2120 2125 2130 Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu Ala Lys Ile Ile Gln 2135 2140 2145 Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Tyr Lys Thr Ala 2150 2155 2160 Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys Leu Pro Leu Met Ile 2165 2170 2175 Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys Asp Met Tyr 2180 2185 2190 Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile Val Asp Gly Leu Arg 2195 2200 2205 Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile Arg Pro Met Arg Glu 2210 2215 2220 Leu Arg Gly Gly Ser Trp Val Val Ile Asp Ala Thr Ile Asn Pro 2225 2230 2235 Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg Gly Gly Val 2240 2245 2250 Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg Lys Glu Asp 2255 2260 2265 Leu Ile Lys Ser Met Arg Arg Ile Asp Pro Ala Tyr Lys Lys Leu 2270 2275 2280 Met Glu Gln Leu Gly Glu Pro Asp Leu Ser Asp Lys Asp Arg Lys 2285 2290 2295 Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu Asp Leu Leu Leu Pro 2300 2305 2310 Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Phe His Asp Thr 2315 2320 2325 Pro Gly Arg Met Leu Glu Lys Gly Val Ile Ser Asp Ile Leu Glu 2330 2335 2340 Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp Arg Leu Arg Arg Leu 2345 2350 2355 Leu Leu Glu Asp Gln Val Lys Gln Glu Ile Leu Gln Ala Ser Gly 2360 2365 2370 Glu Leu Ser His Val His Ile Gln Ser Met Leu Arg Arg Trp Phe 2375 2380 2385 Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp Asp Asn Asn 2390 2395 2400 Gln Val Val Val Gln Trp Leu Glu Gln His Trp Gln Ala Gly Asp 2405 2410 2415 Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile Thr Tyr Leu Lys His 2420 2425 2430 Asp Ser Val Leu Lys Thr Ile Arg Gly Leu Val Glu Glu Asn Pro 2435 2440 2445 Glu Val Ala Val Asp Cys Val Ile Tyr Leu Ser Gln His Ile Ser 2450 2455 2460 Pro Ala Glu Arg Ala Gln Val Val His Leu Leu Ser Thr Met Asp 2465 2470 2475 Ser Pro Ala Ser Thr 2480 3 7368 DNA Homo sapiens CDS (1)..(7368) 3 atg gtc ttg ctt ctt tgt cta tct tgt ctg att ttc tcc tgt ctg acc 48 Met Val Leu Leu Leu Cys Leu Ser Cys Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 ttt tcc tgg tta aaa atc tgg ggg aaa atg acg gac tcc aag ccg atc 96 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 acc aag agt aaa tca gaa gca aac ctc atc ccg agc cag gag ccc ttt 144 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 cca gcc tct gat aac tca ggg gag aca ccg cag aga aat ggg gag ggc 192 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 cac act ctg ccc aag aca ccc agc cag gcc gag cca gcc tcc cac aaa 240 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 ggc ccc aaa gat gcc ggt cgg cgg aga aac tcc cta cca ccc tcc cac 288 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 cag aag ccc cca aga aac ccc ctt tct tcc agt gac gca gca ccc tcc 336 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 cca gag ctt caa gcc aac ggg act ggg aca caa ggt ctg gag gcc aca 384 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 gat acc aat ggc ctg tcc tcc tca gcc agg ccc cag ggc cag caa gct 432 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 ggc tcc ccc tcc aaa gaa gac aag aag cag gca aac atc aag agg cag 480 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 ctg atg acc aac ttc atc ctg ggc tct ttt gat gac tac tcc tcc gac 528 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 gag gac tct gtt gct ggc tca tct cgt gag tct acc cgg aag ggc agc 576 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 cgg gcc agc ttg ggg gcc ctg tcc ctg gag gct tat ctg acc aca ggt 624 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 gaa gct gag acc cgc gtc ccc act atg agg ccg agc atg tcg gga ctc 672 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 cac ctg gtg aag agg gga cgg gaa cac aag aag ctg gac ctg cac aga 720 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 gac ttt acc gtg gct tct ccc gct gag ttt gtc aca cgc ttt ggg ggg 768 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly 245 250 255 gat cgg gtc atc gag aag gtg ctt att gcc aac aac ggg att gcc gcc 816 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 gtg aag tgc atg cgc tcc atc cgc agg tgg gcc tat gag atg ttc cgc 864 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 aac gag cgg gcc atc cgg ttt gtt gtg atg gtg acc ccc gag gac ctt 912 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 aag gcc aac gca gag tac atc aag atg gcg gat cat tac gtc ccc gtc 960 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 cca gga ggg ccc aat aac aac aac tat gcc aac gtg gag ctg att gtg 1008 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 gac att gcc aag aga atc ccc gtg cag gct ggc tgg ggc cat gct tca 1056 Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Gly Trp Gly His Ala Ser 340 345 350 gaa aac cct aaa ctt ccg gag ctg ctg tgc aag aat gga gtt gct ttc 1104 Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly Val Ala Phe 355 360 365 tta ggc cct ccc agt gag gcc atg tgg gcc tta gga gat aag atc gcc 1152 Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp Lys Ile Ala 370 375 380 tcc acc gtt gtc gcc cag acg cta cag gtc cca acc ctg ccc tgg agt 1200 Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu Pro Trp Ser 385 390 395 400 gga agc ggc ctg aca gtg gag tgg aca gaa gat gat ctg cag cag gga 1248 Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu Gln Gln Gly 405 410 415 aaa aga atc agt gtc cca gaa gat gtt tat gac aag ggt tgc gtg aaa 1296 Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly Cys Val Lys 420 425 430 gac gta gat gag ggc ttg gag gca gca gaa aga att ggt ttt cca ttg 1344 Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly Phe Pro Leu 435 440

445 atg atc aaa gct tct gaa ggt ggc gga ggg aag gga atc cgg aag gct 1392 Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Lys Ala 450 455 460 gag agt gcg gag gac ttc ccg atc ctt ttc aga caa gta cag agt gag 1440 Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val Gln Ser Glu 465 470 475 480 atc cca ggc tcg ccc atc ttt ctc atg aag ctg gcc cag cac gcc cgt 1488 Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln His Ala Arg 485 490 495 cac ctg gaa gtt cag atc ctc gct gac cag tat ggg aat gct gtg tct 1536 His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser 500 505 510 ctg ttt ggt cgc gac tgc tcc atc cag cgg cgg cat cag aag atc gtt 1584 Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Val 515 520 525 gag gaa gca ccg gcc acc atc gcc ccg ctg gcc ata ttc gag ttc atg 1632 Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe Glu Phe Met 530 535 540 gag cag tgt gcc atc cgc ctg gcc aag acc gtg ggc tat gtg agt gca 1680 Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr Val Ser Ala 545 550 555 560 ggg aca gtg gaa tac ctc tat agt cag gat ggc agc ttc cac ttc ttg 1728 Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu 565 570 575 gag ctg aat cct cgc ttg cag gtg gaa cat ccc tgc aca gaa atg att 1776 Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile 580 585 590 gct gat gtt aat ctg ccg gcc gcc cag cta cag atc gcc atg ggc gtg 1824 Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val 595 600 605 cca ctg cac cgg ctg aag gat atc cgg ctt ctg tat gga gag tca cca 1872 Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro 610 615 620 tgg gga gtg act ccc att tct ttt gaa acc ccc tca aac cct ccc ctc 1920 Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn Pro Pro Leu 625 630 635 640 gcc cga ggc cac gtc att gcc gcc aga atc acc agc gaa aac cca gac 1968 Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp 645 650 655 gag ggt ttt aag ccg agc tcc ggg act gtc cag gaa ctg aat ttc cgg 2016 Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg 660 665 670 agc agc aag aac gtg tgg ggt tac ttc agc gtg gcc gct act gga ggc 2064 Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Thr Gly Gly 675 680 685 ctg cac gag ttt gcg gat tcc caa ttt ggg cac tgc ttc tcc tgg gga 2112 Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe Ser Trp Gly 690 695 700 gag aac cgg gaa gag gcc att tcg aac atg gtg gtg gct ttg aag gaa 2160 Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu 705 710 715 720 ctg tcc atc cga ggc gac ttt agg act acc gtg gaa tac ctc att aac 2208 Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Ile Asn 725 730 735 ctc ctg gag acc gag agc ttc cag aac aac gac atc gac acc ggg tgg 2256 Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp Thr Gly Trp 740 745 750 ttg gac tac ctc att gct gag aaa gtg cag gcg gag aaa ccg gat atc 2304 Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys Pro Asp Ile 755 760 765 atg ctt ggg gtg gta tgc ggg gcc ttg aac gtg gcc gat gcg atg ttc 2352 Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp Ala Met Phe 770 775 780 aga acg tgc atg aca gat ttc tta cac tcc ctg gaa agg ggc cag gtc 2400 Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg Gly Gln Val 785 790 795 800 ctc cca gcg gat tca cta ctg aac ctc gta gat gtg gaa tta att tac 2448 Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu Leu Ile Tyr 805 810 815 gga ggt gtt aag tac att ctc aag gtg gcc cgg cag tct ctg acc atg 2496 Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser Leu Thr Met 820 825 830 ttc gtt ctc atc atg aat ggc tgc cac atc gag att gat gcc cac cgg 2544 Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg 835 840 845 ctg aat gat ggg ggg ctc ctg ctc tcc tac aat ggg aac agc tac acc 2592 Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn Ser Tyr Thr 850 855 860 acc tac atg aag gaa gag gtt gac agt tac cga att acc atc ggc aat 2640 Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn 865 870 875 880 aag acg tgt gtg ttt gag aag gag aac gat cct aca gtc ctg aga tcc 2688 Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser 885 890 895 ccc tcg gct ggg aag ctg aca cag tac aca gtg gag gat ggg ggc cac 2736 Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp Gly Gly His 900 905 910 gtt gag gct ggg agc agc tac gct gag atg gag gtg atg aag atg atc 2784 Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile 915 920 925 atg acc ctg aac gtt cag gaa aga ggc cgg gtg aag tac atc aag cgt 2832 Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr Ile Lys Arg 930 935 940 cca ggt gcc gtg ctg gaa gca ggc tgc gtg gtg gcc agg ctg gag ctc 2880 Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg Leu Glu Leu 945 950 955 960 gat gac cct tct aaa gtc cac ccg gct gaa ccg ttc aca gga gaa ctc 2928 Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr Gly Glu Leu 965 970 975 cct gcc cag cag aca ctg ccc atc ctc gga gag aaa ctg cac cag gtc 2976 Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu His Gln Val 980 985 990 ttc cac agc gtc ctg gaa aac ctc acc aac gtc atg agt ggc ttt tgt 3024 Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser Gly Phe Cys 995 1000 1005 ctg cca gag ccc gtt ttt agc ata aag ctg aag gag tgg gtg cag 3069 Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu Trp Val Gln 1010 1015 1020 aag ctc atg atg acc ctc cgg cac ccg tca ctg ccg ctg ctg gag 3114 Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu 1025 1030 1035 ctg cag gag atc atg acc agc gtg gca ggc cgc atc ccc gcc cct 3159 Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile Pro Ala Pro 1040 1045 1050 gtg gag aag tct gtc cgc agg gtg atg gcc cag tat gcc agc aac 3204 Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr Ala Ser Asn 1055 1060 1065 atc acc tcg gtg ctg tgc cag ttc ccc agc cag cag ata gcc acc 3249 Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr 1070 1075 1080 atc ctg gac tgc cat gca gcc acc ctg cag cgg aag gct gat cga 3294 Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Ala Asp Arg 1085 1090 1095 gag gtc ttc ttc atc aac acc cag agc atc gtg cag ttg gtc cag 3339 Glu Val Phe Phe Ile Asn Thr Gln Ser Ile Val Gln Leu Val Gln 1100 1105 1110 aga tac cgc agc ggg atc cgc ggc tat atg aaa aca gtg gtg ttg 3384 Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr Val Val Leu 1115 1120 1125 gat ctc ctg aga aga tac ttg cgt gtt gag cac cat ttt cag caa 3429 Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His Phe Gln Gln 1130 1135 1140 gcc cac tac gac aag tgt gtg ata aac ctc agg gag cag ttc aag 3474 Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys 1145 1150 1155 cca gac atg tcc cag gtg ctg gac tgc atc ttc tcc cac gca cag 3519 Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser His Ala Gln 1160 1165 1170 gtg gcc aag aag aac cag ctg gtg atc atg ttg atc gat gag ctg 3564 Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile Asp Glu Leu 1175 1180 1185 tgt ggc cca gac cct tcc ctg tcg gac gag ctg atc tcc atc ctc 3609 Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile Ser Ile Leu 1190 1195 1200 aac gag ctc act cag ctg agc aaa agc gag cac tgc aaa gtg gcc 3654 Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys Lys Val Ala 1205 1210 1215 ctc aga gcc cgg cag atc ctg att gcc tcc cac ctc ccc tcc tac 3699 Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu Pro Ser Tyr 1220 1225 1230 gag ctg cgg cat aac cag gtg gag tcc att ttc ctg tct gcc att 3744 Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu Ser Ala Ile 1235 1240 1245 gac atg tac ggc cac cag ttc tgc ccc gag aac ctc aag aaa tta 3789 Asp Met Tyr Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu 1250 1255 1260 ata ctt tcg gaa aca acc atc ttc gac gtc ctg cct act ttc ttc 3834 Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe 1265 1270 1275 tat cac gca aac aaa gtc gtg tgc atg gcg tcc ttg gag gtt tac 3879 Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr 1280 1285 1290 gtg cgg agg ggc tac atc gcc tat gag tta aac agc ctg cag cac 3924 Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His 1295 1300 1305 cgg cag ctc ccg gac ggc acc tgc gtg gta gaa ttc cag ttc atg 3969 Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met 1310 1315 1320 ctg ccg tcc tcc cac cca aac cgg atg acc gtg ccc atc agc atc 4014 Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro Ile Ser Ile 1325 1330 1335 acc aac cct gac ctg ctg agg cac agc aca gag ctc ttc atg gac 4059 Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu Phe Met Asp 1340 1345 1350 agc ggc ttc tcc cca ctg tgc cag cgc atg gga gcc atg gta gcc 4104 Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 ttc agg aga ttc gag gac ttc acc aga aat ttt gat gaa gtc atc 4149 Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 tct tgc ttc gcc aac gtg ccc aaa gac acc ccc ctc ttc agc gag 4194 Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu Phe Ser Glu 1385 1390 1395 gcc cgc acc tcc cta tac tcc gag gat gac tgc aag agc ctc aga 4239 Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys Ser Leu Arg 1400 1405 1410 gaa gag ccc atc cac att ctg aat gtg tcc atc cag tgt gca gac 4284 Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln Cys Ala Asp 1415 1420 1425 cac ctg gag gat gag gca ctg gtg ccg att tta cgg aca ttc gta 4329 His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg Thr Phe Val 1430 1435 1440 cag tcc aag aaa aat atc ctt gtg gat tat gga ctc cga cga atc 4374 Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 aca ttc ttg att gcc caa gag aaa gaa ttt ccc aag ttt ttc aca 4419 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 ttc aga gca aga gat gag ttt gca gaa gat cgc att tac cgt cac 4464 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 ttg gaa cct gcc ctg gcc ttc cag ctg gaa ctt aac cgg atg cgt 4509 Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn Arg Met Arg 1490 1495 1500 aac ttc gat ctg acc gcc gtg ccc tgt gcc aac cac aag atg cac 4554 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 ctt tac ctg ggt gct gcc aag gtg aag gaa ggt gtg gaa gtg acg 4599 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Val Glu Val Thr 1520 1525 1530 gac cat agg ttc ttc atc cgc gcc atc atc agg cac tct gac ctg 4644 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 atc aca aag gaa gcc tcc ttc gaa tac ctg cag aac gag ggt gag 4689 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 cgg ctg ctc ctg gag gcc atg gac gag ctg gag gtg gcg ttc aat 4734 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 aac acc agc gtg cgc acc gac tgc aac cac atc ttc ctc aac ttc 4779 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 gtg ccc act gtc atc atg gac ccc ttc aag atc gag gag tcc gtg 4824 Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu Glu Ser Val 1595 1600 1605 cgc tac atg gtt atg cgc tac ggc agc cgg ctg tgg aaa ctc cgt 4869 Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 gtg cta cag gct gag gtc aag atc aac atc cgc cag acc acc acc 4914 Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln Thr Thr Thr 1625 1630 1635 ggc agt gcc gtt ccc atc cgc ctg ttc atc acc aat gag tcg ggc 4959 Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 tac tac ctg gac atc agc ctc tac aaa gaa gtg act gac tcc aga 5004 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 tct gga aat atc atg ttt cac tcc ttc ggc aac aag caa ggg ccc 5049 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Pro 1670 1675 1680 cag cac ggg atg ctg atc aat act ccc tac gtc acc aag gat ctg 5094 Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 ctc cag gcc aag cga ttc cag gcc cag acc ctg gga acc acc tac 5139 Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly Thr Thr Tyr 1700 1705 1710 atc tat gac ttc ccg gaa atg ttc agg cag gct ctc ttt aaa ctg 5184 Ile Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 tgg ggc tcc cca gac aag tat ccc aaa gac atc ctg aca tac act 5229 Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu Thr Tyr Thr 1730 1735 1740 gaa tta gtg ttg gac tct cag ggc cag ctg gtg gag atg aac cga 5274 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 ctt cct ggt gga aat gag gtg ggc atg gtg gcc ttc aaa atg agg 5319 Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe Lys Met Arg 1760 1765 1770 ttt aag acc cag gag tac ccg gaa gga cgg gat gtg atc gtc atc 5364 Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val Ile Val Ile 1775 1780 1785 ggc aat gac atc acc ttt cgc att gga tcc ttt ggc cct gga gag 5409 Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly Pro Gly Glu 1790 1795 1800 gac ctt ctg tac ctg cgg gca tcc gag atg gcc cgg gca gag ggc 5454 Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Ala Glu Gly 1805 1810 1815 att ccc aaa att tac gtg gca gcc aac agt ggc gcc cgt att ggc 5499 Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala Arg Ile Gly 1820 1825 1830 atg gca gag gag atc aaa cac atg ttc cac gtg gct tgg gtg gac 5544 Met Ala Glu Glu Ile Lys His Met Phe His Val Ala Trp Val Asp 1835 1840 1845 cca gaa gac ccc cac aaa gga ttt aaa tac ctg tac ctg act ccc 5589 Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr Leu Thr Pro 1850 1855 1860 caa gac tac acc aga atc agc tcc ctg aac tcc gtc cac tgt aaa 5634 Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val His Cys Lys 1865 1870 1875 cac atc gag gaa gga gga gag tcc aga tac atg atc acg gat atc 5679 His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile Thr Asp Ile 1880 1885 1890 atc ggg aag gat gat ggc ttg ggc gtg gag aat ctg agg ggc tca 5724 Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu Arg Gly Ser 1895 1900 1905 ggc atg att gct ggg gag tcc tct ctg gct tac gaa gag atc gtc 5769 Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu Glu Ile Val 1910 1915 1920 acc att agc ttg gtg acc tgc cga gcc att ggg att ggg gcc tac 5814 Thr Ile Ser Leu Val Thr Cys Arg Ala

Ile Gly Ile Gly Ala Tyr 1925 1930 1935 ttg gtg agg ctg ggc cag cga gtg atc cag gtg gag aat tcc cac 5859 Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser His 1940 1945 1950 atc atc ctc aca gga gca agt gct ctc aac aag gtc ctg gga aga 5904 Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val Leu Gly Arg 1955 1960 1965 gag gtc tac aca tcc aac aac cag ctg ggt ggc gtt cag atc atg 5949 Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile Met 1970 1975 1980 cat tac aat ggt gtc tcc cac atc acc gtg cca gat gac ttt gag 5994 His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp Asp Phe Glu 1985 1990 1995 ggg gtt tat acc atc ctg gag tgg ctg tcc tat atg cca aag gat 6039 Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met Pro Lys Asp 2000 2005 2010 aat cac agc cct gtc cct atc atc aca ccc act gac ccc att gac 6084 Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp Pro Ile Asp 2015 2020 2025 aga gaa att gaa ttc ctc cca tcc aga gct ccc tac gac ccc cgg 6129 Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr Asp Pro Arg 2030 2035 2040 tgg atg ctt gca gga agg cct cac cca act ctg aag gga acg tgg 6174 Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr Trp 2045 2050 2055 cag agc gga ttc ttt gac cac ggc agt ttc aag gaa atc atg gca 6219 Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met Ala 2060 2065 2070 ccc tgg gcg cag acc gtg gtg aca gga cga gca agg ctt ggg ggg 6264 Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly Gly 2075 2080 2085 att ccc gtg gga gtg att gct gtg gag aca cgg act gtg gag gtg 6309 Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr Val Glu Val 2090 2095 2100 gca gtc cct gca gac cct gcc aac ctg gat tct gag gcc aag ata 6354 Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu Ala Lys Ile 2105 2110 2115 att cag cag gca gga cag gtg tgg ttc cca gac tca gcc tac aaa 6399 Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Tyr Lys 2120 2125 2130 acc gcc cag gcc gtc aag gac ttc aac cgg gag aag ttg ccc ctg 6444 Thr Ala Gln Ala Val Lys Asp Phe Asn Arg Glu Lys Leu Pro Leu 2135 2140 2145 atg atc ttt gcc aac tgg agg ggg ttc tcc ggt ggc atg aaa gac 6489 Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys Asp 2150 2155 2160 atg tat gac cag gtg ctg aag ttt gga gcc tac atc gtg gac ggc 6534 Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile Val Asp Gly 2165 2170 2175 ctt aga caa tac aaa cag ccc atc ctg atc tat atc ccg ccc tat 6579 Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile Pro Pro Tyr 2180 2185 2190 gcg gag ctc cgg gga ggc tcc tgg gtg gtc ata gat gcc acc atc 6624 Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp Ala Thr Ile 2195 2200 2205 aac ccg ctg tgc ata gaa atg tat gca gac aaa gag agc agg ggt 6669 Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg Gly 2210 2215 2220 ggt gtt ctg gaa cca gag ggg aca gtg gag att aag ttc cga aag 6714 Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg Lys 2225 2230 2235 aaa gat ctg ata aag tcc atg aga agg atc gat cca gct tac aag 6759 Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro Ala Tyr Lys 2240 2245 2250 aag ctc atg gaa cag cta ggg gaa cct gat ctc tcc gac aag gac 6804 Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser Asp Lys Asp 2255 2260 2265 cga aag gac ctg gag ggc cgg cta aag gct cgc gag gac ctg ctg 6849 Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu Asp Leu Leu 2270 2275 2280 ctc ccc atc tac cac cag gtg gcg gtg cag ttc gcc gac ttc cat 6894 Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Phe His 2285 2290 2295 gac aca ccc ggc cgg atg ctg gag aag ggc gtc ata tct gac atc 6939 Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile Ser Asp Ile 2300 2305 2310 ctg gag tgg aag acc gca cgc acc ttc ctg tat tgg cgt ctg cgc 6984 Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp Arg Leu Arg 2315 2320 2325 cgc ctc ctc ctg gag gac cag gtc aag cag gag atc ctg cag gcc 7029 Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile Leu Gln Ala 2330 2335 2340 agc ggg gag ctg agt cac gtg cat atc cag tcc atg ctg cgt cgc 7074 Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met Leu Arg Arg 2345 2350 2355 tgg ttc gtg gag acg gag ggg gct gtc aag gcc tac ttg tgg gac 7119 Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp Asp 2360 2365 2370 aac aac cag gtg gtt gtg cag tgg ctg gaa cag cac tgg cag gca 7164 Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Gln Ala 2375 2380 2385 ggg gat ggc ccg cgc tcc acc atc cgt gag aac atc acg tac ctg 7209 Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile Thr Tyr Leu 2390 2395 2400 aag cac gac tct gtc ctc aag acc atc cga ggc ctg gtt gaa gaa 7254 Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu Val Glu Glu 2405 2410 2415 aac ccc gag gtg gcc gtg gac tgt gtg ata tac ctg agc cag cac 7299 Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu Ser Gln His 2420 2425 2430 atc agc cca gct gag cgg gcg cag gtc gtt cac ctg ctg tct acc 7344 Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu Leu Ser Thr 2435 2440 2445 atg gac agc ccg gcc tcc acc tga 7368 Met Asp Ser Pro Ala Ser Thr 2450 2455 4 2455 PRT Homo sapiens 4 Met Val Leu Leu Leu Cys Leu Ser Cys Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly 245 250 255 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Gly Trp Gly His Ala Ser 340 345 350 Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly Val Ala Phe 355 360 365 Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp Lys Ile Ala 370 375 380 Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu Pro Trp Ser 385 390 395 400 Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu Gln Gln Gly 405 410 415 Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly Cys Val Lys 420 425 430 Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly Phe Pro Leu 435 440 445 Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Lys Ala 450 455 460 Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val Gln Ser Glu 465 470 475 480 Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln His Ala Arg 485 490 495 His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser 500 505 510 Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Val 515 520 525 Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe Glu Phe Met 530 535 540 Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr Val Ser Ala 545 550 555 560 Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu 565 570 575 Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile 580 585 590 Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val 595 600 605 Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro 610 615 620 Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn Pro Pro Leu 625 630 635 640 Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp 645 650 655 Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg 660 665 670 Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Thr Gly Gly 675 680 685 Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe Ser Trp Gly 690 695 700 Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu 705 710 715 720 Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Ile Asn 725 730 735 Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp Thr Gly Trp 740 745 750 Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys Pro Asp Ile 755 760 765 Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp Ala Met Phe 770 775 780 Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg Gly Gln Val 785 790 795 800 Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu Leu Ile Tyr 805 810 815 Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser Leu Thr Met 820 825 830 Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg 835 840 845 Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn Ser Tyr Thr 850 855 860 Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn 865 870 875 880 Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser 885 890 895 Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp Gly Gly His 900 905 910 Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile 915 920 925 Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr Ile Lys Arg 930 935 940 Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg Leu Glu Leu 945 950 955 960 Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr Gly Glu Leu 965 970 975 Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu His Gln Val 980 985 990 Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser Gly Phe Cys 995 1000 1005 Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu Trp Val Gln 1010 1015 1020 Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu 1025 1030 1035 Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile Pro Ala Pro 1040 1045 1050 Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr Ala Ser Asn 1055 1060 1065 Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr 1070 1075 1080 Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Ala Asp Arg 1085 1090 1095 Glu Val Phe Phe Ile Asn Thr Gln Ser Ile Val Gln Leu Val Gln 1100 1105 1110 Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr Val Val Leu 1115 1120 1125 Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His Phe Gln Gln 1130 1135 1140 Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys 1145 1150 1155 Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser His Ala Gln 1160 1165 1170 Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile Asp Glu Leu 1175 1180 1185 Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile Ser Ile Leu 1190 1195 1200 Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys Lys Val Ala 1205 1210 1215 Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu Pro Ser Tyr 1220 1225 1230 Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu Ser Ala Ile 1235 1240 1245 Asp Met Tyr Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu 1250 1255 1260 Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe 1265 1270 1275 Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr 1280 1285 1290 Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His 1295 1300 1305 Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met 1310 1315 1320 Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro Ile Ser Ile 1325 1330 1335 Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu Phe Met Asp 1340 1345 1350 Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu Phe Ser Glu 1385 1390 1395 Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys Ser Leu Arg 1400 1405 1410 Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln Cys Ala Asp 1415 1420 1425 His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg Thr Phe Val 1430 1435 1440 Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn Arg Met Arg 1490 1495 1500 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Val Glu Val Thr 1520 1525 1530 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 Ile Thr Lys Glu Ala Ser

Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu Glu Ser Val 1595 1600 1605 Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln Thr Thr Thr 1625 1630 1635 Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Pro 1670 1675 1680 Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly Thr Thr Tyr 1700 1705 1710 Ile Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu Thr Tyr Thr 1730 1735 1740 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe Lys Met Arg 1760 1765 1770 Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val Ile Val Ile 1775 1780 1785 Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly Pro Gly Glu 1790 1795 1800 Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Ala Glu Gly 1805 1810 1815 Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala Arg Ile Gly 1820 1825 1830 Met Ala Glu Glu Ile Lys His Met Phe His Val Ala Trp Val Asp 1835 1840 1845 Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr Leu Thr Pro 1850 1855 1860 Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val His Cys Lys 1865 1870 1875 His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile Thr Asp Ile 1880 1885 1890 Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu Arg Gly Ser 1895 1900 1905 Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu Glu Ile Val 1910 1915 1920 Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile Gly Ala Tyr 1925 1930 1935 Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser His 1940 1945 1950 Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val Leu Gly Arg 1955 1960 1965 Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile Met 1970 1975 1980 His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp Asp Phe Glu 1985 1990 1995 Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met Pro Lys Asp 2000 2005 2010 Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp Pro Ile Asp 2015 2020 2025 Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr Asp Pro Arg 2030 2035 2040 Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr Trp 2045 2050 2055 Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met Ala 2060 2065 2070 Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly Gly 2075 2080 2085 Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr Val Glu Val 2090 2095 2100 Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu Ala Lys Ile 2105 2110 2115 Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Tyr Lys 2120 2125 2130 Thr Ala Gln Ala Val Lys Asp Phe Asn Arg Glu Lys Leu Pro Leu 2135 2140 2145 Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys Asp 2150 2155 2160 Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile Val Asp Gly 2165 2170 2175 Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile Pro Pro Tyr 2180 2185 2190 Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp Ala Thr Ile 2195 2200 2205 Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg Gly 2210 2215 2220 Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg Lys 2225 2230 2235 Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro Ala Tyr Lys 2240 2245 2250 Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser Asp Lys Asp 2255 2260 2265 Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu Asp Leu Leu 2270 2275 2280 Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Phe His 2285 2290 2295 Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile Ser Asp Ile 2300 2305 2310 Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp Arg Leu Arg 2315 2320 2325 Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile Leu Gln Ala 2330 2335 2340 Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met Leu Arg Arg 2345 2350 2355 Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp Asp 2360 2365 2370 Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Gln Ala 2375 2380 2385 Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile Thr Tyr Leu 2390 2395 2400 Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu Val Glu Glu 2405 2410 2415 Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu Ser Gln His 2420 2425 2430 Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu Leu Ser Thr 2435 2440 2445 Met Asp Ser Pro Ala Ser Thr 2450 2455 5 7377 DNA Homo sapiens CDS (1)..(7377) 5 atg gtc ttg ctt ctt tgt cta tct cgt ctg att ttc tcc tgt ctg acc 48 Met Val Leu Leu Leu Cys Leu Ser Arg Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 ttt tcc tgg tta aaa atc tgg ggg aaa atg acg gac tcc aag ccg atc 96 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 acc aag agt aaa tca gaa gca aac ctc atc ccg agc cag gag ccc ttt 144 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 cca gcc tct gat aac tca ggg gag aca ccg cag aga aat ggg gag ggc 192 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 cac act ctg ccc aag aca ccc agc cag gcc gag cca gcc tcc cac aaa 240 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 ggc ccc aaa gat gcc ggt cgg cgg aga aac tcc cta cca ccc tcc cac 288 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 cag aag ccc cca aga aac ccc ctt tct tcc agt gac gca gca ccc tcc 336 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 cca gag ctt caa gcc aac ggg act ggg aca caa ggt ctg gag gcc aca 384 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 gat acc aat ggc ctg tcc tcc tca gcc agg ccc cag ggc cag caa gct 432 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 ggc tcc ccc tcc aaa gaa gac aag aag cag gca aac atc aag agg cag 480 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 ctg atg acc aac ttc atc ctg ggc tct ttt gat gac tac tcc tct gac 528 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 gag gac tct gtt gct ggc tca tct cgt gag tct acc cgg aag ggc agc 576 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 cgg gcc agc ttg ggg gcc ctg tcc cta gag gct tat ctg acc aca ggt 624 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 gaa gct gag acc cgc gtc ccc act atg agg ccg agc atg tcg gga ctc 672 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 cac ctg gtg aag agg gga cgg gaa cac aag aag ctg gac ctg cac aga 720 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 gac ttt acc gtg gct tct ccc gct gag ttt gtc aca cgc tat ggg ggg 768 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Tyr Gly Gly 245 250 255 gat cgg gtc atc gag aag gtg ctt att gcc aac aac ggg att gcc gcc 816 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 gtg aag tgc atg cgc tcc atc cgc agg tgg gcc tat gag atg ttc cgc 864 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 aac gag cgg gcc atc cgg ttt gtt gtg atg gtg acc ccc gag gac ctt 912 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 aag gcc aac gca gag tac atc aag atg gcg gat cat tac gtc ccc gtc 960 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 cca gga ggg ccc aat aac aac aac tat gcc aac gtg gag ctg att gtg 1008 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 gac att gcc aag aga atc ccc gtg cgg gcg gtg tgg gct ggc tgg ggc 1056 Asp Ile Ala Lys Arg Ile Pro Val Arg Ala Val Trp Ala Gly Trp Gly 340 345 350 cat gct tca gaa aac cct aaa ctt ccg gag ctg ctg tgc aag aat gga 1104 His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 355 360 365 gtt gct ttc tta ggc cct ccc agt gag gcc atg tgg gcc tta gga gat 1152 Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 370 375 380 aag atc gcc tcc acc gtt gtc gcc cag acg cta cag gtc cca acc ctg 1200 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 ccc tgg agt gga agc ggc ctg aca gtg gag tgg aca gaa gat gat ctg 1248 Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 cag cag gga aaa aga atc agt gtc cca gaa gat gtt tat gac aag ggt 1296 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 tgc gtg aaa gac gta gat gag ggc ttg gag gca gca gaa aga att ggt 1344 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 ttt cca ttg atg atc aaa gct tct gaa ggt ggc ggg ggg aag gga atc 1392 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 cgg aag gct gag agt gcg gag gac ttc ccg atc ctt ttc aga caa gta 1440 Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 cag agt gag atc cca ggc tcg ccc atc ttt ctc atg aag ctg gcc cag 1488 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 cac gcc cgt cac ctg gaa gtt cag atc ctc gct gac cag tat ggg aat 1536 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 gct gtg tct ctg ttt ggt cgc gac tgc tcc atc cag cgg cgg cat cag 1584 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 aag atc gtt gag gaa gca ccg gcc acc atc gcc ccg ctg gcc ata ttc 1632 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 gag ttc atg gag cag tgt gcc atc cgc ctg gcc aag acc gtg ggc tat 1680 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 gtg agt gca ggg gca gtg gaa tac ctc tat agt cag gat ggc agc ttc 1728 Val Ser Ala Gly Ala Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 cac ttc ttg gag ctg aat cct cgc ttg cag gtg gaa cat ccc tgc aca 1776 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 gaa atg att gct gac gtt aat ctg ccg gcc gcc cag cta cag atc gcc 1824 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 atg ggc gtg cca ctg cac cgg ctg aag gat atc cgg ctt ctg tat gga 1872 Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 gag tca cca tgg gga gtg act ccc att tct ttt gaa acc ccc tca aac 1920 Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 625 630 635 640 cct ccc ctc gcc cga ggc cac gtc att gcc gcc aga atc acc agc gaa 1968 Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu 645 650 655 aac cca gac gag ggt ttt aag ccg agc tcc ggg act gtc cag gaa ctg 2016 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 aat ttc cgg agc agc aag aac gtg tgg ggt tac ttc agc gtg gcc gct 2064 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 675 680 685 act gga ggc ctg cac gag ttt gcg gat tcc caa ttt ggg cac tgc ttc 2112 Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 690 695 700 tcc tgg gga gag aac cgg gaa gag gcc att tcg aac atg gtg gtg gct 2160 Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 ttg aag gaa ctg tcc atc cga ggt gac ttt agg act acc gtg gaa tac 2208 Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 ctc att aac ctc ctg gag acc gag agc ttc cag aac aac gac atc gac 2256 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp 740 745 750 acc ggg tgg ttg gac tac ctc att gct gag aaa gtg cag gcg gag aaa 2304 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 755 760 765 ccg gat atc atg ctt ggg gtg gta tgc ggg gcc ttg aac gtg gcc gat 2352 Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 770 775 780 gcg atg ttc aga acg tgc atg aca gat ttc tta cac tcc ctg gaa agg 2400 Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg 785 790 795 800 ggc cag gtc ctc cca gcg gat tca cta ctg aac ctt gta gat gtg gaa 2448 Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 805 810 815 tta att tac gga ggt gtt aag tac att ctc aag gtg gcc cgg cag tct 2496 Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 820 825 830 ctg acc atg ttc gtt ctc atc atg tat ggc tgc cac atc gag att gat 2544 Leu Thr Met Phe Val Leu Ile Met Tyr Gly Cys His Ile Glu Ile Asp 835 840 845 gcc cac cgg ctg aat gat ggg ggg ctc ctg ctc tcc tac aat ggg aac 2592 Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 850 855 860 agc tac acc acc tac atg aag gaa gag gtt gac agt tac cga att acc 2640 Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 865 870 875 880 atc ggc aat aag acg tgt gtg ttt gag aag gag aac gat cct aca gtc 2688 Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 885 890 895 ctg aga tcc ccc tcg gct ggg aag ctg aca cag tac aca gtg gag gat 2736 Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 900 905 910 ggg ggc cac gtt gag gct ggg agc agc tac gct gag atg gag gtg atg 2784 Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 915 920 925 aag atg atc atg acc ctg aac gtt cag gaa aga ggc cgg gtg aag tac 2832 Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 930 935 940 atc aag

cgt cca ggt gcc gtg ctg gaa gca ggc tgc gtg gtg gcc agg 2880 Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 945 950 955 960 ctg gag ctc gat gac cct tct aaa gtc cac ccg gct gaa ccg ttc aca 2928 Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 965 970 975 gga gaa ctc cct gcc cag cag aca ctg ccc atc ctc gga gag aaa ctg 2976 Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 980 985 990 cac cag gtc ttc cac agc gtc ctg gaa aac ctc acc aac gtc atg agt 3024 His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser 995 1000 1005 ggc ttt tgt ctg cca gag ccc gtt ttt agc ata aag ctg aag gag 3069 Gly Phe Cys Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu 1010 1015 1020 tgg gtg cag aag ctc atg atg acc ctc cgg cac ccg tca ctg ccg 3114 Trp Val Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro 1025 1030 1035 ctg ctg gag ctg cag gag atc atg acc agc gtg gca ggc cgc atc 3159 Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile 1040 1045 1050 ccc gcc cct gtg gag aag tct gtc cgc agg gtg atg gcc cag tat 3204 Pro Ala Pro Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr 1055 1060 1065 gcc agc aac atc acc tcg gtg ctg tgc cag ttc ccc agc cag cag 3249 Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln 1070 1075 1080 ata gcc acc atc ctg gac tgc cat gca gcc acc ctg cag cgg aag 3294 Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys 1085 1090 1095 gct gat cga gag gcc ttc ttc atc aac acc cag agc atc gtg cag 3339 Ala Asp Arg Glu Ala Phe Phe Ile Asn Thr Gln Ser Ile Val Gln 1100 1105 1110 ttg gtc cag aga tac cgc agc ggg atc cgc ggc tat atg aaa aca 3384 Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr 1115 1120 1125 gtg gtg ttg gat ctc ctg aga aga tac ttg cgt gtt gag cac cat 3429 Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His 1130 1135 1140 ttt cag caa gcc cac tac gac aag tgt gtg ata aac ctc agg gag 3474 Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu 1145 1150 1155 cag ttc aag cca gac atg tcc cag gtg ctg gac tgc atc ttc tcc 3519 Gln Phe Lys Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser 1160 1165 1170 cac gca cag gtg gcc aag aag aac cag ctg gtg atc atg ttg atc 3564 His Ala Gln Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile 1175 1180 1185 gat gag ctg tgt ggc cca gac cct tcc ctg tcg gac gag ctg atc 3609 Asp Glu Leu Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile 1190 1195 1200 tcc atc ctc aac gag ctc act cag ctg agc aaa agc gag cac tgc 3654 Ser Ile Leu Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys 1205 1210 1215 aaa gtg gcc ctc aga gcc cgg cag atc ctg att gcc tcc cac ctc 3699 Lys Val Ala Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu 1220 1225 1230 ccc tcc tac gag ctg cgg cat aac cag gtg gag tcc att ttc ctg 3744 Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu 1235 1240 1245 tct gcc att gac atg tac ggc cac cag ttc cgc ccc gag aac ctc 3789 Ser Ala Ile Asp Met Tyr Gly His Gln Phe Arg Pro Glu Asn Leu 1250 1255 1260 aag aaa tta ata ctt tcg gaa aca acc atc ttc gac gtc ctg cct 3834 Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro 1265 1270 1275 act ttc ttc tat cac gca aac aaa gtc gtg tgc atg gcg tcc ttg 3879 Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu 1280 1285 1290 gag gtt tac gtg cgg agg ggc tac atc gcc tat gag tta aac agc 3924 Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser 1295 1300 1305 ctg cag cac cgg cag ctc ccg gac ggc acc tgc gtg gta gaa ttc 3969 Leu Gln His Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe 1310 1315 1320 cag ttc atg ctg ccg tcc tcc cac cca aac cgg atg acc gtg ccc 4014 Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro 1325 1330 1335 atc agc atc acc aac cct gac ctg ctg agg cac agc aca gag ctc 4059 Ile Ser Ile Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu 1340 1345 1350 ttc atg gac agc ggc ttc tcc cca ctg tgc cag cgc atg gga gcc 4104 Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala 1355 1360 1365 atg gta gcc ttc agg aga ttc gag gac ttc acc aga aat ttt gat 4149 Met Val Ala Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp 1370 1375 1380 gaa gtc atc tct tgc ttc gcc aac gtg ccc aaa gac acc ccc ctc 4194 Glu Val Ile Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu 1385 1390 1395 ttc agc gag gcc cgc acc tcc cta tac tcc gag gat gac tgc aag 4239 Phe Ser Glu Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys 1400 1405 1410 agc ctc aga gaa gag ccc atc cac att ctg aat gtg tcc atc cag 4284 Ser Leu Arg Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln 1415 1420 1425 tgt gca gac cac ctg gag gat gag gca ctg gtg ccg att tta cgg 4329 Cys Ala Asp His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg 1430 1435 1440 aca ttc gta cag tcc aag aaa aat atc ctt gtg gat tat gga ctc 4374 Thr Phe Val Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu 1445 1450 1455 cga cga atc aca ttc ttg att gcc caa gag aaa gaa ttt ccc aag 4419 Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys 1460 1465 1470 ttt ttc aca ttc aga gca aga gat gag ttt gca gaa gat cgc att 4464 Phe Phe Thr Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile 1475 1480 1485 tac cgt cac ttg gaa cct gcc ctg gcc ttc cag ctg gaa ctc aac 4509 Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn 1490 1495 1500 cgg atg cgt aac ttc gat ctg acc gcc gtg ccc tgt gcc aac cac 4554 Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His 1505 1510 1515 aag atg cac ctt tac ctg ggt gtt gcc aag gtg aag gaa ggt gtg 4599 Lys Met His Leu Tyr Leu Gly Val Ala Lys Val Lys Glu Gly Val 1520 1525 1530 gaa gtg acg gac cat agg ttc ttc atc cgc gcc atc atc agg cac 4644 Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His 1535 1540 1545 tct gac ctg atc aca aag gaa gcc tcc ttc gaa tac ctg cag aac 4689 Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn 1550 1555 1560 gag ggt gag cgg ctg ctc ctg gag gcc atg gac gag ctg gag gtg 4734 Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val 1565 1570 1575 gcg ttc aat aac acc agc gtg cgc acc gac tgc aac cac atc ttc 4779 Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe 1580 1585 1590 ctc aac ttc gtg ccc act gtc atc atg gac ccc ttc aag atc gag 4824 Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu 1595 1600 1605 gag tcc gtg cgc tac atg gtt atg cgc tac ggc agc cgg ctg tgg 4869 Glu Ser Val Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp 1610 1615 1620 aaa ctc cgt gtg cta cag gct gag gtc aag atc aac atc cgc cag 4914 Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln 1625 1630 1635 acc acc acc ggc agt gcc gtt ccc atc cgc ctg ttc atc acc aat 4959 Thr Thr Thr Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn 1640 1645 1650 gag tcg ggc tac tac ctg gac atc agc ctc tac aaa gaa gtg act 5004 Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr 1655 1660 1665 gac tcc aga tct gga aat atc atg ttt cac tcc ttc ggc aac aag 5049 Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys 1670 1675 1680 caa ggg ccc cag cac ggg atg ctg atc aat act ccc tac gtc acc 5094 Gln Gly Pro Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr 1685 1690 1695 aag gat ctg ctc cag gcc aag cga ttc cag gcc cag acc ctg gga 5139 Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly 1700 1705 1710 acc acc tac gtc tat gac ttc ccg gaa atg ttc agg cag gct ctc 5184 Thr Thr Tyr Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu 1715 1720 1725 ttt aaa ctg tgg ggc tcc cca gac aag tat ccc aaa gac atc ctg 5229 Phe Lys Leu Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu 1730 1735 1740 aca tac act gaa tta gtg ttg gac tct cag ggc cag ctg gtg gag 5274 Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu 1745 1750 1755 atg aac cga ctt cct ggt gga aat gag gtg ggc atg gtg gcc ttc 5319 Met Asn Arg Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe 1760 1765 1770 aaa atg agg ttt aag acc cag gag tac ccg gaa gga cgg gat gtg 5364 Lys Met Arg Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val 1775 1780 1785 atc gtc atc ggc aat gac atc acc ttt cgc att gga tcc ttt ggc 5409 Ile Val Ile Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly 1790 1795 1800 cct gga gag gac ctt ctg tac ctg cgg gca tcc gag atg gcc cgg 5454 Pro Gly Glu Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg 1805 1810 1815 gca gag ggc att ccc aaa att tac gtg gca gcc aac agt ggc gcc 5499 Ala Glu Gly Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala 1820 1825 1830 cgt att ggc atg gca gag gag atc aaa cac atg ttc cac gtg gct 5544 Arg Ile Gly Met Ala Glu Glu Ile Lys His Met Phe His Val Ala 1835 1840 1845 tgg gtg gac cca gaa gac ccc cac aaa gga ttt aaa tac ctg tac 5589 Trp Val Asp Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr 1850 1855 1860 ctg act ccc caa gac tac acc aga atc agc tcc ctg aac tcc gtc 5634 Leu Thr Pro Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val 1865 1870 1875 cac tgt aaa cac atc gag gaa gga gga gag tcc aga tac atg atc 5679 His Cys Lys His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile 1880 1885 1890 acg gat atc atc ggg aag gat gat ggc ttg ggc gtg gag aat ctg 5724 Thr Asp Ile Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu 1895 1900 1905 agg ggc tca ggc atg att gct ggg gag tcc tct ctg gct tac gaa 5769 Arg Gly Ser Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu 1910 1915 1920 gag atc gtc acc att agc ttg gtg acc tgc cga gcc att ggg att 5814 Glu Ile Val Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile 1925 1930 1935 ggg gcc tac ttg gtg agg ctg ggc cag cga gtg atc cag gtg gag 5859 Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu 1940 1945 1950 aat tcc cac atc atc ctc aca gga gca agt gct ctc aac aag gtc 5904 Asn Ser His Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val 1955 1960 1965 ctg gga aga gag gtc tac aca tcc aac aac cag ctg ggt ggc gtt 5949 Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val 1970 1975 1980 cag atc atg cat tac aat ggt gtc tcc cac atc acc gtg cca gat 5994 Gln Ile Met His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp 1985 1990 1995 gac ttt gag ggg gtt tat acc atc ctg gag tgg ctg tcc tat atg 6039 Asp Phe Glu Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met 2000 2005 2010 cca aag gat aat cac agc cct gtc cct atc atc aca ccc act gac 6084 Pro Lys Asp Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp 2015 2020 2025 ccc att gac aga gaa att gaa ttc ctc cca tcc aga gct ccc tac 6129 Pro Ile Asp Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr 2030 2035 2040 gac ccc cgg tgg atg ctt gca gga agg cct cac cca act ctg aag 6174 Asp Pro Arg Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys 2045 2050 2055 gga acg tgg cag agc gga ttc ttt gac cac ggc agt ttc aag gaa 6219 Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu 2060 2065 2070 atc atg gca ccc tgg gcg cag acc gtg gtg aca gga cga gca agg 6264 Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg 2075 2080 2085 ctt ggg ggg att ccc gtg gga gtg att gct gtg gag aca cgg act 6309 Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr 2090 2095 2100 gtg gag gtg gca gtc cct gca gac cct gcc aac ctg gat tct gag 6354 Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu 2105 2110 2115 gcc aag ata att cag cag gca gga cag gtg tgg ttc cca gac tca 6399 Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser 2120 2125 2130 gcc tac aaa acc gcc cag gcc atc aag gac ttc aac cgg gag aag 6444 Ala Tyr Lys Thr Ala Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys 2135 2140 2145 ttg ccc ctg atg atc ttt gcc aac tgg agg ggg ttc tcc ggt ggc 6489 Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly 2150 2155 2160 atg aaa gac atg tat gac cag gtg ctg aag ttt gga gcc tac atc 6534 Met Lys Asp Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile 2165 2170 2175 gtg gac ggc ctt aga caa tac aaa cag ccc atc ctg atc tat atc 6579 Val Asp Gly Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile 2180 2185 2190 ccg ccc tat gcg gag ctc cgg gga ggc tcc tgg gtg gtc ata gat 6624 Pro Pro Tyr Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp 2195 2200 2205 gcc acc atc aac ccg ctg tgc ata gaa atg tat gca gac aaa gag 6669 Ala Thr Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu 2210 2215 2220 agc agg ggt ggt gtt ctg gaa cca gag ggg aca gtg gag att aag 6714 Ser Arg Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys 2225 2230 2235 ttc cga aag aaa gat ctg ata aag tcc atg aga agg atc gat cca 6759 Phe Arg Lys Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro 2240 2245 2250 gct tac aag aag ctc atg gaa cag cta ggg gaa cct gat ctc tcc 6804 Ala Tyr Lys Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser 2255 2260 2265 gac aag gac cga aag gac ctg gag ggc cgg cta aag gct cgc gag 6849 Asp Lys Asp Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu 2270 2275 2280 gac ctg ctg ctc ccc atc tac cac cag gtg gcg gtg cag ttc gcc 6894 Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala 2285 2290 2295 gac ttc cat gac aca ccc ggc cgg atg ctg gag aag ggc gtc ata 6939 Asp Phe His Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile 2300 2305 2310 tct gac atc ctg gag tgg aag acc gca cgc acc ttc ctg tat tgg 6984 Ser Asp Ile Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp 2315 2320 2325 cgt ctg cgc cgc ctc ctc ctg gag gac cag gtc aag cag gag atc 7029 Arg Leu Arg Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile 2330 2335 2340 ctg cag gcc agc ggg gag ctg agt cac gtg cat atc cag tcc atg 7074 Leu Gln Ala Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met 2345 2350 2355 ctg cgt cgc tgg ttc gtg gag acg gag ggg gct gtc aag gcc tac 7119 Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr 2360 2365 2370 ttg tgg gac aac aac cag gtg gtt gtg cag tgg ctg gaa cag cac 7164 Leu Trp Asp Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His 2375 2380 2385 tgg cag gca ggg gat ggc ccg cgc tcc acc atc cgt gag aac atc 7209 Trp Gln Ala Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile 2390 2395 2400 acg tac ctg aag cac gac tct gtc ctc aag acc atc cga ggc ctg 7254 Thr Tyr Leu Lys

His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu 2405 2410 2415 gtt gaa gaa aac ccc gag gtg gcc gtg gac tgt gtg ata tac ctg 7299 Val Glu Glu Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu 2420 2425 2430 agc cag cac atc agc cca gct gag cgg gcg cag gtc gtt cac ctg 7344 Ser Gln His Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu 2435 2440 2445 ctg tct acc atg gac agc ccg gcc tcc acc tga 7377 Leu Ser Thr Met Asp Ser Pro Ala Ser Thr 2450 2455 6 2458 PRT Homo sapiens 6 Met Val Leu Leu Leu Cys Leu Ser Arg Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Tyr Gly Gly 245 250 255 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 Asp Ile Ala Lys Arg Ile Pro Val Arg Ala Val Trp Ala Gly Trp Gly 340 345 350 His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 355 360 365 Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 370 375 380 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 Val Ser Ala Gly Ala Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 625 630 635 640 Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu 645 650 655 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 675 680 685 Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 690 695 700 Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp 740 745 750 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 755 760 765 Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 770 775 780 Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg 785 790 795 800 Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 805 810 815 Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 820 825 830 Leu Thr Met Phe Val Leu Ile Met Tyr Gly Cys His Ile Glu Ile Asp 835 840 845 Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 850 855 860 Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 865 870 875 880 Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 885 890 895 Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 900 905 910 Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 915 920 925 Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 930 935 940 Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 945 950 955 960 Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 965 970 975 Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 980 985 990 His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser 995 1000 1005 Gly Phe Cys Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu 1010 1015 1020 Trp Val Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro 1025 1030 1035 Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile 1040 1045 1050 Pro Ala Pro Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr 1055 1060 1065 Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln 1070 1075 1080 Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys 1085 1090 1095 Ala Asp Arg Glu Ala Phe Phe Ile Asn Thr Gln Ser Ile Val Gln 1100 1105 1110 Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr 1115 1120 1125 Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His 1130 1135 1140 Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu 1145 1150 1155 Gln Phe Lys Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser 1160 1165 1170 His Ala Gln Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile 1175 1180 1185 Asp Glu Leu Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile 1190 1195 1200 Ser Ile Leu Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys 1205 1210 1215 Lys Val Ala Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu 1220 1225 1230 Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu 1235 1240 1245 Ser Ala Ile Asp Met Tyr Gly His Gln Phe Arg Pro Glu Asn Leu 1250 1255 1260 Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro 1265 1270 1275 Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu 1280 1285 1290 Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser 1295 1300 1305 Leu Gln His Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe 1310 1315 1320 Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro 1325 1330 1335 Ile Ser Ile Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu 1340 1345 1350 Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala 1355 1360 1365 Met Val Ala Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp 1370 1375 1380 Glu Val Ile Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu 1385 1390 1395 Phe Ser Glu Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys 1400 1405 1410 Ser Leu Arg Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln 1415 1420 1425 Cys Ala Asp His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg 1430 1435 1440 Thr Phe Val Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu 1445 1450 1455 Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys 1460 1465 1470 Phe Phe Thr Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile 1475 1480 1485 Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn 1490 1495 1500 Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His 1505 1510 1515 Lys Met His Leu Tyr Leu Gly Val Ala Lys Val Lys Glu Gly Val 1520 1525 1530 Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His 1535 1540 1545 Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn 1550 1555 1560 Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val 1565 1570 1575 Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe 1580 1585 1590 Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu 1595 1600 1605 Glu Ser Val Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp 1610 1615 1620 Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln 1625 1630 1635 Thr Thr Thr Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn 1640 1645 1650 Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr 1655 1660 1665 Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys 1670 1675 1680 Gln Gly Pro Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr 1685 1690 1695 Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly 1700 1705 1710 Thr Thr Tyr Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu 1715 1720 1725 Phe Lys Leu Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu 1730 1735 1740 Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu 1745 1750 1755 Met Asn Arg Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe 1760 1765 1770 Lys Met Arg Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val 1775 1780 1785 Ile Val Ile Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly 1790 1795 1800 Pro Gly Glu Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg 1805 1810 1815 Ala Glu Gly Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala 1820 1825 1830 Arg Ile Gly Met Ala Glu Glu Ile Lys His Met Phe His Val Ala 1835 1840 1845 Trp Val Asp Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr 1850 1855 1860 Leu Thr Pro Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val 1865 1870 1875 His Cys Lys His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile 1880 1885 1890 Thr Asp Ile Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu 1895 1900 1905 Arg Gly Ser Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu 1910 1915 1920 Glu Ile Val Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile 1925 1930 1935 Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu 1940 1945 1950 Asn Ser His Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val 1955 1960 1965 Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val 1970 1975 1980 Gln Ile Met His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp 1985 1990 1995 Asp Phe Glu Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met 2000 2005 2010 Pro Lys Asp Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp 2015 2020 2025 Pro Ile Asp Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr 2030 2035 2040 Asp Pro Arg Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys 2045 2050 2055 Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu 2060 2065 2070 Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg 2075 2080 2085 Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr 2090 2095 2100 Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu 2105 2110 2115 Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser 2120 2125 2130 Ala Tyr Lys Thr Ala Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys 2135 2140 2145 Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly 2150 2155 2160 Met Lys Asp Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile 2165 2170 2175 Val Asp Gly Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile 2180 2185 2190 Pro Pro Tyr Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp 2195 2200 2205 Ala Thr Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu 2210 2215 2220 Ser Arg Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys 2225 2230 2235 Phe Arg Lys Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro 2240 2245 2250 Ala Tyr Lys Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser 2255 2260 2265 Asp Lys Asp Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu 2270 2275 2280 Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala 2285 2290 2295 Asp Phe His Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile 2300 2305 2310 Ser Asp Ile Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp 2315 2320 2325 Arg Leu Arg Arg Leu Leu Leu Glu Asp Gln Val

Lys Gln Glu Ile 2330 2335 2340 Leu Gln Ala Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met 2345 2350 2355 Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr 2360 2365 2370 Leu Trp Asp Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His 2375 2380 2385 Trp Gln Ala Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile 2390 2395 2400 Thr Tyr Leu Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu 2405 2410 2415 Val Glu Glu Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu 2420 2425 2430 Ser Gln His Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu 2435 2440 2445 Leu Ser Thr Met Asp Ser Pro Ala Ser Thr 2450 2455 7 7371 DNA Rattus norvegicus CDS (1)..(7371) 7 atg gtc ttg ctt ctc ttt ctg act tac ctg gtt ttc tcc tgc ctg acc 48 Met Val Leu Leu Leu Phe Leu Thr Tyr Leu Val Phe Ser Cys Leu Thr 1 5 10 15 att tcc tgg tta aaa atc tgg ggg aag atg aca gac tcg agg ccg ctc 96 Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Arg Pro Leu 20 25 30 agc aac agt aag gtg gat gca agc ctc ctt ccg agc aag gag gag tct 144 Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Pro Ser Lys Glu Glu Ser 35 40 45 ttt gcc tcg gac cag tca gag gag cat ggc gac tgc agc tgt ccg ttg 192 Phe Ala Ser Asp Gln Ser Glu Glu His Gly Asp Cys Ser Cys Pro Leu 50 55 60 aca act cct gac cag gag gag ctg gcc tcc cac gga ggt cct gta gat 240 Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser His Gly Gly Pro Val Asp 65 70 75 80 gcc agt cag cag agg aac tct gta cca acc tca cac cag aag cct ccg 288 Ala Ser Gln Gln Arg Asn Ser Val Pro Thr Ser His Gln Lys Pro Pro 85 90 95 agg aac cca cta tct tcc aat gac acc tgt tcc tcc cca gaa ctc caa 336 Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys Ser Ser Pro Glu Leu Gln 100 105 110 acc aac ggg gta gca gca cct ggc tca gag gtt cca gaa gcc aac ggg 384 Thr Asn Gly Val Ala Ala Pro Gly Ser Glu Val Pro Glu Ala Asn Gly 115 120 125 ttg cct ttc cca gcc agg cct cag acc cag aga acg gga tcc ccc act 432 Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln Arg Thr Gly Ser Pro Thr 130 135 140 agg gag gac aag aag cag gca ccc atc aag agg cag ctg atg acc agc 480 Arg Glu Asp Lys Lys Gln Ala Pro Ile Lys Arg Gln Leu Met Thr Ser 145 150 155 160 ttt atc ctg ggc tcc ctc gat gac aac tcc tct gac gag gac cct agt 528 Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser Ser Asp Glu Asp Pro Ser 165 170 175 tct aac tcc ttt cag acc tcc tct cgg aag ggc agc agg gat agc ctg 576 Ser Asn Ser Phe Gln Thr Ser Ser Arg Lys Gly Ser Arg Asp Ser Leu 180 185 190 ggc acc tgt tcc cag gag gct gca ttg aac aca gct gat cct gag tct 624 Gly Thr Cys Ser Gln Glu Ala Ala Leu Asn Thr Ala Asp Pro Glu Ser 195 200 205 cac aca cct act atg agg ccc agc atg tct gga ctc cat ctg gtg aag 672 His Thr Pro Thr Met Arg Pro Ser Met Ser Gly Leu His Leu Val Lys 210 215 220 aga ggc cgt gaa cac aag aaa ctg gac ctg cac aga gat ttc act gta 720 Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp Phe Thr Val 225 230 235 240 gct tcc cca gcc gaa ttt gtc acc cgc ttt gga ggc aac agg gtt atc 768 Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Arg Val Ile 245 250 255 gag acg gtg ctc atc gcc aat aat ggt atc gct gcg gtc aag tgg atg 816 Glu Thr Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Trp Met 260 265 270 cgc tcc atc cgc cgc tgg gcc tat gag atg ttc cgt aat gaa cgc gct 864 Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn Glu Arg Ala 275 280 285 atc cgg ttt gtg gtt atg gtg aca ccc gag gat ctt aag gcc aac gca 912 Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn Ala 290 295 300 gag tac tac aag atg gcg gac cca gta ctt ccg gtc cca gga gga ccc 960 Glu Tyr Tyr Lys Met Ala Asp Pro Val Leu Pro Val Pro Gly Gly Pro 305 310 315 320 aat aat aac aac tac gcc aac gtt gag ctg atc ata gac att gcc aag 1008 Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Ile Asp Ile Ala Lys 325 330 335 aga atc cct gtg cag gcc gtg tgg gct ggc tgg ggc cac gct tcg gaa 1056 Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser Glu 340 345 350 aac ccc aaa ctt cca gag cta ctg tgc aag cac ggg att gct ttt cta 1104 Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys His Gly Ile Ala Phe Leu 355 360 365 ggt ccc cga gtg agg cca atg ttg ggc ctg gga gac agg ctc tcc tcc 1152 Gly Pro Arg Val Arg Pro Met Leu Gly Leu Gly Asp Arg Leu Ser Ser 370 375 380 acc att gta gcc cag aca ttg cag atc cca act cta ccc tgg agc gga 1200 Thr Ile Val Ala Gln Thr Leu Gln Ile Pro Thr Leu Pro Trp Ser Gly 385 390 395 400 agc ggt ctc aca gtg gag tgg acg gag gac agc cag cat cag ggc aaa 1248 Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Ser Gln His Gln Gly Lys 405 410 415 tgc atc agc gtc acg gaa gac gtt tat gaa caa ggc tgt gtg aga gat 1296 Cys Ile Ser Val Thr Glu Asp Val Tyr Glu Gln Gly Cys Val Arg Asp 420 425 430 gtg gac gaa ggc ttg cag gca gca gaa aaa gta gga ttt cct ctg atg 1344 Val Asp Glu Gly Leu Gln Ala Ala Glu Lys Val Gly Phe Pro Leu Met 435 440 445 atc aaa gcc tct gaa ggt gga gga ggg aaa gga atc cgg cag gct gag 1392 Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Gln Ala Glu 450 455 460 agt gca gag gac ttc cca tgc ttt ttc aga cag gtg cag agt gag atc 1440 Ser Ala Glu Asp Phe Pro Cys Phe Phe Arg Gln Val Gln Ser Glu Ile 465 470 475 480 ccg ggc tcg ccc atc ttt ctc atg aag ctg gcc cag aat gcc cgg cac 1488 Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln Asn Ala Arg His 485 490 495 ttg gag gtc cag gtc ttg gca gat cag tat ggg aac gca gtg tcc ctg 1536 Leu Glu Val Gln Val Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser Leu 500 505 510 ttt gga cga gac tgc tcc atc cag agg cgg cac cag aag atc att gag 1584 Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Ile Glu 515 520 525 gag gct ccg gcc aac atc gct gct ccg gct gtg ttt gag ttc atg gaa 1632 Glu Ala Pro Ala Asn Ile Ala Ala Pro Ala Val Phe Glu Phe Met Glu 530 535 540 cag tgt gcc gtc ctc ctg gcc aag act gtg gtt tat gtg agc gcg gga 1680 Gln Cys Ala Val Leu Leu Ala Lys Thr Val Val Tyr Val Ser Ala Gly 545 550 555 560 acc gtg ggg tac cta tac agc cag gat ggc agc ttt cac ttc ttg gag 1728 Thr Val Gly Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu Glu 565 570 575 ctg aac cca cgc ctg cag gtg gaa cat ccc tgc act gaa atg att gca 1776 Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile Ala 580 585 590 gat gtc aac ctg ccc gct gca cag tta cag atc gcc atg ggc gtg ccc 1824 Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val Pro 595 600 605 ctg cac cgg ctg aag gac ata cgg ctt ctg tac gga gag tcc ccc tgg 1872 Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro Trp 610 615 620 gga gtg acc ccc gtt tct ttt gag acc cct ttg agc cct ccc att gcc 1920 Gly Val Thr Pro Val Ser Phe Glu Thr Pro Leu Ser Pro Pro Ile Ala 625 630 635 640 cga ggc cat gtc att gca gcc agg atc acc agc gaa aac cca gac gag 1968 Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp Glu 645 650 655 gcc ttt aag cca agc tca ggg aca gta cag gag ctg aac ttc cgc agc 2016 Ala Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg Ser 660 665 670 aac aag aac gtg tgg ggt tac ttc agc gtg gcc gct gct gga ggc ttg 2064 Asn Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly Leu 675 680 685 cac gag ttt ccg att tcc cag ttt ggg cac tgc ttc tcc tgg ggc gag 2112 His Glu Phe Pro Ile Ser Gln Phe Gly His Cys Phe Ser Trp Gly Glu 690 695 700 aac cag gaa gag gct att tcg aac atg gtg gtg gct ttg aaa gaa ctg 2160 Asn Gln Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu Leu 705 710 715 720 tct atc cgg ggt gac ttc cgg acc acc gtg gaa tat ctc gtc aac ctt 2208 Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Val Asn Leu 725 730 735 ctg gag acg gag agc tta cag aac aat gat atc gac acg ggg tgg ctg 2256 Leu Glu Thr Glu Ser Leu Gln Asn Asn Asp Ile Asp Thr Gly Trp Leu 740 745 750 gac cac ctc atc gct cag cgg gtg cag gca gag aag ccg gac atc atg 2304 Asp His Leu Ile Ala Gln Arg Val Gln Ala Glu Lys Pro Asp Ile Met 755 760 765 ctc ggg gtg gtg ttt ggg gcc ttg aac gtg gca gac gca atg ttc aga 2352 Leu Gly Val Val Phe Gly Ala Leu Asn Val Ala Asp Ala Met Phe Arg 770 775 780 acc tgt att acg gaa ttc ctg cat tcc ttg gaa agg ggt cag gtc ctc 2400 Thr Cys Ile Thr Glu Phe Leu His Ser Leu Glu Arg Gly Gln Val Leu 785 790 795 800 ccg gct gat tct ctg ctg aac atc gtg gac gtt gaa ttg att tac gga 2448 Pro Ala Asp Ser Leu Leu Asn Ile Val Asp Val Glu Leu Ile Tyr Gly 805 810 815 ggc atc aaa tat gtt ctc aag gtg gcc cgg cag tcc ctg acc atg ttt 2496 Gly Ile Lys Tyr Val Leu Lys Val Ala Arg Gln Ser Leu Thr Met Phe 820 825 830 gtc ctc atc atg aat ggt tgc cac atc gag atc gat gcc cac cgg ccg 2544 Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg Pro 835 840 845 aac gat ggg ggc ctg ctc ctg tcc tac aat ggt agc agt tac act aca 2592 Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Ser Ser Tyr Thr Thr 850 855 860 tac atg aag gaa gag gtg gac agt tac cgg atc act atc ggc aat aag 2640 Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn Lys 865 870 875 880 aca tgc gtg ttt gaa aag gaa aac gac ccc acc gtc ctg aga tcc ccc 2688 Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser Pro 885 890 895 tcg gct ggg aag ctg atg cag tac acg gtg gag gat ggc cag cac gtg 2736 Ser Ala Gly Lys Leu Met Gln Tyr Thr Val Glu Asp Gly Gln His Val 900 905 910 gaa gtc ggg agc agc tat gct gag atg gag gtg atg aag atg atc atg 2784 Glu Val Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile Met 915 920 925 acc ctg aac gtg caa gag agc ggc cgg gtg aac tac atc aag cga cca 2832 Thr Leu Asn Val Gln Glu Ser Gly Arg Val Asn Tyr Ile Lys Arg Pro 930 935 940 ggg gcg gta ttg gag gct ggc tgc gtg gtg gca aag cta gaa ctc gat 2880 Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Lys Leu Glu Leu Asp 945 950 955 960 gac cct tca aaa gtg cac gcg gca cag ccg ttc aca ggg gag ctc ccc 2928 Asp Pro Ser Lys Val His Ala Ala Gln Pro Phe Thr Gly Glu Leu Pro 965 970 975 gcc cag cag act ctg ccc atc ctc ggg gag agg ctg cat cag gtg ttc 2976 Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Arg Leu His Gln Val Phe 980 985 990 cac agc gtc ttg gaa aat ctg acc aat gtc atg aat ggc tac tgc ctg 3024 His Ser Val Leu Glu Asn Leu Thr Asn Val Met Asn Gly Tyr Cys Leu 995 1000 1005 ccc gag ccc ttc ttc agc atg aag ctg aag gac tgg gtg gag aag 3069 Pro Glu Pro Phe Phe Ser Met Lys Leu Lys Asp Trp Val Glu Lys 1010 1015 1020 ccc atg atg act ctc cgg cat ccc tcc cta cct ctg ctg gag ctg 3114 Pro Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu Leu 1025 1030 1035 cag gag atc atg acc agc gtg gca gac cgc atc ccg gtt ccg gtg 3159 Gln Glu Ile Met Thr Ser Val Ala Asp Arg Ile Pro Val Pro Val 1040 1045 1050 gag aag gca gtc cgc agg gtg ttt gcg cag gac gcc agc aac atc 3204 Glu Lys Ala Val Arg Arg Val Phe Ala Gln Asp Ala Ser Asn Ile 1055 1060 1065 act tcg gtg ctc tgc cag ttc ccc agc cag cag ata gcc acc atc 3249 Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr Ile 1070 1075 1080 ctg gac tgc cac gcc gcc acc ctg cag cgt aag gtg gac cga gag 3294 Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Val Asp Arg Glu 1085 1090 1095 gcc ttc ttc atg aac aca cag agc atc gtg cag ctg atc cag aga 3339 Ala Phe Phe Met Asn Thr Gln Ser Ile Val Gln Leu Ile Gln Arg 1100 1105 1110 tac cgc agt ggg acc cgt ggc atc atg aag gct gtg gtg cta gac 3384 Tyr Arg Ser Gly Thr Arg Gly Ile Met Lys Ala Val Val Leu Asp 1115 1120 1125 ctc ctg agg aga tat ctg aac gtg gag cat cat ttc cag caa gcc 3429 Leu Leu Arg Arg Tyr Leu Asn Val Glu His His Phe Gln Gln Ala 1130 1135 1140 cac tat gac aag tgt gtg atc aac ctg agg gag cag ttc aag gcg 3474 His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys Ala 1145 1150 1155 gac atg act cgg gtg ctg gac tgc atc ttc tca cac tca caa gtg 3519 Asp Met Thr Arg Val Leu Asp Cys Ile Phe Ser His Ser Gln Val 1160 1165 1170 gcc aag aag aac cag ctg gtg acc atg ttg ata gat gag ctg tgt 3564 Ala Lys Lys Asn Gln Leu Val Thr Met Leu Ile Asp Glu Leu Cys 1175 1180 1185 ggc cca gac ccc acc ctg tca gaa gag ctg acc tcc atc ctc aag 3609 Gly Pro Asp Pro Thr Leu Ser Glu Glu Leu Thr Ser Ile Leu Lys 1190 1195 1200 gaa ctc acg cag ttg agc agg agt gag cac tgc aag gtg gcc ctc 3654 Glu Leu Thr Gln Leu Ser Arg Ser Glu His Cys Lys Val Ala Leu 1205 1210 1215 aga gcc agg cag gtc ctg att gcc tct cac ctc ccc tcc tac gag 3699 Arg Ala Arg Gln Val Leu Ile Ala Ser His Leu Pro Ser Tyr Glu 1220 1225 1230 ctg cgg cac aac cag gtg gag tca tct tcc tgt cag cca ttg aca 3744 Leu Arg His Asn Gln Val Glu Ser Ser Ser Cys Gln Pro Leu Thr 1235 1240 1245 tgt aat ggc cac cag ttc tgc ccg gaa aac ctc aag aaa cta ata 3789 Cys Asn Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu Ile 1250 1255 1260 ctt tcg gaa acg acc ata ttc gat gtc ctg ccc act ttc ttc tat 3834 Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe Tyr 1265 1270 1275 cac gct aac aag gtc gtc tgt atg gcg tcc ctg gag gtt tat gtg 3879 His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val 1280 1285 1290 agg aga ggt tac atc gcc tac gag tta aac agc cta cag cac cgg 3924 Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His Arg 1295 1300 1305 gag ctc cct gac ggc acc tgc gtg gtg gag ttc cag ttc atg ctg 3969 Glu Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu 1310 1315 1320 ccg tct tcc cac ccc aac cgg atg gcc atg ccc atc aat gtc tct 4014 Pro Ser Ser His Pro Asn Arg Met Ala Met Pro Ile Asn Val Ser 1325 1330 1335 gac cct gac ctg ctg aga cac agt aag gaa ctc ttc atg gac agt 4059 Asp Pro Asp Leu Leu Arg His Ser Lys Glu Leu Phe Met Asp Ser 1340 1345 1350 ggc ttc tcc cca ctg tgt cac cag cgg atg ggg gcc atg gtg gcc 4104 Gly Phe Ser Pro Leu Cys His Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 ttc agg aga ttt gag gag ttc acc agg aac ttc gat gaa gtc atc 4149 Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 tcc tgc ttt gcc aac gtg cct aca gac act cct ctc ttc agt aag 4194 Ser Cys Phe Ala Asn Val Pro Thr Asp Thr Pro Leu Phe Ser Lys 1385 1390 1395 gcg tgc act tcc ctc tac tca gag gag gac agc aag agc ctt caa 4239 Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp Ser Lys Ser Leu Gln 1400 1405 1410 gag gag ccc atc cac atc ctg aat gtg gcc atc cag tgc gcc gac 4284 Glu Glu Pro Ile His Ile Leu Asn Val

Ala Ile Gln Cys Ala Asp 1415 1420 1425 cac atg gag gac gag aga ctg gtg ccg gtt ttc cgt gcc ttt gta 4329 His Met Glu Asp Glu Arg Leu Val Pro Val Phe Arg Ala Phe Val 1430 1435 1440 cag tcc aag aaa cac atc ctt gtg gat tac gga ctg cga aga atc 4374 Gln Ser Lys Lys His Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 aca ttc ctt atc gcc caa gag aag gaa ttt ccc aag ttc ttc acg 4419 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 ttc aga gcg aga gat gag ttt gca gaa gac cgg att tac cgc cac 4464 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 ttg gag ccg ggc ctg gcc ttc cag ctg gag ctg agc cgg atg cgc 4509 Leu Glu Pro Gly Leu Ala Phe Gln Leu Glu Leu Ser Arg Met Arg 1490 1495 1500 aac ttt gac ttg acg gcc gtg ccc tgt gcc aac cat aag atg cat 4554 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 ctt tac ctg gga gcc gcc aag gtg aag gaa ggg ctg gag gtg act 4599 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Leu Glu Val Thr 1520 1525 1530 gac cac agg ttc ttc atc cga gcc atc ata agg cac tca gac ctg 4644 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 atc acc aag gaa gcc tcc ttc gag tac ctg cag aat gaa ggg gag 4689 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 cgg ctg ctg ctg gaa gcc atg gac gag ctg gag gtg gcg ttc aac 4734 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 aac acc agc gtg cgc act gac tgc aac cac atc ttc ctc aac ttc 4779 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 gtg gcc cac gtc atc atg gac cca ctc aag atc gag gag tcg gtg 4824 Val Ala His Val Ile Met Asp Pro Leu Lys Ile Glu Glu Ser Val 1595 1600 1605 cgt gcc atg gtc atg cgt tac ggc agt cgg ctg tgg aag ctc cgt 4869 Arg Ala Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 gtg ctg cag gca caa gtt aag atc aac atc cgt cag acg acc tcg 4914 Val Leu Gln Ala Gln Val Lys Ile Asn Ile Arg Gln Thr Thr Ser 1625 1630 1635 gac tgc gcc gtc ccc att cgc ctc ttc atc acc aac gag tcc ggc 4959 Asp Cys Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 tac tac ctg gac atc agc ctc tac aaa gaa gtg acc gac tcc aga 5004 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 tcc gga aac atc atg ttt cat tcc ttc ggc aac aaa caa ggg agc 5049 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Ser 1670 1675 1680 ctg cac ggg atg ctg atc aac acg ccc tac gtc acc aag gat ctg 5094 Leu His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 ctc caa gcc aag cga ttc cag gcg cag tcc ctg ggg acc acc tat 5139 Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser Leu Gly Thr Thr Tyr 1700 1705 1710 gtg tac gac ttc cca gag atg ttc agg cag gct ctc ttt aaa ttg 5184 Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 tgg ggc tcc cca gag aag tac ggg ccc gat atc ctg aca tac aca 5229 Trp Gly Ser Pro Glu Lys Tyr Gly Pro Asp Ile Leu Thr Tyr Thr 1730 1735 1740 gag ctg gtg ttg gac tcc cag ggc cag ctg gtg gag atg aac cgg 5274 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 ctt cct ggt tgt aac gag gtg ggc atg gtg gtt ttc aaa atg agg 5319 Leu Pro Gly Cys Asn Glu Val Gly Met Val Val Phe Lys Met Arg 1760 1765 1770 ttc aag acc ccg gag tat cca gaa ggc cgg gac act atc gtc atc 5364 Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg Asp Thr Ile Val Ile 1775 1780 1785 ggc aac gac att acc ttc caa atc ggc tct ttc ggc ata gga gag 5409 Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser Phe Gly Ile Gly Glu 1790 1795 1800 gac ttc ctg tat cta cgg gca tcg gag atg gcc cgg aca gag ggc 5454 Asp Phe Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Thr Glu Gly 1805 1810 1815 atc ccc caa atc tat ctg gca gcc aac agc ggc gcc gta ttg ggc 5499 Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser Gly Ala Val Leu Gly 1820 1825 1830 ctg tcc gag gag atc aag cag ata ttc caa gtg gca tgg gtg gac 5544 Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln Val Ala Trp Val Asp 1835 1840 1845 cct gag gat ccc tac aaa gga ttt aga tac ctg tac ctg tac ctg 5589 Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr Leu Tyr Leu Tyr Leu 1850 1855 1860 acg ccc caa gac tac acc cag atc agc tcc cag aac tcc gtg cac 5634 Thr Pro Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn Ser Val His 1865 1870 1875 tgc aaa cac atc gag gac gaa ggc gag tca ggt att atc gtt gat 5679 Cys Lys His Ile Glu Asp Glu Gly Glu Ser Gly Ile Ile Val Asp 1880 1885 1890 gtc atc ggg aag gac agc agc ctg ggt gtg gag aac ctg cgg ggc 5724 Val Ile Gly Lys Asp Ser Ser Leu Gly Val Glu Asn Leu Arg Gly 1895 1900 1905 tcg ggc atg att gca gga gag gct tct ctg gct tac gaa aaa aat 5769 Ser Gly Met Ile Ala Gly Glu Ala Ser Leu Ala Tyr Glu Lys Asn 1910 1915 1920 gtc acc atc agc atg gtc gac tgc cgc gcc atc gga atc ggg gct 5814 Val Thr Ile Ser Met Val Asp Cys Arg Ala Ile Gly Ile Gly Ala 1925 1930 1935 tac ctg gtg agg ctg ggc cag cgg gtg atc cag gtg gaa aac tcc 5859 Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser 1940 1945 1950 cac atc atc ctc acg gga gcc ggt gct ctc aac aag gtt ctg gga 5904 His Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn Lys Val Leu Gly 1955 1960 1965 aga gag gtc tac aca tcc aac aac caa ctg ggc ggt gtg cag atc 5949 Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile 1970 1975 1980 atg cac acc aac ggg gtc tcc cac gtc acg gtg cca gat gac ttc 5994 Met His Thr Asn Gly Val Ser His Val Thr Val Pro Asp Asp Phe 1985 1990 1995 gag ggg gtc tgc acc att ctg gaa tgg ctg tca tat ata cca aag 6039 Glu Gly Val Cys Thr Ile Leu Glu Trp Leu Ser Tyr Ile Pro Lys 2000 2005 2010 gac aat caa agc cca gtc ccc atc atc act cct tct gac ccc atc 6084 Asp Asn Gln Ser Pro Val Pro Ile Ile Thr Pro Ser Asp Pro Ile 2015 2020 2025 gac agg gaa att gaa ttc acc cca acc aaa gct ccc tat gac ccc 6129 Asp Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala Pro Tyr Asp Pro 2030 2035 2040 agg tgg ctg ctg gca ggg agg cct cac cca act ctg aag ggg acc 6174 Arg Trp Leu Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr 2045 2050 2055 tgg cag agt gga ttc ttc gac cat ggc agt ttc aag gaa atc atg 6219 Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met 2060 2065 2070 gca ccc tgg gac cag act gtg gtg act gga cga gca agg ctg ggg 6264 Ala Pro Trp Asp Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly 2075 2080 2085 ggc atc cct gta ggg gtg att gcc gtg gag act cgg tct gtg gag 6309 Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Ser Val Glu 2090 2095 2100 gtg gct gtc cct gct cac cca gcc aac ttg gat tct gag gcc aag 6354 Val Ala Val Pro Ala His Pro Ala Asn Leu Asp Ser Glu Ala Lys 2105 2110 2115 atc atc cag cag gca ggc cag gtg tgg ttc ccg gac tct gcc ttc 6399 Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Phe 2120 2125 2130 aag acg gct cag gtc atc agg gac ttc aac cag gag cat ctg ctt 6444 Lys Thr Ala Gln Val Ile Arg Asp Phe Asn Gln Glu His Leu Leu 2135 2140 2145 ctc atg atc ttt gct aac tgg aga ggc ttc tcg ggc ggc atg aaa 6489 Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys 2150 2155 2160 gac atg tcc gag cag atg ctg aag ttt ggc gcc tac atc gtg gac 6534 Asp Met Ser Glu Gln Met Leu Lys Phe Gly Ala Tyr Ile Val Asp 2165 2170 2175 agt ctc cgt ctg tcc aag cag cca gtc ctc atc tat atc cct ccc 6579 Ser Leu Arg Leu Ser Lys Gln Pro Val Leu Ile Tyr Ile Pro Pro 2180 2185 2190 ggt gcc gaa ctc cga ggg ggc tcc tgg gtt gtc ctc gac tcc agc 6624 Gly Ala Glu Leu Arg Gly Gly Ser Trp Val Val Leu Asp Ser Ser 2195 2200 2205 atc aac ccc ctg tgc ata gag atg tac gca gac aaa gag agc agg 6669 Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg 2210 2215 2220 ggg ggt gtt ctg gag ccc gag ggc act gtg gag att aag ttc cgg 6714 Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg 2225 2230 2235 aag aaa gat ttg gtg aag acc ata agg agg att gac cca gtg tgc 6759 Lys Lys Asp Leu Val Lys Thr Ile Arg Arg Ile Asp Pro Val Cys 2240 2245 2250 aag aaa ctc ctg gaa cca gct ggg gac acc cag ctc cct gac aag 6804 Lys Lys Leu Leu Glu Pro Ala Gly Asp Thr Gln Leu Pro Asp Lys 2255 2260 2265 gac cgg aaa gag ctg gag agc cag ctg aag gcc cgg gag gac ctg 6849 Asp Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala Arg Glu Asp Leu 2270 2275 2280 ctg ctc ccc atc tac cac cag gtg gca gtg cag ttc gcc gac ctg 6894 Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Leu 2285 2290 2295 cat gac acg ccg ggc cac atg ctg aag aag gga atc att tct gat 6939 His Asp Thr Pro Gly His Met Leu Lys Lys Gly Ile Ile Ser Asp 2300 2305 2310 gtc ctg gag tgg aag acc aca cgt act tac ttc tac tgg agg ctg 6984 Val Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe Tyr Trp Arg Leu 2315 2320 2325 cgc cgg ctg ctg ctg gag gca cag gtg aag cag gag att ctg cga 7029 Arg Arg Leu Leu Leu Glu Ala Gln Val Lys Gln Glu Ile Leu Arg 2330 2335 2340 gcc agc cct gag ctg agc cat gag cac acg cag tcc atg ctg cga 7074 Ala Ser Pro Glu Leu Ser His Glu His Thr Gln Ser Met Leu Arg 2345 2350 2355 cgc tgg ttt gtg gag acc gag ggc gcc gtc aag gcc tac ctg tgg 7119 Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp 2360 2365 2370 gac agc aac cag gtg gta gtc cag tgg ctg gaa cag cac tgg tca 7164 Asp Ser Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Ser 2375 2380 2385 gcc agg gac aac ctg cgt tcc act atc cga gag aac ctc aat tat 7209 Ala Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu Asn Leu Asn Tyr 2390 2395 2400 ctg aag cgg gac tct gtc ctc aag acc atc caa agc cta gtt caa 7254 Leu Lys Arg Asp Ser Val Leu Lys Thr Ile Gln Ser Leu Val Gln 2405 2410 2415 gaa cac cca gag gcg acc atg gga ctg tgt gga tac ctg agc cag 7299 Glu His Pro Glu Ala Thr Met Gly Leu Cys Gly Tyr Leu Ser Gln 2420 2425 2430 cac ctc acg ccc gct gag cag atg cag gtg gtt cag ctg ctg tcg 7344 His Leu Thr Pro Ala Glu Gln Met Gln Val Val Gln Leu Leu Ser 2435 2440 2445 acc acg gag agc cca gct tcc cac tga 7371 Thr Thr Glu Ser Pro Ala Ser His 2450 2455 8 2456 PRT Rattus norvegicus 8 Met Val Leu Leu Leu Phe Leu Thr Tyr Leu Val Phe Ser Cys Leu Thr 1 5 10 15 Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Arg Pro Leu 20 25 30 Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Pro Ser Lys Glu Glu Ser 35 40 45 Phe Ala Ser Asp Gln Ser Glu Glu His Gly Asp Cys Ser Cys Pro Leu 50 55 60 Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser His Gly Gly Pro Val Asp 65 70 75 80 Ala Ser Gln Gln Arg Asn Ser Val Pro Thr Ser His Gln Lys Pro Pro 85 90 95 Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys Ser Ser Pro Glu Leu Gln 100 105 110 Thr Asn Gly Val Ala Ala Pro Gly Ser Glu Val Pro Glu Ala Asn Gly 115 120 125 Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln Arg Thr Gly Ser Pro Thr 130 135 140 Arg Glu Asp Lys Lys Gln Ala Pro Ile Lys Arg Gln Leu Met Thr Ser 145 150 155 160 Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser Ser Asp Glu Asp Pro Ser 165 170 175 Ser Asn Ser Phe Gln Thr Ser Ser Arg Lys Gly Ser Arg Asp Ser Leu 180 185 190 Gly Thr Cys Ser Gln Glu Ala Ala Leu Asn Thr Ala Asp Pro Glu Ser 195 200 205 His Thr Pro Thr Met Arg Pro Ser Met Ser Gly Leu His Leu Val Lys 210 215 220 Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp Phe Thr Val 225 230 235 240 Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Arg Val Ile 245 250 255 Glu Thr Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Trp Met 260 265 270 Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn Glu Arg Ala 275 280 285 Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn Ala 290 295 300 Glu Tyr Tyr Lys Met Ala Asp Pro Val Leu Pro Val Pro Gly Gly Pro 305 310 315 320 Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Ile Asp Ile Ala Lys 325 330 335 Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser Glu 340 345 350 Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys His Gly Ile Ala Phe Leu 355 360 365 Gly Pro Arg Val Arg Pro Met Leu Gly Leu Gly Asp Arg Leu Ser Ser 370 375 380 Thr Ile Val Ala Gln Thr Leu Gln Ile Pro Thr Leu Pro Trp Ser Gly 385 390 395 400 Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Ser Gln His Gln Gly Lys 405 410 415 Cys Ile Ser Val Thr Glu Asp Val Tyr Glu Gln Gly Cys Val Arg Asp 420 425 430 Val Asp Glu Gly Leu Gln Ala Ala Glu Lys Val Gly Phe Pro Leu Met 435 440 445 Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Gln Ala Glu 450 455 460 Ser Ala Glu Asp Phe Pro Cys Phe Phe Arg Gln Val Gln Ser Glu Ile 465 470 475 480 Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln Asn Ala Arg His 485 490 495 Leu Glu Val Gln Val Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser Leu 500 505 510 Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Ile Glu 515 520 525 Glu Ala Pro Ala Asn Ile Ala Ala Pro Ala Val Phe Glu Phe Met Glu 530 535 540 Gln Cys Ala Val Leu Leu Ala Lys Thr Val Val Tyr Val Ser Ala Gly 545 550 555 560 Thr Val Gly Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu Glu 565 570 575 Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile Ala 580 585 590 Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val Pro 595 600 605 Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro Trp 610 615 620 Gly Val Thr Pro Val Ser Phe Glu Thr Pro Leu Ser Pro Pro Ile Ala 625 630 635 640 Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp Glu 645 650 655 Ala Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg Ser 660 665 670 Asn Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly Leu 675 680 685 His Glu Phe Pro Ile Ser Gln Phe Gly His Cys Phe Ser Trp Gly Glu 690 695 700 Asn Gln Glu Glu Ala Ile Ser Asn Met Val Val Ala

Leu Lys Glu Leu 705 710 715 720 Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Val Asn Leu 725 730 735 Leu Glu Thr Glu Ser Leu Gln Asn Asn Asp Ile Asp Thr Gly Trp Leu 740 745 750 Asp His Leu Ile Ala Gln Arg Val Gln Ala Glu Lys Pro Asp Ile Met 755 760 765 Leu Gly Val Val Phe Gly Ala Leu Asn Val Ala Asp Ala Met Phe Arg 770 775 780 Thr Cys Ile Thr Glu Phe Leu His Ser Leu Glu Arg Gly Gln Val Leu 785 790 795 800 Pro Ala Asp Ser Leu Leu Asn Ile Val Asp Val Glu Leu Ile Tyr Gly 805 810 815 Gly Ile Lys Tyr Val Leu Lys Val Ala Arg Gln Ser Leu Thr Met Phe 820 825 830 Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg Pro 835 840 845 Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Ser Ser Tyr Thr Thr 850 855 860 Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn Lys 865 870 875 880 Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser Pro 885 890 895 Ser Ala Gly Lys Leu Met Gln Tyr Thr Val Glu Asp Gly Gln His Val 900 905 910 Glu Val Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile Met 915 920 925 Thr Leu Asn Val Gln Glu Ser Gly Arg Val Asn Tyr Ile Lys Arg Pro 930 935 940 Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Lys Leu Glu Leu Asp 945 950 955 960 Asp Pro Ser Lys Val His Ala Ala Gln Pro Phe Thr Gly Glu Leu Pro 965 970 975 Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Arg Leu His Gln Val Phe 980 985 990 His Ser Val Leu Glu Asn Leu Thr Asn Val Met Asn Gly Tyr Cys Leu 995 1000 1005 Pro Glu Pro Phe Phe Ser Met Lys Leu Lys Asp Trp Val Glu Lys 1010 1015 1020 Pro Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu Leu 1025 1030 1035 Gln Glu Ile Met Thr Ser Val Ala Asp Arg Ile Pro Val Pro Val 1040 1045 1050 Glu Lys Ala Val Arg Arg Val Phe Ala Gln Asp Ala Ser Asn Ile 1055 1060 1065 Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr Ile 1070 1075 1080 Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Val Asp Arg Glu 1085 1090 1095 Ala Phe Phe Met Asn Thr Gln Ser Ile Val Gln Leu Ile Gln Arg 1100 1105 1110 Tyr Arg Ser Gly Thr Arg Gly Ile Met Lys Ala Val Val Leu Asp 1115 1120 1125 Leu Leu Arg Arg Tyr Leu Asn Val Glu His His Phe Gln Gln Ala 1130 1135 1140 His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys Ala 1145 1150 1155 Asp Met Thr Arg Val Leu Asp Cys Ile Phe Ser His Ser Gln Val 1160 1165 1170 Ala Lys Lys Asn Gln Leu Val Thr Met Leu Ile Asp Glu Leu Cys 1175 1180 1185 Gly Pro Asp Pro Thr Leu Ser Glu Glu Leu Thr Ser Ile Leu Lys 1190 1195 1200 Glu Leu Thr Gln Leu Ser Arg Ser Glu His Cys Lys Val Ala Leu 1205 1210 1215 Arg Ala Arg Gln Val Leu Ile Ala Ser His Leu Pro Ser Tyr Glu 1220 1225 1230 Leu Arg His Asn Gln Val Glu Ser Ser Ser Cys Gln Pro Leu Thr 1235 1240 1245 Cys Asn Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu Ile 1250 1255 1260 Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe Tyr 1265 1270 1275 His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val 1280 1285 1290 Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His Arg 1295 1300 1305 Glu Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu 1310 1315 1320 Pro Ser Ser His Pro Asn Arg Met Ala Met Pro Ile Asn Val Ser 1325 1330 1335 Asp Pro Asp Leu Leu Arg His Ser Lys Glu Leu Phe Met Asp Ser 1340 1345 1350 Gly Phe Ser Pro Leu Cys His Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 Ser Cys Phe Ala Asn Val Pro Thr Asp Thr Pro Leu Phe Ser Lys 1385 1390 1395 Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp Ser Lys Ser Leu Gln 1400 1405 1410 Glu Glu Pro Ile His Ile Leu Asn Val Ala Ile Gln Cys Ala Asp 1415 1420 1425 His Met Glu Asp Glu Arg Leu Val Pro Val Phe Arg Ala Phe Val 1430 1435 1440 Gln Ser Lys Lys His Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 Leu Glu Pro Gly Leu Ala Phe Gln Leu Glu Leu Ser Arg Met Arg 1490 1495 1500 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Leu Glu Val Thr 1520 1525 1530 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 Val Ala His Val Ile Met Asp Pro Leu Lys Ile Glu Glu Ser Val 1595 1600 1605 Arg Ala Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 Val Leu Gln Ala Gln Val Lys Ile Asn Ile Arg Gln Thr Thr Ser 1625 1630 1635 Asp Cys Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Ser 1670 1675 1680 Leu His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser Leu Gly Thr Thr Tyr 1700 1705 1710 Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 Trp Gly Ser Pro Glu Lys Tyr Gly Pro Asp Ile Leu Thr Tyr Thr 1730 1735 1740 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 Leu Pro Gly Cys Asn Glu Val Gly Met Val Val Phe Lys Met Arg 1760 1765 1770 Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg Asp Thr Ile Val Ile 1775 1780 1785 Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser Phe Gly Ile Gly Glu 1790 1795 1800 Asp Phe Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Thr Glu Gly 1805 1810 1815 Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser Gly Ala Val Leu Gly 1820 1825 1830 Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln Val Ala Trp Val Asp 1835 1840 1845 Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr Leu Tyr Leu Tyr Leu 1850 1855 1860 Thr Pro Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn Ser Val His 1865 1870 1875 Cys Lys His Ile Glu Asp Glu Gly Glu Ser Gly Ile Ile Val Asp 1880 1885 1890 Val Ile Gly Lys Asp Ser Ser Leu Gly Val Glu Asn Leu Arg Gly 1895 1900 1905 Ser Gly Met Ile Ala Gly Glu Ala Ser Leu Ala Tyr Glu Lys Asn 1910 1915 1920 Val Thr Ile Ser Met Val Asp Cys Arg Ala Ile Gly Ile Gly Ala 1925 1930 1935 Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser 1940 1945 1950 His Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn Lys Val Leu Gly 1955 1960 1965 Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile 1970 1975 1980 Met His Thr Asn Gly Val Ser His Val Thr Val Pro Asp Asp Phe 1985 1990 1995 Glu Gly Val Cys Thr Ile Leu Glu Trp Leu Ser Tyr Ile Pro Lys 2000 2005 2010 Asp Asn Gln Ser Pro Val Pro Ile Ile Thr Pro Ser Asp Pro Ile 2015 2020 2025 Asp Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala Pro Tyr Asp Pro 2030 2035 2040 Arg Trp Leu Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr 2045 2050 2055 Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met 2060 2065 2070 Ala Pro Trp Asp Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly 2075 2080 2085 Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Ser Val Glu 2090 2095 2100 Val Ala Val Pro Ala His Pro Ala Asn Leu Asp Ser Glu Ala Lys 2105 2110 2115 Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Phe 2120 2125 2130 Lys Thr Ala Gln Val Ile Arg Asp Phe Asn Gln Glu His Leu Leu 2135 2140 2145 Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys 2150 2155 2160 Asp Met Ser Glu Gln Met Leu Lys Phe Gly Ala Tyr Ile Val Asp 2165 2170 2175 Ser Leu Arg Leu Ser Lys Gln Pro Val Leu Ile Tyr Ile Pro Pro 2180 2185 2190 Gly Ala Glu Leu Arg Gly Gly Ser Trp Val Val Leu Asp Ser Ser 2195 2200 2205 Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg 2210 2215 2220 Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg 2225 2230 2235 Lys Lys Asp Leu Val Lys Thr Ile Arg Arg Ile Asp Pro Val Cys 2240 2245 2250 Lys Lys Leu Leu Glu Pro Ala Gly Asp Thr Gln Leu Pro Asp Lys 2255 2260 2265 Asp Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala Arg Glu Asp Leu 2270 2275 2280 Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Leu 2285 2290 2295 His Asp Thr Pro Gly His Met Leu Lys Lys Gly Ile Ile Ser Asp 2300 2305 2310 Val Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe Tyr Trp Arg Leu 2315 2320 2325 Arg Arg Leu Leu Leu Glu Ala Gln Val Lys Gln Glu Ile Leu Arg 2330 2335 2340 Ala Ser Pro Glu Leu Ser His Glu His Thr Gln Ser Met Leu Arg 2345 2350 2355 Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp 2360 2365 2370 Asp Ser Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Ser 2375 2380 2385 Ala Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu Asn Leu Asn Tyr 2390 2395 2400 Leu Lys Arg Asp Ser Val Leu Lys Thr Ile Gln Ser Leu Val Gln 2405 2410 2415 Glu His Pro Glu Ala Thr Met Gly Leu Cys Gly Tyr Leu Ser Gln 2420 2425 2430 His Leu Thr Pro Ala Glu Gln Met Gln Val Val Gln Leu Leu Ser 2435 2440 2445 Thr Thr Glu Ser Pro Ala Ser His 2450 2455 9 7371 DNA Rattus norvegicus CDS (1)..(7371) 9 atg gtc ttg ctt ctc ttt ctg act tac ctg gtt ttc tcc tgc ctg acc 48 Met Val Leu Leu Leu Phe Leu Thr Tyr Leu Val Phe Ser Cys Leu Thr 1 5 10 15 att tcc tgg tta aaa atc tgg ggg aag atg aca gac tcg agg ccg ctc 96 Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Arg Pro Leu 20 25 30 agc aac agt aag gtg gat gca agc ctc ctt ccg agc aag gag gag tct 144 Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Pro Ser Lys Glu Glu Ser 35 40 45 ttt gcc tcg gac cag tca gag gag cat ggc gac tgc agc tgt ccg ttg 192 Phe Ala Ser Asp Gln Ser Glu Glu His Gly Asp Cys Ser Cys Pro Leu 50 55 60 aca act cct gac cag gag gag ctg gcc tcc cac gga ggt cct gta gat 240 Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser His Gly Gly Pro Val Asp 65 70 75 80 gcc agt cag cag agg aac tct gta cca acc tca cac cag aag cct ccg 288 Ala Ser Gln Gln Arg Asn Ser Val Pro Thr Ser His Gln Lys Pro Pro 85 90 95 agg aac cca cta tct tcc aat gac acc tgt tcc tcc cca gaa ctc caa 336 Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys Ser Ser Pro Glu Leu Gln 100 105 110 acc aac ggg gta gca gca cct ggc tca gag gtt cca gaa gcc aac ggg 384 Thr Asn Gly Val Ala Ala Pro Gly Ser Glu Val Pro Glu Ala Asn Gly 115 120 125 ttg cct ttc cca gcc agg cct cag acc cag aga acg gga tcc ccc act 432 Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln Arg Thr Gly Ser Pro Thr 130 135 140 agg gag gac aag aag cag gca ccc atc aag agg cag ctg atg acc agc 480 Arg Glu Asp Lys Lys Gln Ala Pro Ile Lys Arg Gln Leu Met Thr Ser 145 150 155 160 ttt atc ctg ggc tcc ctc gat gac aac tcc tct gac gag gac cct agt 528 Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser Ser Asp Glu Asp Pro Ser 165 170 175 tct aac tcc ttt cag acc tcc tct cgg aag ggc agc agg gat agc ctg 576 Ser Asn Ser Phe Gln Thr Ser Ser Arg Lys Gly Ser Arg Asp Ser Leu 180 185 190 ggc acc tgt tcc cag gag gct gca ttg aac aca gct gat cct gag tct 624 Gly Thr Cys Ser Gln Glu Ala Ala Leu Asn Thr Ala Asp Pro Glu Ser 195 200 205 cac aca cct act atg agg ccc agc atg tct gga ctc cat ctg gtg aag 672 His Thr Pro Thr Met Arg Pro Ser Met Ser Gly Leu His Leu Val Lys 210 215 220 aga ggc cgt gaa cac aag aaa ctg gac ctg cac aga gat ttc act gta 720 Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp Phe Thr Val 225 230 235 240 gct tcc cca gcc gaa ttt gtc acc cgc ttt gga ggc aac agg gtt atc 768 Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Arg Val Ile 245 250 255 gag acg gtg ctc atc gcc aat aat ggt atc gct gcg gtc aag tgg atg 816 Glu Thr Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Trp Met 260 265 270 cgc tcc atc cgc cgc tgg gcc tat gag atg ttc cgt aat gaa cgc gct 864 Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn Glu Arg Ala 275 280 285 atc cgg ttt gtg gtt atg gtg aca ccc gag gat ctt aag gcc aac gca 912 Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn Ala 290 295 300 gag tac tac aag atg gcg gac cca gta ctt ccg gtc cca gga gga ccc 960 Glu Tyr Tyr Lys Met Ala Asp Pro Val Leu Pro Val Pro Gly Gly Pro 305 310 315 320 aat aat aac aac tac gcc aac gtt gag ctg atc ata gac att gcc aag 1008 Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Ile Asp Ile Ala Lys 325 330 335 aga atc cct gtg cag gcc gtg tgg gct ggc tgg ggc cac gct tcg gaa 1056 Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser Glu 340 345 350 aac ccc aaa ctt cca gag cta ctg tgc aag cac ggg att gct ttt cta 1104 Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys His Gly Ile Ala Phe Leu 355 360 365 ggt ccc cga gtg agg cca atg ttg ggc ctg gga gac agg ctc tcc tcc 1152 Gly Pro Arg Val Arg Pro Met Leu Gly Leu Gly Asp Arg Leu Ser Ser 370 375 380 acc att gta gcc cag aca ttg cag atc cca act cta ccc tgg agc gga 1200 Thr Ile Val Ala Gln Thr Leu Gln Ile Pro Thr Leu Pro Trp Ser Gly 385 390 395 400 agc ggt ctc aca gtg gag tgg acg gag gac agc cag cat cag ggc aaa 1248 Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Ser Gln His Gln Gly Lys

405 410 415 tgc atc agc gtc acg gaa gac gtt tat gaa caa ggc tgt gtg aga gat 1296 Cys Ile Ser Val Thr Glu Asp Val Tyr Glu Gln Gly Cys Val Arg Asp 420 425 430 gtg gac gaa ggc ttg cag gca gca gaa aaa gta gga ttt cct ctg atg 1344 Val Asp Glu Gly Leu Gln Ala Ala Glu Lys Val Gly Phe Pro Leu Met 435 440 445 atc aaa gcc tct gaa ggt gga gga ggg aaa gga atc cgg cag gct gag 1392 Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Gln Ala Glu 450 455 460 agt gca gag gac ttc cca tgc ttt ttc aga cag gtg cag agt gag atc 1440 Ser Ala Glu Asp Phe Pro Cys Phe Phe Arg Gln Val Gln Ser Glu Ile 465 470 475 480 ccg ggc tcg ccc atc ttt ctc atg aag ctg gcc cag aat gcc cgg cac 1488 Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln Asn Ala Arg His 485 490 495 ttg gag gtc cag gtc ttg gca gat cag tat ggg aac gca gtg tcc ctg 1536 Leu Glu Val Gln Val Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser Leu 500 505 510 ttt gga cga gac tgc tcc atc cag agg cgg cac cag aag atc att gag 1584 Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Ile Glu 515 520 525 gag gct ccg gcc aac atc gct gct ccg gct gtg ttt gag ttc atg gaa 1632 Glu Ala Pro Ala Asn Ile Ala Ala Pro Ala Val Phe Glu Phe Met Glu 530 535 540 cag tgt gcc gtc ctc ctg gcc aag act gtg gtt tat gtg agc gcg gga 1680 Gln Cys Ala Val Leu Leu Ala Lys Thr Val Val Tyr Val Ser Ala Gly 545 550 555 560 acc gtg ggg tac cta tac agc cag gat ggc agc ttt cac ttc ttg gag 1728 Thr Val Gly Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu Glu 565 570 575 ctg aac cca cgc ctg cag gtg gaa cat ccc tgc act gaa atg att gca 1776 Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile Ala 580 585 590 gat gtc aac ctg ccc gct gca cag tta cag atc gcc atg ggc gtg ccc 1824 Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val Pro 595 600 605 ctg cac cgg ctg aag gac ata cgg ctt ctg tac gga gag tcc ccc tgg 1872 Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro Trp 610 615 620 gga gtg acc ccc gtt tct ttt gag acc cct ttg agc cct ccc att gcc 1920 Gly Val Thr Pro Val Ser Phe Glu Thr Pro Leu Ser Pro Pro Ile Ala 625 630 635 640 cga ggc cat gtc att gca gcc agg atc acc agc gaa aac cca gac gag 1968 Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp Glu 645 650 655 gcc ttt aag cca agc tca ggg aca gta cag gag ctg aac ttc cgc agc 2016 Ala Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg Ser 660 665 670 aac aag aac gtg tgg ggt tac ttc agc gtg gcc gct gct gga ggc ttg 2064 Asn Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly Leu 675 680 685 cac gag ttt ccg att tcc cag ttt ggg cac tgc ttc tcc tgg ggc gag 2112 His Glu Phe Pro Ile Ser Gln Phe Gly His Cys Phe Ser Trp Gly Glu 690 695 700 aac cag gaa gag gct att tcg aac atg gtg gtg gct ttg aaa gaa ctg 2160 Asn Gln Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu Leu 705 710 715 720 tct atc cgg ggt gac ttc cgg acc acc gtg gaa tat ctc gtc aac ctt 2208 Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Val Asn Leu 725 730 735 ctg gag acg gag agc tta cag aac aat gat atc gac acg ggg tgg ctg 2256 Leu Glu Thr Glu Ser Leu Gln Asn Asn Asp Ile Asp Thr Gly Trp Leu 740 745 750 gac cac ctc atc gct cag cgg gtg cag gca gag aag ccg gac atc atg 2304 Asp His Leu Ile Ala Gln Arg Val Gln Ala Glu Lys Pro Asp Ile Met 755 760 765 ctc ggg gtg gtg ttt ggg gcc ttg aac gtg gca gac gca atg ttc aga 2352 Leu Gly Val Val Phe Gly Ala Leu Asn Val Ala Asp Ala Met Phe Arg 770 775 780 acc tgt att acg gaa ttc ctg cat tcc ttg gaa agg ggt cag gtc ctc 2400 Thr Cys Ile Thr Glu Phe Leu His Ser Leu Glu Arg Gly Gln Val Leu 785 790 795 800 ccg gct gat tct ctg ctg aac atc gtg gac gtt gaa ttg att tac gga 2448 Pro Ala Asp Ser Leu Leu Asn Ile Val Asp Val Glu Leu Ile Tyr Gly 805 810 815 ggc atc aaa tat gtt ctc aag gtg gcc cgg cag tcc ctg acc atg ttt 2496 Gly Ile Lys Tyr Val Leu Lys Val Ala Arg Gln Ser Leu Thr Met Phe 820 825 830 gtc ctc atc atg aat ggt tgc cac atc gag atc gat gcc cac cgg ccg 2544 Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg Pro 835 840 845 aac gat ggg ggc ctg ctc ctg tcc tac aat ggt agc agt tac act aca 2592 Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Ser Ser Tyr Thr Thr 850 855 860 tac atg aag gaa gag gtg gac agt tac cgg atc act atc ggc aat aag 2640 Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn Lys 865 870 875 880 aca tgc gtg ttt gaa aag gaa aac gac ccc acc gtc ctg aga tcc ccc 2688 Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser Pro 885 890 895 tcg gct ggg aag ctg atg cag tac acg gtg gag gat ggc cag cac gtg 2736 Ser Ala Gly Lys Leu Met Gln Tyr Thr Val Glu Asp Gly Gln His Val 900 905 910 gaa gtc ggg agc agc tat gct gag atg gag gtg atg aag atg atc atg 2784 Glu Val Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile Met 915 920 925 acc ctg aac gtg caa gag agc ggc cgg gtg aac tac atc aag cga cca 2832 Thr Leu Asn Val Gln Glu Ser Gly Arg Val Asn Tyr Ile Lys Arg Pro 930 935 940 ggg gcg gta ttg gag gct ggc tgc gtg gtg gca aag cta gaa ctc gat 2880 Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Lys Leu Glu Leu Asp 945 950 955 960 gac cct tca aaa gtg cac gcg gca cag ccg ttc aca ggg gag ctc ccc 2928 Asp Pro Ser Lys Val His Ala Ala Gln Pro Phe Thr Gly Glu Leu Pro 965 970 975 gcc cag cag act ctg ccc atc ctc ggg gag agg ctg cat cag gtg ttc 2976 Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Arg Leu His Gln Val Phe 980 985 990 cac agc gtc ttg gaa aat ctg acc aat gtc atg aat ggc tac tgc ctg 3024 His Ser Val Leu Glu Asn Leu Thr Asn Val Met Asn Gly Tyr Cys Leu 995 1000 1005 ccc gag ccc ttc ttc agc atg aag ctg aag gac tgg gtg gag aag 3069 Pro Glu Pro Phe Phe Ser Met Lys Leu Lys Asp Trp Val Glu Lys 1010 1015 1020 ccc atg atg act ctc cgg cat ccc tcc cta cct ctg ctg gag ctg 3114 Pro Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu Leu 1025 1030 1035 cag gag atc atg acc agc gtg gca gac cgc atc ccg gtt ccg gtg 3159 Gln Glu Ile Met Thr Ser Val Ala Asp Arg Ile Pro Val Pro Val 1040 1045 1050 gag aag gca gtc cgc agg gtg ttt gcg cag gac gcc agc aac atc 3204 Glu Lys Ala Val Arg Arg Val Phe Ala Gln Asp Ala Ser Asn Ile 1055 1060 1065 act tcg gtg ctc tgc cag ttc ccc agc cag cag ata gcc acc atc 3249 Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr Ile 1070 1075 1080 ctg gac tgc cac gcc gcc acc ctg cag cgt aag gtg gac cga gag 3294 Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Val Asp Arg Glu 1085 1090 1095 gcc ttc ttc atg aac aca cag agc atc gtg cag ctg atc cag aga 3339 Ala Phe Phe Met Asn Thr Gln Ser Ile Val Gln Leu Ile Gln Arg 1100 1105 1110 tac cgc agt ggg acc cgt ggc atc atg aag gct gtg gtg cta gac 3384 Tyr Arg Ser Gly Thr Arg Gly Ile Met Lys Ala Val Val Leu Asp 1115 1120 1125 ctc ctg agg aga tat ctg aac gtg gag cat cat ttc cag caa gcc 3429 Leu Leu Arg Arg Tyr Leu Asn Val Glu His His Phe Gln Gln Ala 1130 1135 1140 cac tat gac aag tgt gtg atc aac ctg agg gag cag ttc aag gcg 3474 His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys Ala 1145 1150 1155 gac atg act cgg gtg ctg gac tgc atc ttc tca cac tca caa gtg 3519 Asp Met Thr Arg Val Leu Asp Cys Ile Phe Ser His Ser Gln Val 1160 1165 1170 gcc aag aag aac cag ctg gtg acc atg ttg ata gat gag ctg tgt 3564 Ala Lys Lys Asn Gln Leu Val Thr Met Leu Ile Asp Glu Leu Cys 1175 1180 1185 ggc cca gac ccc acc ctg tca gaa gag ctg acc tcc atc ctc aag 3609 Gly Pro Asp Pro Thr Leu Ser Glu Glu Leu Thr Ser Ile Leu Lys 1190 1195 1200 gaa ctc acg cag ttg agc agg agt gag cac tgc aag gtg gcc ctc 3654 Glu Leu Thr Gln Leu Ser Arg Ser Glu His Cys Lys Val Ala Leu 1205 1210 1215 aga gcc agg cag gtc ctg att gcc tct cac ctc ccc tcc tac gag 3699 Arg Ala Arg Gln Val Leu Ile Ala Ser His Leu Pro Ser Tyr Glu 1220 1225 1230 ctg cgg cac aac cag gtg gag tca tct tcc tgt cag cca ttg aca 3744 Leu Arg His Asn Gln Val Glu Ser Ser Ser Cys Gln Pro Leu Thr 1235 1240 1245 tgt aat ggc cac cag ttc tgc ccg gaa aac ctc aag aaa cta ata 3789 Cys Asn Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu Ile 1250 1255 1260 ctt tcg gaa acg acc ata ttc gat gtc ctg ccc act ttc ttc tat 3834 Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe Tyr 1265 1270 1275 cac gct aac aag gtc gtc tgt atg gcg tcc ctg gag gtt tat gtg 3879 His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val 1280 1285 1290 agg aga ggt tac atc gcc tac gag tta aac agc cta cag cac cgg 3924 Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His Arg 1295 1300 1305 gag ctc cct gac ggc acc tgc gtg gtg gag ttc cag ttc atg ctg 3969 Glu Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu 1310 1315 1320 ccg tct tcc cac ccc aac cgg atg gcc atg ccc atc aat gtc tct 4014 Pro Ser Ser His Pro Asn Arg Met Ala Met Pro Ile Asn Val Ser 1325 1330 1335 gac cct gac ctg ctg aga cac agt aag gaa ctc ttc atg gac agt 4059 Asp Pro Asp Leu Leu Arg His Ser Lys Glu Leu Phe Met Asp Ser 1340 1345 1350 ggc ttc tcc cca ctg tgt cac cag cgg atg ggg gcc atg gtg gcc 4104 Gly Phe Ser Pro Leu Cys His Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 ttc agg aga ttt gag gag ttc acc agg aac ttc gat gaa gtc atc 4149 Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 tcc tgc ttt gcc aac gtg cct aca gac act cct ctc ttc agt aag 4194 Ser Cys Phe Ala Asn Val Pro Thr Asp Thr Pro Leu Phe Ser Lys 1385 1390 1395 gcg tgc act tcc ctc tac tca gag gag gac agc aag agc ctt caa 4239 Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp Ser Lys Ser Leu Gln 1400 1405 1410 gag gag ccc atc cac atc ctg aat gtg gcc atc cag tgc gcc gac 4284 Glu Glu Pro Ile His Ile Leu Asn Val Ala Ile Gln Cys Ala Asp 1415 1420 1425 cac atg gag gac gag aga ctg gtg ccg gtt ttc cgt gcc ttt gta 4329 His Met Glu Asp Glu Arg Leu Val Pro Val Phe Arg Ala Phe Val 1430 1435 1440 cag tcc aag aaa cac atc ctt gtg gat tac gga ctg cga aga atc 4374 Gln Ser Lys Lys His Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 aca ttc ctt atc gcc caa gag aag gaa ttt ccc aag ttc ttc acg 4419 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 ttc aga gcg aga gat gag ttt gca gaa gac cgg att tac cgc cac 4464 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 ttg gag ccg ggc ctg gcc ttc cag ctg gag ctg agc cgg atg cgc 4509 Leu Glu Pro Gly Leu Ala Phe Gln Leu Glu Leu Ser Arg Met Arg 1490 1495 1500 aac ttt gac ttg acg gcc gtg ccc tgt gcc aac cat aag atg cat 4554 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 ctt tac ctg gga gcc gcc aag gtg aag gaa ggg ctg gag gtg act 4599 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Leu Glu Val Thr 1520 1525 1530 gac cac agg ttc ttc atc cga gcc atc ata agg cac tca gac ctg 4644 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 atc acc aag gaa gcc tcc ttc gag tac ctg cag aat gaa ggg gag 4689 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 cgg ctg ctg ctg gaa gcc atg gac gag ctg gag gtg gcg ttc aac 4734 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 aac acc agc gtg cgc act gac tgc aac cac atc ttc ctc aac ttc 4779 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 gtg gcc cac gtc atc atg gac cca ctc aag atc gag gag tcg gtg 4824 Val Ala His Val Ile Met Asp Pro Leu Lys Ile Glu Glu Ser Val 1595 1600 1605 cgt gcc atg gtc atg cgt tac ggc agt cgg ctg tgg aag ctc cgt 4869 Arg Ala Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 gtg ctg cag gca caa gtt aag atc aac atc cgt cag acg acc tcg 4914 Val Leu Gln Ala Gln Val Lys Ile Asn Ile Arg Gln Thr Thr Ser 1625 1630 1635 gac tgc gcc gtc ccc att cgc ctc ttc atc acc aac gag tcc ggc 4959 Asp Cys Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 tac tac ctg gac atc agc ctc tac aaa gaa gtg acc gac tcc aga 5004 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 tcc gga aac atc atg ttt cat tcc ttc ggc aac aaa caa ggg agc 5049 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Ser 1670 1675 1680 ctg cac ggg atg ctg atc aac acg ccc tac gtc acc aag gat ctg 5094 Leu His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 ctc caa gcc aag cga ttc cag gcg cag tcc ctg ggg acc acc tat 5139 Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser Leu Gly Thr Thr Tyr 1700 1705 1710 gtg tac gac ttc cca gag atg ttc agg cag gct ctc ttt aaa ttg 5184 Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 tgg ggc tcc cca gag aag tac ggg ccc gat atc ctg aca tac aca 5229 Trp Gly Ser Pro Glu Lys Tyr Gly Pro Asp Ile Leu Thr Tyr Thr 1730 1735 1740 gag ctg gtg ttg gac tcc cag ggc cag ctg gtg gag atg aac cgg 5274 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 ctt cct ggt tgt aac gag gtg ggc atg gtg gtt ttc aaa atg agg 5319 Leu Pro Gly Cys Asn Glu Val Gly Met Val Val Phe Lys Met Arg 1760 1765 1770 ttc aag acc ccg gag tat cca gaa ggc cgg gac act atc gtc atc 5364 Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg Asp Thr Ile Val Ile 1775 1780 1785 ggc aac gac att acc ttc caa atc ggc tct ttc ggc ata gga gag 5409 Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser Phe Gly Ile Gly Glu 1790 1795 1800 gac ttc ctg tat cta cgg gca tcg gag atg gcc cgg aca gag ggc 5454 Asp Phe Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Thr Glu Gly 1805 1810 1815 atc ccc caa atc tat ctg gca gcc aac agc ggc gcc gta ttg ggc 5499 Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser Gly Ala Val Leu Gly 1820 1825 1830 ctg tcc gag gag atc aag cag ata ttc caa gtg gca tgg gtg gac 5544 Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln Val Ala Trp Val Asp 1835 1840 1845 cct gag gat ccc tac aaa gga ttt aga tac ctg tac ctg tac ctg 5589 Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr Leu Tyr Leu Tyr Leu 1850 1855 1860 acg ccc caa gac tac acc cag atc agc tcc cag aac tcc gtg cac 5634 Thr Pro Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn Ser Val His 1865 1870 1875 tgc aaa cac atc gag gac gaa ggc gag tca ggt att atc gtt gat 5679 Cys Lys His Ile Glu Asp Glu Gly Glu Ser Gly Ile Ile Val Asp 1880 1885 1890 gtc atc ggg aag gac agc agc ctg ggt gtg gag aac ctg cgg ggc 5724 Val

Ile Gly Lys Asp Ser Ser Leu Gly Val Glu Asn Leu Arg Gly 1895 1900 1905 tcg ggc atg att gca gga gag gct tct ctg gct tac gaa aaa aat 5769 Ser Gly Met Ile Ala Gly Glu Ala Ser Leu Ala Tyr Glu Lys Asn 1910 1915 1920 gtc acc atc agc atg gtc gac tgc cgc gcc atc gga atc ggg gct 5814 Val Thr Ile Ser Met Val Asp Cys Arg Ala Ile Gly Ile Gly Ala 1925 1930 1935 tac ctg gtg agg ctg ggc cag cgg gtg atc cag gtg gaa aac tcc 5859 Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser 1940 1945 1950 cac atc atc ctc acg gga gcc ggt gct ctc aac aag gtt ctg gga 5904 His Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn Lys Val Leu Gly 1955 1960 1965 aga gag gtc tac aca tcc aac aac caa ctg ggc ggt gtg cag atc 5949 Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile 1970 1975 1980 atg cac acc aac ggg gtc tcc cac gtc acg gtg cca gat gac ttc 5994 Met His Thr Asn Gly Val Ser His Val Thr Val Pro Asp Asp Phe 1985 1990 1995 gag ggg gtc tgc acc att ctg gaa tgg ctg tca tat ata cca aag 6039 Glu Gly Val Cys Thr Ile Leu Glu Trp Leu Ser Tyr Ile Pro Lys 2000 2005 2010 gac aat caa agc cca gtc ccc atc atc act cct tct gac ccc atc 6084 Asp Asn Gln Ser Pro Val Pro Ile Ile Thr Pro Ser Asp Pro Ile 2015 2020 2025 gac agg gaa att gaa ttc acc cca acc aaa gct ccc tat gac ccc 6129 Asp Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala Pro Tyr Asp Pro 2030 2035 2040 agg tgg ctg ctg gca ggg agg cct cac cca act ctg aag ggg acc 6174 Arg Trp Leu Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr 2045 2050 2055 tgg cag agt gga ttc ttc gac cat ggc agt ttc aag gaa atc atg 6219 Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met 2060 2065 2070 gca ccc tgg gac cag act gtg gtg act gga cga gca agg ctg ggg 6264 Ala Pro Trp Asp Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly 2075 2080 2085 ggc atc cct gta ggg gtg att gcc gtg gag act cgg tct gtg gag 6309 Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Ser Val Glu 2090 2095 2100 gtg gct gtc cct gct cac cca gcc aac ttg gat tct gag gcc aag 6354 Val Ala Val Pro Ala His Pro Ala Asn Leu Asp Ser Glu Ala Lys 2105 2110 2115 atc atc cag cag gca ggc cag gtg tgg ttc ccg gac tct gcc ttc 6399 Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Phe 2120 2125 2130 aag acg gct cag gtc atc agg gac ttc aac cag gag cat ctg ctt 6444 Lys Thr Ala Gln Val Ile Arg Asp Phe Asn Gln Glu His Leu Leu 2135 2140 2145 ctc atg atc ttt gct aac tgg aga ggc ttc tcg ggc ggc atg aaa 6489 Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys 2150 2155 2160 gac atg tcc gag cag atg ctg aag ttt ggc gcc tac atc gtg gac 6534 Asp Met Ser Glu Gln Met Leu Lys Phe Gly Ala Tyr Ile Val Asp 2165 2170 2175 agt ctc cgt ctg tcc aag cag cca gtc ctc atc tat atc cct ccc 6579 Ser Leu Arg Leu Ser Lys Gln Pro Val Leu Ile Tyr Ile Pro Pro 2180 2185 2190 ggt gcc gaa ctc cga ggg ggc tcc tgg gtt gtc ctc gac tcc agc 6624 Gly Ala Glu Leu Arg Gly Gly Ser Trp Val Val Leu Asp Ser Ser 2195 2200 2205 atc aac ccc ctg tgc ata gag atg tac gca gac aaa gag agc agg 6669 Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg 2210 2215 2220 ggg ggt gtt ctg gag ccc gag ggc act gtg gag att aag ttc cgg 6714 Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg 2225 2230 2235 aag aaa gat ttg gtg aag acc ata agg agg att gac cca gtg tgc 6759 Lys Lys Asp Leu Val Lys Thr Ile Arg Arg Ile Asp Pro Val Cys 2240 2245 2250 aag aaa ctc ctg gaa cca gct ggg gac acc cag ctc cct gac aag 6804 Lys Lys Leu Leu Glu Pro Ala Gly Asp Thr Gln Leu Pro Asp Lys 2255 2260 2265 gac cgg aaa gag ctg gag agc cag ctg aag gcc cgg gag gac ctg 6849 Asp Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala Arg Glu Asp Leu 2270 2275 2280 ctg ctc ccc atc tac cac cag gtg gca gtg cag ttc gcc gac ctg 6894 Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Leu 2285 2290 2295 cat gac acg ccg ggc cac atg ctg aag aag gga atc att tct gat 6939 His Asp Thr Pro Gly His Met Leu Lys Lys Gly Ile Ile Ser Asp 2300 2305 2310 gtc ctg gag tgg aag acc aca cgt act tac ttc tac tgg agg ctg 6984 Val Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe Tyr Trp Arg Leu 2315 2320 2325 cgc cgg ctg ctg ctg gag gca cag gtg aag cag gag att ctg cga 7029 Arg Arg Leu Leu Leu Glu Ala Gln Val Lys Gln Glu Ile Leu Arg 2330 2335 2340 gcc agc cct gag ctg agc cat gag cac acg cag tcc atg ctg cga 7074 Ala Ser Pro Glu Leu Ser His Glu His Thr Gln Ser Met Leu Arg 2345 2350 2355 cgc tgg ttt gtg gag acc gag ggc gcc gtc aag gcc tac ctg tgg 7119 Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp 2360 2365 2370 gac agc aac cag gtg gta gtc cag tgg ctg gaa cag cac tgg tca 7164 Asp Ser Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Ser 2375 2380 2385 gcc agg gac aac ctg cgt tcc act atc cga gag aac ctc aat tat 7209 Ala Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu Asn Leu Asn Tyr 2390 2395 2400 ctg aag cgg gac tct gtc ctc aag acc atc caa agc cta gtt caa 7254 Leu Lys Arg Asp Ser Val Leu Lys Thr Ile Gln Ser Leu Val Gln 2405 2410 2415 gaa cac cca gag gcg acc atg gga ctg tgt gga tac ctg agc cag 7299 Glu His Pro Glu Ala Thr Met Gly Leu Cys Gly Tyr Leu Ser Gln 2420 2425 2430 cac ctc acg ccc gct gag cag atg cag gtg gtt cag ctg ctg tcg 7344 His Leu Thr Pro Ala Glu Gln Met Gln Val Val Gln Leu Leu Ser 2435 2440 2445 acc acg gag agc cca gct tcc cac tga 7371 Thr Thr Glu Ser Pro Ala Ser His 2450 2455 10 2456 PRT Rattus norvegicus 10 Met Val Leu Leu Leu Phe Leu Thr Tyr Leu Val Phe Ser Cys Leu Thr 1 5 10 15 Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Arg Pro Leu 20 25 30 Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Pro Ser Lys Glu Glu Ser 35 40 45 Phe Ala Ser Asp Gln Ser Glu Glu His Gly Asp Cys Ser Cys Pro Leu 50 55 60 Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser His Gly Gly Pro Val Asp 65 70 75 80 Ala Ser Gln Gln Arg Asn Ser Val Pro Thr Ser His Gln Lys Pro Pro 85 90 95 Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys Ser Ser Pro Glu Leu Gln 100 105 110 Thr Asn Gly Val Ala Ala Pro Gly Ser Glu Val Pro Glu Ala Asn Gly 115 120 125 Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln Arg Thr Gly Ser Pro Thr 130 135 140 Arg Glu Asp Lys Lys Gln Ala Pro Ile Lys Arg Gln Leu Met Thr Ser 145 150 155 160 Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser Ser Asp Glu Asp Pro Ser 165 170 175 Ser Asn Ser Phe Gln Thr Ser Ser Arg Lys Gly Ser Arg Asp Ser Leu 180 185 190 Gly Thr Cys Ser Gln Glu Ala Ala Leu Asn Thr Ala Asp Pro Glu Ser 195 200 205 His Thr Pro Thr Met Arg Pro Ser Met Ser Gly Leu His Leu Val Lys 210 215 220 Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp Phe Thr Val 225 230 235 240 Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Arg Val Ile 245 250 255 Glu Thr Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Trp Met 260 265 270 Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn Glu Arg Ala 275 280 285 Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn Ala 290 295 300 Glu Tyr Tyr Lys Met Ala Asp Pro Val Leu Pro Val Pro Gly Gly Pro 305 310 315 320 Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Ile Asp Ile Ala Lys 325 330 335 Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser Glu 340 345 350 Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys His Gly Ile Ala Phe Leu 355 360 365 Gly Pro Arg Val Arg Pro Met Leu Gly Leu Gly Asp Arg Leu Ser Ser 370 375 380 Thr Ile Val Ala Gln Thr Leu Gln Ile Pro Thr Leu Pro Trp Ser Gly 385 390 395 400 Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Ser Gln His Gln Gly Lys 405 410 415 Cys Ile Ser Val Thr Glu Asp Val Tyr Glu Gln Gly Cys Val Arg Asp 420 425 430 Val Asp Glu Gly Leu Gln Ala Ala Glu Lys Val Gly Phe Pro Leu Met 435 440 445 Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Gln Ala Glu 450 455 460 Ser Ala Glu Asp Phe Pro Cys Phe Phe Arg Gln Val Gln Ser Glu Ile 465 470 475 480 Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln Asn Ala Arg His 485 490 495 Leu Glu Val Gln Val Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser Leu 500 505 510 Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Ile Glu 515 520 525 Glu Ala Pro Ala Asn Ile Ala Ala Pro Ala Val Phe Glu Phe Met Glu 530 535 540 Gln Cys Ala Val Leu Leu Ala Lys Thr Val Val Tyr Val Ser Ala Gly 545 550 555 560 Thr Val Gly Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu Glu 565 570 575 Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile Ala 580 585 590 Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val Pro 595 600 605 Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro Trp 610 615 620 Gly Val Thr Pro Val Ser Phe Glu Thr Pro Leu Ser Pro Pro Ile Ala 625 630 635 640 Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp Glu 645 650 655 Ala Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg Ser 660 665 670 Asn Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly Leu 675 680 685 His Glu Phe Pro Ile Ser Gln Phe Gly His Cys Phe Ser Trp Gly Glu 690 695 700 Asn Gln Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu Leu 705 710 715 720 Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Val Asn Leu 725 730 735 Leu Glu Thr Glu Ser Leu Gln Asn Asn Asp Ile Asp Thr Gly Trp Leu 740 745 750 Asp His Leu Ile Ala Gln Arg Val Gln Ala Glu Lys Pro Asp Ile Met 755 760 765 Leu Gly Val Val Phe Gly Ala Leu Asn Val Ala Asp Ala Met Phe Arg 770 775 780 Thr Cys Ile Thr Glu Phe Leu His Ser Leu Glu Arg Gly Gln Val Leu 785 790 795 800 Pro Ala Asp Ser Leu Leu Asn Ile Val Asp Val Glu Leu Ile Tyr Gly 805 810 815 Gly Ile Lys Tyr Val Leu Lys Val Ala Arg Gln Ser Leu Thr Met Phe 820 825 830 Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg Pro 835 840 845 Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Ser Ser Tyr Thr Thr 850 855 860 Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn Lys 865 870 875 880 Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser Pro 885 890 895 Ser Ala Gly Lys Leu Met Gln Tyr Thr Val Glu Asp Gly Gln His Val 900 905 910 Glu Val Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile Met 915 920 925 Thr Leu Asn Val Gln Glu Ser Gly Arg Val Asn Tyr Ile Lys Arg Pro 930 935 940 Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Lys Leu Glu Leu Asp 945 950 955 960 Asp Pro Ser Lys Val His Ala Ala Gln Pro Phe Thr Gly Glu Leu Pro 965 970 975 Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Arg Leu His Gln Val Phe 980 985 990 His Ser Val Leu Glu Asn Leu Thr Asn Val Met Asn Gly Tyr Cys Leu 995 1000 1005 Pro Glu Pro Phe Phe Ser Met Lys Leu Lys Asp Trp Val Glu Lys 1010 1015 1020 Pro Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu Leu 1025 1030 1035 Gln Glu Ile Met Thr Ser Val Ala Asp Arg Ile Pro Val Pro Val 1040 1045 1050 Glu Lys Ala Val Arg Arg Val Phe Ala Gln Asp Ala Ser Asn Ile 1055 1060 1065 Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr Ile 1070 1075 1080 Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Val Asp Arg Glu 1085 1090 1095 Ala Phe Phe Met Asn Thr Gln Ser Ile Val Gln Leu Ile Gln Arg 1100 1105 1110 Tyr Arg Ser Gly Thr Arg Gly Ile Met Lys Ala Val Val Leu Asp 1115 1120 1125 Leu Leu Arg Arg Tyr Leu Asn Val Glu His His Phe Gln Gln Ala 1130 1135 1140 His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys Ala 1145 1150 1155 Asp Met Thr Arg Val Leu Asp Cys Ile Phe Ser His Ser Gln Val 1160 1165 1170 Ala Lys Lys Asn Gln Leu Val Thr Met Leu Ile Asp Glu Leu Cys 1175 1180 1185 Gly Pro Asp Pro Thr Leu Ser Glu Glu Leu Thr Ser Ile Leu Lys 1190 1195 1200 Glu Leu Thr Gln Leu Ser Arg Ser Glu His Cys Lys Val Ala Leu 1205 1210 1215 Arg Ala Arg Gln Val Leu Ile Ala Ser His Leu Pro Ser Tyr Glu 1220 1225 1230 Leu Arg His Asn Gln Val Glu Ser Ser Ser Cys Gln Pro Leu Thr 1235 1240 1245 Cys Asn Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu Ile 1250 1255 1260 Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe Tyr 1265 1270 1275 His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr Val 1280 1285 1290 Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His Arg 1295 1300 1305 Glu Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met Leu 1310 1315 1320 Pro Ser Ser His Pro Asn Arg Met Ala Met Pro Ile Asn Val Ser 1325 1330 1335 Asp Pro Asp Leu Leu Arg His Ser Lys Glu Leu Phe Met Asp Ser 1340 1345 1350 Gly Phe Ser Pro Leu Cys His Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 Ser Cys Phe Ala Asn Val Pro Thr Asp Thr Pro Leu Phe Ser Lys 1385 1390 1395 Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp Ser Lys Ser Leu Gln 1400 1405 1410 Glu Glu Pro Ile His Ile Leu Asn Val Ala Ile Gln Cys Ala Asp 1415 1420 1425 His Met Glu Asp Glu Arg Leu Val Pro Val Phe Arg Ala Phe Val 1430 1435 1440 Gln Ser Lys Lys His Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 Leu Glu Pro Gly Leu Ala Phe Gln Leu Glu Leu Ser Arg Met Arg

1490 1495 1500 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Leu Glu Val Thr 1520 1525 1530 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 Val Ala His Val Ile Met Asp Pro Leu Lys Ile Glu Glu Ser Val 1595 1600 1605 Arg Ala Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 Val Leu Gln Ala Gln Val Lys Ile Asn Ile Arg Gln Thr Thr Ser 1625 1630 1635 Asp Cys Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Ser 1670 1675 1680 Leu His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser Leu Gly Thr Thr Tyr 1700 1705 1710 Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 Trp Gly Ser Pro Glu Lys Tyr Gly Pro Asp Ile Leu Thr Tyr Thr 1730 1735 1740 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 Leu Pro Gly Cys Asn Glu Val Gly Met Val Val Phe Lys Met Arg 1760 1765 1770 Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg Asp Thr Ile Val Ile 1775 1780 1785 Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser Phe Gly Ile Gly Glu 1790 1795 1800 Asp Phe Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Thr Glu Gly 1805 1810 1815 Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser Gly Ala Val Leu Gly 1820 1825 1830 Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln Val Ala Trp Val Asp 1835 1840 1845 Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr Leu Tyr Leu Tyr Leu 1850 1855 1860 Thr Pro Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn Ser Val His 1865 1870 1875 Cys Lys His Ile Glu Asp Glu Gly Glu Ser Gly Ile Ile Val Asp 1880 1885 1890 Val Ile Gly Lys Asp Ser Ser Leu Gly Val Glu Asn Leu Arg Gly 1895 1900 1905 Ser Gly Met Ile Ala Gly Glu Ala Ser Leu Ala Tyr Glu Lys Asn 1910 1915 1920 Val Thr Ile Ser Met Val Asp Cys Arg Ala Ile Gly Ile Gly Ala 1925 1930 1935 Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser 1940 1945 1950 His Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn Lys Val Leu Gly 1955 1960 1965 Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile 1970 1975 1980 Met His Thr Asn Gly Val Ser His Val Thr Val Pro Asp Asp Phe 1985 1990 1995 Glu Gly Val Cys Thr Ile Leu Glu Trp Leu Ser Tyr Ile Pro Lys 2000 2005 2010 Asp Asn Gln Ser Pro Val Pro Ile Ile Thr Pro Ser Asp Pro Ile 2015 2020 2025 Asp Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala Pro Tyr Asp Pro 2030 2035 2040 Arg Trp Leu Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr 2045 2050 2055 Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met 2060 2065 2070 Ala Pro Trp Asp Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly 2075 2080 2085 Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Ser Val Glu 2090 2095 2100 Val Ala Val Pro Ala His Pro Ala Asn Leu Asp Ser Glu Ala Lys 2105 2110 2115 Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Phe 2120 2125 2130 Lys Thr Ala Gln Val Ile Arg Asp Phe Asn Gln Glu His Leu Leu 2135 2140 2145 Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys 2150 2155 2160 Asp Met Ser Glu Gln Met Leu Lys Phe Gly Ala Tyr Ile Val Asp 2165 2170 2175 Ser Leu Arg Leu Ser Lys Gln Pro Val Leu Ile Tyr Ile Pro Pro 2180 2185 2190 Gly Ala Glu Leu Arg Gly Gly Ser Trp Val Val Leu Asp Ser Ser 2195 2200 2205 Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg 2210 2215 2220 Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg 2225 2230 2235 Lys Lys Asp Leu Val Lys Thr Ile Arg Arg Ile Asp Pro Val Cys 2240 2245 2250 Lys Lys Leu Leu Glu Pro Ala Gly Asp Thr Gln Leu Pro Asp Lys 2255 2260 2265 Asp Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala Arg Glu Asp Leu 2270 2275 2280 Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Leu 2285 2290 2295 His Asp Thr Pro Gly His Met Leu Lys Lys Gly Ile Ile Ser Asp 2300 2305 2310 Val Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe Tyr Trp Arg Leu 2315 2320 2325 Arg Arg Leu Leu Leu Glu Ala Gln Val Lys Gln Glu Ile Leu Arg 2330 2335 2340 Ala Ser Pro Glu Leu Ser His Glu His Thr Gln Ser Met Leu Arg 2345 2350 2355 Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp 2360 2365 2370 Asp Ser Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Ser 2375 2380 2385 Ala Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu Asn Leu Asn Tyr 2390 2395 2400 Leu Lys Arg Asp Ser Val Leu Lys Thr Ile Gln Ser Leu Val Gln 2405 2410 2415 Glu His Pro Glu Ala Thr Met Gly Leu Cys Gly Tyr Leu Ser Gln 2420 2425 2430 His Leu Thr Pro Ala Glu Gln Met Gln Val Val Gln Leu Leu Ser 2435 2440 2445 Thr Thr Glu Ser Pro Ala Ser His 2450 2455 11 2458 PRT Homo sapiens MISC_FEATURE (1)..(2458) Xaa is any amino acid 11 Met Val Leu Leu Leu Cys Leu Ser Xaa Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Xaa Ser 100 105 110 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Xaa Thr 115 120 125 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Xaa Gly Gly 245 250 255 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 Asp Ile Ala Lys Arg Ile Pro Val Xaa Ala Xaa Trp Xaa Xaa Xaa Xaa 340 345 350 His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 355 360 365 Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 370 375 380 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 Phe Xaa Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 Val Ser Ala Gly Xaa Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 Met Gly Val Pro Leu Xaa Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 625 630 635 640 Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Xaa 645 650 655 Asn Pro Asp Glu Gly Xaa Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 675 680 685 Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 690 695 700 Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 Leu Ile Asn Leu Leu Xaa Xaa Glu Ser Phe Gln Asn Asn Asp Ile Asp 740 745 750 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 755 760 765 Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 770 775 780 Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Xaa Arg 785 790 795 800 Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 805 810 815 Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 820 825 830 Leu Thr Met Phe Val Leu Ile Met Xaa Gly Cys His Ile Glu Ile Asp 835 840 845 Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 850 855 860 Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 865 870 875 880 Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 885 890 895 Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 900 905 910 Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 915 920 925 Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 930 935 940 Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 945 950 955 960 Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 965 970 975 Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 980 985 990 His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser 995 1000 1005 Gly Phe Cys Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu 1010 1015 1020 Trp Xaa Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro 1025 1030 1035 Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile 1040 1045 1050 Pro Ala Pro Val Glu Lys Ser Val Arg Arg Xaa Met Ala Gln Tyr 1055 1060 1065 Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln 1070 1075 1080 Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys 1085 1090 1095 Ala Asp Arg Glu Xaa Phe Phe Ile Asn Thr Gln Ser Ile Val Gln 1100 1105 1110 Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr 1115 1120 1125 Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His 1130 1135 1140 Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu 1145 1150 1155 Gln Phe Lys Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser 1160 1165 1170 His Ala Gln Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile 1175 1180 1185 Asp Glu Leu Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile 1190 1195 1200 Ser Ile Leu Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys 1205 1210 1215 Lys Val Ala Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu 1220 1225 1230 Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu 1235 1240 1245 Ser Ala Ile Asp Met Tyr Gly His Gln Phe Xaa Pro Glu Asn Leu 1250 1255 1260 Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro 1265 1270 1275 Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu 1280 1285 1290 Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser 1295 1300 1305 Leu Gln His Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe 1310 1315 1320 Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro 1325 1330 1335 Ile Ser Ile Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu 1340 1345 1350 Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala 1355 1360 1365 Met Val Ala Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp 1370 1375 1380 Glu Val Ile Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu 1385 1390 1395 Phe Ser Glu Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys 1400 1405 1410 Ser Leu Arg Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln 1415 1420 1425 Cys Ala Asp His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg 1430 1435 1440 Thr Phe Val Gln Ser Lys

Lys Asn Ile Leu Val Asp Tyr Gly Leu 1445 1450 1455 Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys 1460 1465 1470 Phe Phe Thr Phe Arg Ala Xaa Asp Glu Phe Ala Glu Asp Arg Ile 1475 1480 1485 Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn 1490 1495 1500 Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His 1505 1510 1515 Lys Met His Leu Tyr Leu Gly Xaa Ala Lys Val Lys Glu Gly Val 1520 1525 1530 Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile Xaa His 1535 1540 1545 Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn 1550 1555 1560 Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val 1565 1570 1575 Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe 1580 1585 1590 Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu 1595 1600 1605 Glu Ser Val Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp 1610 1615 1620 Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln 1625 1630 1635 Thr Thr Thr Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn 1640 1645 1650 Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr 1655 1660 1665 Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys 1670 1675 1680 Gln Gly Pro Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr 1685 1690 1695 Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly 1700 1705 1710 Thr Thr Tyr Xaa Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu 1715 1720 1725 Phe Lys Leu Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu 1730 1735 1740 Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu 1745 1750 1755 Met Asn Arg Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe 1760 1765 1770 Lys Met Arg Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val 1775 1780 1785 Ile Val Ile Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly 1790 1795 1800 Pro Gly Glu Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg 1805 1810 1815 Ala Glu Xaa Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala 1820 1825 1830 Arg Ile Gly Met Ala Glu Glu Ile Lys His Met Phe His Val Ala 1835 1840 1845 Trp Val Asp Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr 1850 1855 1860 Leu Thr Pro Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val 1865 1870 1875 His Cys Lys His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile 1880 1885 1890 Thr Asp Ile Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu 1895 1900 1905 Arg Gly Ser Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu 1910 1915 1920 Glu Ile Val Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile 1925 1930 1935 Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu 1940 1945 1950 Asn Ser His Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val 1955 1960 1965 Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val 1970 1975 1980 Gln Ile Met His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp 1985 1990 1995 Asp Phe Glu Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met 2000 2005 2010 Pro Lys Asp Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp 2015 2020 2025 Pro Ile Asp Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr 2030 2035 2040 Asp Pro Arg Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys 2045 2050 2055 Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu 2060 2065 2070 Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg 2075 2080 2085 Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr 2090 2095 2100 Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu 2105 2110 2115 Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser 2120 2125 2130 Ala Tyr Lys Thr Ala Gln Ala Xaa Lys Asp Phe Asn Arg Glu Lys 2135 2140 2145 Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly 2150 2155 2160 Met Lys Asp Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile 2165 2170 2175 Val Asp Gly Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile 2180 2185 2190 Xaa Xaa Xaa Xaa Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp 2195 2200 2205 Ala Thr Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu 2210 2215 2220 Ser Arg Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys 2225 2230 2235 Phe Arg Lys Xaa Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro 2240 2245 2250 Ala Tyr Lys Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser 2255 2260 2265 Asp Lys Asp Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu 2270 2275 2280 Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala 2285 2290 2295 Asp Phe His Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile 2300 2305 2310 Ser Asp Ile Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp 2315 2320 2325 Arg Leu Arg Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile 2330 2335 2340 Leu Gln Ala Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met 2345 2350 2355 Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr 2360 2365 2370 Leu Trp Asp Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His 2375 2380 2385 Trp Gln Ala Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile 2390 2395 2400 Thr Tyr Leu Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu 2405 2410 2415 Val Glu Glu Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu 2420 2425 2430 Ser Gln His Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu 2435 2440 2445 Leu Ser Thr Met Asp Ser Pro Ala Ser Thr 2450 2455 12 7377 DNA Homo sapiens CDS (1)..(7377) 12 atg gtc ttg ctt ctt tgt cta tct cgt ctg att ttc tcc tgt ctg acc 48 Met Val Leu Leu Leu Cys Leu Ser Arg Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 ttt tcc tgg tta aaa atc tgg ggg aaa atg acg gac tcc aag ccg atc 96 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 acc aag agt aaa tca gaa gca aac ctc atc ccg agc cag gag ccc ttt 144 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 cca gcc tct gat aac tca ggg gag aca ccg cag aga aat ggg gag ggc 192 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 cac act ctg ccc aag aca ccc agc cag gcc gag cca gcc tcc cac aaa 240 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 ggc ccc aaa gat gcc ggt cgg cgg aga aac tcc cta cca ccc tcc cac 288 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 cag aag ccc cca aga aac ccc ctt tct tcc agt gac gca gca ccc tcc 336 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 cca gag ctt caa gcc aac ggg act ggg aca caa ggt ctg gag gcc aca 384 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 gat acc aat ggc ctg tcc tcc tca gcc agg ccc cag ggc cag caa gct 432 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 ggc tcc ccc tcc aaa gaa gac aag aag cag gca aac atc aag agg cag 480 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 ctg atg acc aac ttc atc ctg ggc tct ttt gat gac tac tcc tct gac 528 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 gag gac tct gtt gct ggc tca tct cgt gag tct acc cgg aag ggc agc 576 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 cgg gcc agc ttg ggg gcc ctg tcc cta gag gct tat ctg acc aca ggt 624 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 gaa gct gag acc cgc gtc ccc act atg agg ccg agc atg tcg gga ctc 672 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 cac ctg gtg aag agg gga cgg gaa cac aag aag ctg gac ctg cac aga 720 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 gac ttt acc gtg gct tct ccc gct gag ttt gtc aca cgc ttt ggg ggg 768 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly 245 250 255 gat cgg gtc atc gag aag gtg ctt att gcc aac aac ggg att gcc gcc 816 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 gtg aag tgc atg cgc tcc atc cgc agg tgg gcc tat gag atg ttc cgc 864 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 aac gag cgg gcc atc cgg ttt gtt gtg atg gtg acc ccc gag gac ctt 912 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 aag gcc aac gca gag tac atc aag atg gcg gat cat tac gtc ccc gtc 960 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 cca gga ggg ccc aat aac aac aac tat gcc aac gtg gag ctg att gtg 1008 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 gac att gcc aag aga atc ccc gtg cag gcg gtg tgg gct ggc tgg ggc 1056 Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly 340 345 350 cat gct tca gaa aac cct aaa ctt ccg gag ctg ctg tgc aag aat gga 1104 His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 355 360 365 gtt gct ttc tta ggc cct ccc agt gag gcc atg tgg gcc tta gga gat 1152 Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 370 375 380 aag atc gcc tcc acc gtt gtc gcc cag acg cta cag gtc cca acc ctg 1200 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 ccc tgg agt gga agc ggc ctg aca gtg gag tgg aca gaa gat gat ctg 1248 Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 cag cag gga aaa aga atc agt gtc cca gaa gat gtt tat gac aag ggt 1296 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 tgc gtg aaa gac gta gat gag ggc ttg gag gca gca gaa aga att ggt 1344 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 ttt cca ttg atg atc aaa gct tct gaa ggt ggc ggg ggg aag gga atc 1392 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 cgg aag gct gag agt gcg gag gac ttc ccg atc ctt ttc aga caa gta 1440 Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 cag agt gag atc cca ggc tcg ccc atc ttt ctc atg aag ctg gcc cag 1488 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 cac gcc cgt cac ctg gaa gtt cag atc ctc gct gac cag tat ggg aat 1536 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 gct gtg tct ctg ttt ggt cgc gac tgc tcc atc cag cgg cgg cat cag 1584 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 aag atc gtt gag gaa gca ccg gcc acc atc gcc ccg ctg gcc ata ttc 1632 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 gag ttc atg gag cag tgt gcc atc cgc ctg gcc aag acc gtg ggc tat 1680 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 gtg agt gca ggg aca gtg gaa tac ctc tat agt cag gat ggc agc ttc 1728 Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 cac ttc ttg gag ctg aat cct cgc ttg cag gtg gaa cat ccc tgc aca 1776 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 gaa atg att gct gac gtt aat ctg ccg gcc gcc cag cta cag atc gcc 1824 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 atg ggc gtg cca ctg cac cgg ctg aag gat atc cgg ctt ctg tat gga 1872 Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 gag tca cca tgg gga gtg act ccc att tct ttt gaa acc ccc tca aac 1920 Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 625 630 635 640 cct ccc ctc gcc cga ggc cac gtc att gcc gcc aga atc acc agc gaa 1968 Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu 645 650 655 aac cca gac gag ggt ttt aag ccg agc tcc ggg act gtc cag gaa ctg 2016 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 aat ttc cgg agc agc aag aac gtg tgg ggt tac ttc agc gtg gcc gct 2064 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 675 680 685 act gga ggc ctg cac gag ttt gcg gat tcc caa ttt ggg cac tgc ttc 2112 Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 690 695 700 tcc tgg gga gag aac cgg gaa gag gcc att tcg aac atg gtg gtg gct 2160 Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 ttg aag gaa ctg tcc atc cga ggt gac ttt agg act acc gtg gaa tac 2208 Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 ctc att aac ctc ctg gag acc gag agc ttc cag aac aac gac atc gac 2256 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp 740 745 750 acc ggg tgg ttg gac tac ctc att gct gag aaa gtg cag gcg gag aaa 2304 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 755 760 765 ccg gat atc atg ctt ggg gtg gta tgc ggg gcc ttg aac gtg gcc gat 2352 Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 770 775 780 gcg atg ttc aga acg tgc atg aca gat ttc tta cac tcc ctg gaa agg 2400 Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg 785 790 795 800 ggc cag gtc ctc cca gcg gat tca cta ctg aac ctt gta gat gtg gaa 2448 Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 805 810 815 tta att tac gga ggt gtt aag tac att ctc aag gtg gcc cgg cag tct 2496 Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 820 825 830 ctg acc atg ttc gtt ctc atc atg aat ggc tgc cac atc gag att gat 2544 Leu Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp 835 840 845 gcc cac cgg ctg aat gat ggg ggg ctc ctg ctc tcc tac aat ggg aac 2592 Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 850 855 860 agc tac acc acc tac atg aag gaa gag gtt gac agt tac cga att acc 2640 Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 865

870 875 880 atc ggc aat aag acg tgt gtg ttt gag aag gag aac gat cct aca gtc 2688 Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 885 890 895 ctg aga tcc ccc tcg gct ggg aag ctg aca cag tac aca gtg gag gat 2736 Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 900 905 910 ggg ggc cac gtt gag gct ggg agc agc tac gct gag atg gag gtg atg 2784 Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 915 920 925 aag atg atc atg acc ctg aac gtt cag gaa aga ggc cgg gtg aag tac 2832 Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 930 935 940 atc aag cgt cca ggt gcc gtg ctg gaa gca ggc tgc gtg gtg gcc agg 2880 Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 945 950 955 960 ctg gag ctc gat gac cct tct aaa gtc cac ccg gct gaa ccg ttc aca 2928 Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 965 970 975 gga gaa ctc cct gcc cag cag aca ctg ccc atc ctc gga gag aaa ctg 2976 Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 980 985 990 cac cag gtc ttc cac agc gtc ctg gaa aac ctc acc aac gtc atg agt 3024 His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser 995 1000 1005 ggc ttt tgt ctg cca gag ccc gtt ttt agc ata aag ctg aag gag 3069 Gly Phe Cys Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu 1010 1015 1020 tgg gtg cag aag ctc atg atg acc ctc cgg cac ccg tca ctg ccg 3114 Trp Val Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro 1025 1030 1035 ctg ctg gag ctg cag gag atc atg acc agc gtg gca ggc cgc atc 3159 Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile 1040 1045 1050 ccc gcc cct gtg gag aag tct gtc cgc agg gtg atg gcc cag tat 3204 Pro Ala Pro Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr 1055 1060 1065 gcc agc aac atc acc tcg gtg ctg tgc cag ttc ccc agc cag cag 3249 Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln 1070 1075 1080 ata gcc acc atc ctg gac tgc cat gca gcc acc ctg cag cgg aag 3294 Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys 1085 1090 1095 gct gat cga gag gtc ttc ttc atc aac acc cag agc atc gtg cag 3339 Ala Asp Arg Glu Val Phe Phe Ile Asn Thr Gln Ser Ile Val Gln 1100 1105 1110 ttg gtc cag aga tac cgc agc ggg atc cgc ggc tat atg aaa aca 3384 Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr 1115 1120 1125 gtg gtg ttg gat ctc ctg aga aga tac ttg cgt gtt gag cac cat 3429 Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His 1130 1135 1140 ttt cag caa gcc cac tac gac aag tgt gtg ata aac ctc agg gag 3474 Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu 1145 1150 1155 cag ttc aag cca gac atg tcc cag gtg ctg gac tgc atc ttc tcc 3519 Gln Phe Lys Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser 1160 1165 1170 cac gca cag gtg gcc aag aag aac cag ctg gtg atc atg ttg atc 3564 His Ala Gln Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile 1175 1180 1185 gat gag ctg tgt ggc cca gac cct tcc ctg tcg gac gag ctg atc 3609 Asp Glu Leu Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile 1190 1195 1200 tcc atc ctc aac gag ctc act cag ctg agc aaa agc gag cac tgc 3654 Ser Ile Leu Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys 1205 1210 1215 aaa gtg gcc ctc aga gcc cgg cag atc ctg att gcc tcc cac ctc 3699 Lys Val Ala Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu 1220 1225 1230 ccc tcc tac gag ctg cgg cat aac cag gtg gag tcc att ttc ctg 3744 Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu 1235 1240 1245 tct gcc att gac atg tac ggc cac cag ttc tgc ccc gag aac ctc 3789 Ser Ala Ile Asp Met Tyr Gly His Gln Phe Cys Pro Glu Asn Leu 1250 1255 1260 aag aaa tta ata ctt tcg gaa aca acc atc ttc gac gtc ctg cct 3834 Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro 1265 1270 1275 act ttc ttc tat cac gca aac aaa gtc gtg tgc atg gcg tcc ttg 3879 Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu 1280 1285 1290 gag gtt tac gtg cgg agg ggc tac atc gcc tat gag tta aac agc 3924 Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser 1295 1300 1305 ctg cag cac cgg cag ctc ccg gac ggc acc tgc gtg gta gaa ttc 3969 Leu Gln His Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe 1310 1315 1320 cag ttc atg ctg ccg tcc tcc cac cca aac cgg atg acc gtg ccc 4014 Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro 1325 1330 1335 atc agc atc acc aac cct gac ctg ctg agg cac agc aca gag ctc 4059 Ile Ser Ile Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu 1340 1345 1350 ttc atg gac agc ggc ttc tcc cca ctg tgc cag cgc atg gga gcc 4104 Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala 1355 1360 1365 atg gta gcc ttc agg aga ttc gag gac ttc acc aga aat ttt gat 4149 Met Val Ala Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp 1370 1375 1380 gaa gtc atc tct tgc ttc gcc aac gtg ccc aaa gac acc ccc ctc 4194 Glu Val Ile Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu 1385 1390 1395 ttc agc gag gcc cgc acc tcc cta tac tcc gag gat gac tgc aag 4239 Phe Ser Glu Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys 1400 1405 1410 agc ctc aga gaa gag ccc atc cac att ctg aat gtg tcc atc cag 4284 Ser Leu Arg Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln 1415 1420 1425 tgt gca gac cac ctg gag gat gag gca ctg gtg ccg att tta cgg 4329 Cys Ala Asp His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg 1430 1435 1440 aca ttc gta cag tcc aag aaa aat atc ctt gtg gat tat gga ctc 4374 Thr Phe Val Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu 1445 1450 1455 cga cga atc aca ttc ttg att gcc caa gag aaa gaa ttt ccc aag 4419 Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys 1460 1465 1470 ttt ttc aca ttc aga gca aga gat gag ttt gca gaa gat cgc att 4464 Phe Phe Thr Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile 1475 1480 1485 tac cgt cac ttg gaa cct gcc ctg gcc ttc cag ctg gaa ctc aac 4509 Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn 1490 1495 1500 cgg atg cgt aac ttc gat ctg acc gcc gtg ccc tgt gcc aac cac 4554 Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His 1505 1510 1515 aag atg cac ctt tac ctg ggt gct gcc aag gtg aag gaa ggt gtg 4599 Lys Met His Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Val 1520 1525 1530 gaa gtg acg gac cat agg ttc ttc atc cgc gcc atc atc agg cac 4644 Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His 1535 1540 1545 tct gac ctg atc aca aag gaa gcc tcc ttc gaa tac ctg cag aac 4689 Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn 1550 1555 1560 gag ggt gag cgg ctg ctc ctg gag gcc atg gac gag ctg gag gtg 4734 Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val 1565 1570 1575 gcg ttc aat aac acc agc gtg cgc acc gac tgc aac cac atc ttc 4779 Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe 1580 1585 1590 ctc aac ttc gtg ccc act gtc atc atg gac ccc ttc aag atc gag 4824 Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu 1595 1600 1605 gag tcc gtg cgc tac atg gtt atg cgc tac ggc agc cgg ctg tgg 4869 Glu Ser Val Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp 1610 1615 1620 aaa ctc cgt gtg cta cag gct gag gtc aag atc aac atc cgc cag 4914 Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln 1625 1630 1635 acc acc acc ggc agt gcc gtt ccc atc cgc ctg ttc atc acc aat 4959 Thr Thr Thr Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn 1640 1645 1650 gag tcg ggc tac tac ctg gac atc agc ctc tac aaa gaa gtg act 5004 Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr 1655 1660 1665 gac tcc aga tct gga aat atc atg ttt cac tcc ttc ggc aac aag 5049 Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys 1670 1675 1680 caa ggg ccc cag cac ggg atg ctg atc aat act ccc tac gtc acc 5094 Gln Gly Pro Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr 1685 1690 1695 aag gat ctg ctc cag gcc aag cga ttc cag gcc cag acc ctg gga 5139 Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly 1700 1705 1710 acc acc tac atc tat gac ttc ccg gaa atg ttc agg cag gct ctc 5184 Thr Thr Tyr Ile Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu 1715 1720 1725 ttt aaa ctg tgg ggc tcc cca gac aag tat ccc aaa gac atc ctg 5229 Phe Lys Leu Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu 1730 1735 1740 aca tac act gaa tta gtg ttg gac tct cag ggc cag ctg gtg gag 5274 Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu 1745 1750 1755 atg aac cga ctt cct ggt gga aat gag gtg ggc atg gtg gcc ttc 5319 Met Asn Arg Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe 1760 1765 1770 aaa atg agg ttt aag acc cag gag tac ccg gaa gga cgg gat gtg 5364 Lys Met Arg Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val 1775 1780 1785 atc gtc atc ggc aat gac atc acc ttt cgc att gga tcc ttt ggc 5409 Ile Val Ile Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly 1790 1795 1800 cct gga gag gac ctt ctg tac ctg cgg gca tcc gag atg gcc cgg 5454 Pro Gly Glu Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg 1805 1810 1815 gca gag ggc att ccc aaa att tac gtg gca gcc aac agt ggc gcc 5499 Ala Glu Gly Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala 1820 1825 1830 cgt att ggc atg gca gag gag atc aaa cac atg ttc cac gtg gct 5544 Arg Ile Gly Met Ala Glu Glu Ile Lys His Met Phe His Val Ala 1835 1840 1845 tgg gtg gac cca gaa gac ccc cac aaa gga ttt aaa tac ctg tac 5589 Trp Val Asp Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr 1850 1855 1860 ctg act ccc caa gac tac acc aga atc agc tcc ctg aac tcc gtc 5634 Leu Thr Pro Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val 1865 1870 1875 cac tgt aaa cac atc gag gaa gga gga gag tcc aga tac atg atc 5679 His Cys Lys His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile 1880 1885 1890 acg gat atc atc ggg aag gat gat ggc ttg ggc gtg gag aat ctg 5724 Thr Asp Ile Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu 1895 1900 1905 agg ggc tca ggc atg att gct ggg gag tcc tct ctg gct tac gaa 5769 Arg Gly Ser Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu 1910 1915 1920 gag atc gtc acc att agc ttg gtg acc tgc cga gcc att ggg att 5814 Glu Ile Val Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile 1925 1930 1935 ggg gcc tac ttg gtg agg ctg ggc cag cga gtg atc cag gtg gag 5859 Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu 1940 1945 1950 aat tcc cac atc atc ctc aca gga gca agt gct ctc aac aag gtc 5904 Asn Ser His Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val 1955 1960 1965 ctg gga aga gag gtc tac aca tcc aac aac cag ctg ggt ggc gtt 5949 Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val 1970 1975 1980 cag atc atg cat tac aat ggt gtc tcc cac atc acc gtg cca gat 5994 Gln Ile Met His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp 1985 1990 1995 gac ttt gag ggg gtt tat acc atc ctg gag tgg ctg tcc tat atg 6039 Asp Phe Glu Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met 2000 2005 2010 cca aag gat aat cac agc cct gtc cct atc atc aca ccc act gac 6084 Pro Lys Asp Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp 2015 2020 2025 ccc att gac aga gaa att gaa ttc ctc cca tcc aga gct ccc tac 6129 Pro Ile Asp Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr 2030 2035 2040 gac ccc cgg tgg atg ctt gca gga agg cct cac cca act ctg aag 6174 Asp Pro Arg Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys 2045 2050 2055 gga acg tgg cag agc gga ttc ttt gac cac ggc agt ttc aag gaa 6219 Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu 2060 2065 2070 atc atg gca ccc tgg gcg cag acc gtg gtg aca gga cga gca agg 6264 Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg 2075 2080 2085 ctt ggg ggg att ccc gtg gga gtg att gct gtg gag aca cgg act 6309 Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr 2090 2095 2100 gtg gag gtg gca gtc cct gca gac cct gcc aac ctg gat tct gag 6354 Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu 2105 2110 2115 gcc aag ata att cag cag gca gga cag gtg tgg ttc cca gac tca 6399 Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser 2120 2125 2130 gcc tac aaa acc gcc cag gcc atc aag gac ttc aac cgg gag aag 6444 Ala Tyr Lys Thr Ala Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys 2135 2140 2145 ttg ccc ctg atg atc ttt gcc aac tgg agg ggg ttc tcc ggt ggc 6489 Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly 2150 2155 2160 atg aaa gac atg tat gac cag gtg ctg aag ttt gga gcc tac atc 6534 Met Lys Asp Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile 2165 2170 2175 gtg gac ggc ctt aga caa tac aaa cag ccc atc ctg atc tat atc 6579 Val Asp Gly Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile 2180 2185 2190 ccg ccc tat gcg gag ctc cgg gga ggc tcc tgg gtg gtc ata gat 6624 Pro Pro Tyr Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp 2195 2200 2205 gcc acc atc aac ccg ctg tgc ata gaa atg tat gca gac aaa gag 6669 Ala Thr Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu 2210 2215 2220 agc agg ggt ggt gtt ctg gaa cca gag ggg aca gtg gag att aag 6714 Ser Arg Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys 2225 2230 2235 ttc cga aag aaa gat ctg ata aag tcc atg aga agg atc gat cca 6759 Phe Arg Lys Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro 2240 2245 2250 gct tac aag aag ctc atg gaa cag cta ggg gaa cct gat ctc tcc 6804 Ala Tyr Lys Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser 2255 2260 2265 gac aag gac cga aag gac ctg gag ggc cgg cta aag gct cgc gag 6849 Asp Lys Asp Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu 2270 2275 2280 gac ctg ctg ctc ccc atc tac cac cag gtg gcg gtg cag ttc gcc 6894 Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala 2285 2290 2295 gac ttc cat gac aca ccc ggc cgg atg ctg gag aag ggc gtc ata 6939 Asp Phe His Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile 2300 2305 2310 tct gac atc ctg gag tgg aag acc gca cgc acc ttc ctg tat tgg 6984 Ser Asp Ile Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp 2315 2320 2325 cgt ctg cgc cgc ctc ctc ctg gag gac cag gtc aag cag gag atc 7029 Arg Leu Arg Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile 2330 2335 2340 ctg cag gcc agc ggg gag

ctg agt cac gtg cat atc cag tcc atg 7074 Leu Gln Ala Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met 2345 2350 2355 ctg cgt cgc tgg ttc gtg gag acg gag ggg gct gtc aag gcc tac 7119 Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr 2360 2365 2370 ttg tgg gac aac aac cag gtg gtt gtg cag tgg ctg gaa cag cac 7164 Leu Trp Asp Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His 2375 2380 2385 tgg cag gca ggg gat ggc ccg cgc tcc acc atc cgt gag aac atc 7209 Trp Gln Ala Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile 2390 2395 2400 acg tac ctg aag cac gac tct gtc ctc aag acc atc cga ggc ctg 7254 Thr Tyr Leu Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu 2405 2410 2415 gtt gaa gaa aac ccc gag gtg gcc gtg gac tgt gtg ata tac ctg 7299 Val Glu Glu Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu 2420 2425 2430 agc cag cac atc agc cca gct gag cgg gcg cag gtc gtt cac ctg 7344 Ser Gln His Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu 2435 2440 2445 ctg tct acc atg gac agc ccg gcc tcc acc tga 7377 Leu Ser Thr Met Asp Ser Pro Ala Ser Thr 2450 2455 13 2458 PRT Homo sapiens 13 Met Val Leu Leu Leu Cys Leu Ser Arg Leu Ile Phe Ser Cys Leu Thr 1 5 10 15 Phe Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Ile 20 25 30 Thr Lys Ser Lys Ser Glu Ala Asn Leu Ile Pro Ser Gln Glu Pro Phe 35 40 45 Pro Ala Ser Asp Asn Ser Gly Glu Thr Pro Gln Arg Asn Gly Glu Gly 50 55 60 His Thr Leu Pro Lys Thr Pro Ser Gln Ala Glu Pro Ala Ser His Lys 65 70 75 80 Gly Pro Lys Asp Ala Gly Arg Arg Arg Asn Ser Leu Pro Pro Ser His 85 90 95 Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Ser Asp Ala Ala Pro Ser 100 105 110 Pro Glu Leu Gln Ala Asn Gly Thr Gly Thr Gln Gly Leu Glu Ala Thr 115 120 125 Asp Thr Asn Gly Leu Ser Ser Ser Ala Arg Pro Gln Gly Gln Gln Ala 130 135 140 Gly Ser Pro Ser Lys Glu Asp Lys Lys Gln Ala Asn Ile Lys Arg Gln 145 150 155 160 Leu Met Thr Asn Phe Ile Leu Gly Ser Phe Asp Asp Tyr Ser Ser Asp 165 170 175 Glu Asp Ser Val Ala Gly Ser Ser Arg Glu Ser Thr Arg Lys Gly Ser 180 185 190 Arg Ala Ser Leu Gly Ala Leu Ser Leu Glu Ala Tyr Leu Thr Thr Gly 195 200 205 Glu Ala Glu Thr Arg Val Pro Thr Met Arg Pro Ser Met Ser Gly Leu 210 215 220 His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg 225 230 235 240 Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly 245 250 255 Asp Arg Val Ile Glu Lys Val Leu Ile Ala Asn Asn Gly Ile Ala Ala 260 265 270 Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg 275 280 285 Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu 290 295 300 Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp His Tyr Val Pro Val 305 310 315 320 Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Val 325 330 335 Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly 340 345 350 His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys Asn Gly 355 360 365 Val Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp 370 375 380 Lys Ile Ala Ser Thr Val Val Ala Gln Thr Leu Gln Val Pro Thr Leu 385 390 395 400 Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Asp Leu 405 410 415 Gln Gln Gly Lys Arg Ile Ser Val Pro Glu Asp Val Tyr Asp Lys Gly 420 425 430 Cys Val Lys Asp Val Asp Glu Gly Leu Glu Ala Ala Glu Arg Ile Gly 435 440 445 Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile 450 455 460 Arg Lys Ala Glu Ser Ala Glu Asp Phe Pro Ile Leu Phe Arg Gln Val 465 470 475 480 Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln 485 490 495 His Ala Arg His Leu Glu Val Gln Ile Leu Ala Asp Gln Tyr Gly Asn 500 505 510 Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln 515 520 525 Lys Ile Val Glu Glu Ala Pro Ala Thr Ile Ala Pro Leu Ala Ile Phe 530 535 540 Glu Phe Met Glu Gln Cys Ala Ile Arg Leu Ala Lys Thr Val Gly Tyr 545 550 555 560 Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe 565 570 575 His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr 580 585 590 Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala 595 600 605 Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly 610 615 620 Glu Ser Pro Trp Gly Val Thr Pro Ile Ser Phe Glu Thr Pro Ser Asn 625 630 635 640 Pro Pro Leu Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu 645 650 655 Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu 660 665 670 Asn Phe Arg Ser Ser Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala 675 680 685 Thr Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe 690 695 700 Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala 705 710 715 720 Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr 725 730 735 Leu Ile Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp 740 745 750 Thr Gly Trp Leu Asp Tyr Leu Ile Ala Glu Lys Val Gln Ala Glu Lys 755 760 765 Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp 770 775 780 Ala Met Phe Arg Thr Cys Met Thr Asp Phe Leu His Ser Leu Glu Arg 785 790 795 800 Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Leu Val Asp Val Glu 805 810 815 Leu Ile Tyr Gly Gly Val Lys Tyr Ile Leu Lys Val Ala Arg Gln Ser 820 825 830 Leu Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp 835 840 845 Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Asn 850 855 860 Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr 865 870 875 880 Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val 885 890 895 Leu Arg Ser Pro Ser Ala Gly Lys Leu Thr Gln Tyr Thr Val Glu Asp 900 905 910 Gly Gly His Val Glu Ala Gly Ser Ser Tyr Ala Glu Met Glu Val Met 915 920 925 Lys Met Ile Met Thr Leu Asn Val Gln Glu Arg Gly Arg Val Lys Tyr 930 935 940 Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Arg 945 950 955 960 Leu Glu Leu Asp Asp Pro Ser Lys Val His Pro Ala Glu Pro Phe Thr 965 970 975 Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Lys Leu 980 985 990 His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Ser 995 1000 1005 Gly Phe Cys Leu Pro Glu Pro Val Phe Ser Ile Lys Leu Lys Glu 1010 1015 1020 Trp Val Gln Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro 1025 1030 1035 Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile 1040 1045 1050 Pro Ala Pro Val Glu Lys Ser Val Arg Arg Val Met Ala Gln Tyr 1055 1060 1065 Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln 1070 1075 1080 Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys 1085 1090 1095 Ala Asp Arg Glu Val Phe Phe Ile Asn Thr Gln Ser Ile Val Gln 1100 1105 1110 Leu Val Gln Arg Tyr Arg Ser Gly Ile Arg Gly Tyr Met Lys Thr 1115 1120 1125 Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Arg Val Glu His His 1130 1135 1140 Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu 1145 1150 1155 Gln Phe Lys Pro Asp Met Ser Gln Val Leu Asp Cys Ile Phe Ser 1160 1165 1170 His Ala Gln Val Ala Lys Lys Asn Gln Leu Val Ile Met Leu Ile 1175 1180 1185 Asp Glu Leu Cys Gly Pro Asp Pro Ser Leu Ser Asp Glu Leu Ile 1190 1195 1200 Ser Ile Leu Asn Glu Leu Thr Gln Leu Ser Lys Ser Glu His Cys 1205 1210 1215 Lys Val Ala Leu Arg Ala Arg Gln Ile Leu Ile Ala Ser His Leu 1220 1225 1230 Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu 1235 1240 1245 Ser Ala Ile Asp Met Tyr Gly His Gln Phe Cys Pro Glu Asn Leu 1250 1255 1260 Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro 1265 1270 1275 Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu 1280 1285 1290 Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser 1295 1300 1305 Leu Gln His Arg Gln Leu Pro Asp Gly Thr Cys Val Val Glu Phe 1310 1315 1320 Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Thr Val Pro 1325 1330 1335 Ile Ser Ile Thr Asn Pro Asp Leu Leu Arg His Ser Thr Glu Leu 1340 1345 1350 Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala 1355 1360 1365 Met Val Ala Phe Arg Arg Phe Glu Asp Phe Thr Arg Asn Phe Asp 1370 1375 1380 Glu Val Ile Ser Cys Phe Ala Asn Val Pro Lys Asp Thr Pro Leu 1385 1390 1395 Phe Ser Glu Ala Arg Thr Ser Leu Tyr Ser Glu Asp Asp Cys Lys 1400 1405 1410 Ser Leu Arg Glu Glu Pro Ile His Ile Leu Asn Val Ser Ile Gln 1415 1420 1425 Cys Ala Asp His Leu Glu Asp Glu Ala Leu Val Pro Ile Leu Arg 1430 1435 1440 Thr Phe Val Gln Ser Lys Lys Asn Ile Leu Val Asp Tyr Gly Leu 1445 1450 1455 Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Lys Glu Phe Pro Lys 1460 1465 1470 Phe Phe Thr Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile 1475 1480 1485 Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Asn 1490 1495 1500 Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His 1505 1510 1515 Lys Met His Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Val 1520 1525 1530 Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His 1535 1540 1545 Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn 1550 1555 1560 Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val 1565 1570 1575 Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe 1580 1585 1590 Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Phe Lys Ile Glu 1595 1600 1605 Glu Ser Val Arg Tyr Met Val Met Arg Tyr Gly Ser Arg Leu Trp 1610 1615 1620 Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln 1625 1630 1635 Thr Thr Thr Gly Ser Ala Val Pro Ile Arg Leu Phe Ile Thr Asn 1640 1645 1650 Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr 1655 1660 1665 Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys 1670 1675 1680 Gln Gly Pro Gln His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr 1685 1690 1695 Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Thr Leu Gly 1700 1705 1710 Thr Thr Tyr Ile Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu 1715 1720 1725 Phe Lys Leu Trp Gly Ser Pro Asp Lys Tyr Pro Lys Asp Ile Leu 1730 1735 1740 Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu 1745 1750 1755 Met Asn Arg Leu Pro Gly Gly Asn Glu Val Gly Met Val Ala Phe 1760 1765 1770 Lys Met Arg Phe Lys Thr Gln Glu Tyr Pro Glu Gly Arg Asp Val 1775 1780 1785 Ile Val Ile Gly Asn Asp Ile Thr Phe Arg Ile Gly Ser Phe Gly 1790 1795 1800 Pro Gly Glu Asp Leu Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg 1805 1810 1815 Ala Glu Gly Ile Pro Lys Ile Tyr Val Ala Ala Asn Ser Gly Ala 1820 1825 1830 Arg Ile Gly Met Ala Glu Glu Ile Lys His Met Phe His Val Ala 1835 1840 1845 Trp Val Asp Pro Glu Asp Pro His Lys Gly Phe Lys Tyr Leu Tyr 1850 1855 1860 Leu Thr Pro Gln Asp Tyr Thr Arg Ile Ser Ser Leu Asn Ser Val 1865 1870 1875 His Cys Lys His Ile Glu Glu Gly Gly Glu Ser Arg Tyr Met Ile 1880 1885 1890 Thr Asp Ile Ile Gly Lys Asp Asp Gly Leu Gly Val Glu Asn Leu 1895 1900 1905 Arg Gly Ser Gly Met Ile Ala Gly Glu Ser Ser Leu Ala Tyr Glu 1910 1915 1920 Glu Ile Val Thr Ile Ser Leu Val Thr Cys Arg Ala Ile Gly Ile 1925 1930 1935 Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu 1940 1945 1950 Asn Ser His Ile Ile Leu Thr Gly Ala Ser Ala Leu Asn Lys Val 1955 1960 1965 Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val 1970 1975 1980 Gln Ile Met His Tyr Asn Gly Val Ser His Ile Thr Val Pro Asp 1985 1990 1995 Asp Phe Glu Gly Val Tyr Thr Ile Leu Glu Trp Leu Ser Tyr Met 2000 2005 2010 Pro Lys Asp Asn His Ser Pro Val Pro Ile Ile Thr Pro Thr Asp 2015 2020 2025 Pro Ile Asp Arg Glu Ile Glu Phe Leu Pro Ser Arg Ala Pro Tyr 2030 2035 2040 Asp Pro Arg Trp Met Leu Ala Gly Arg Pro His Pro Thr Leu Lys 2045 2050 2055 Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu 2060 2065 2070 Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg 2075 2080 2085 Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Thr 2090 2095 2100 Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu 2105 2110 2115 Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser 2120 2125 2130 Ala Tyr Lys Thr Ala Gln Ala Ile Lys Asp Phe Asn Arg Glu Lys 2135 2140 2145 Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly 2150 2155 2160 Met Lys Asp Met Tyr Asp Gln Val Leu Lys Phe Gly Ala Tyr Ile 2165 2170 2175 Val Asp Gly Leu Arg Gln Tyr Lys Gln Pro Ile Leu Ile Tyr Ile 2180 2185 2190 Pro Pro Tyr Ala Glu Leu Arg Gly Gly Ser Trp Val Val Ile Asp 2195 2200 2205 Ala Thr Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu 2210 2215 2220 Ser Arg Gly Gly Val Leu Glu Pro Glu

Gly Thr Val Glu Ile Lys 2225 2230 2235 Phe Arg Lys Lys Asp Leu Ile Lys Ser Met Arg Arg Ile Asp Pro 2240 2245 2250 Ala Tyr Lys Lys Leu Met Glu Gln Leu Gly Glu Pro Asp Leu Ser 2255 2260 2265 Asp Lys Asp Arg Lys Asp Leu Glu Gly Arg Leu Lys Ala Arg Glu 2270 2275 2280 Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala 2285 2290 2295 Asp Phe His Asp Thr Pro Gly Arg Met Leu Glu Lys Gly Val Ile 2300 2305 2310 Ser Asp Ile Leu Glu Trp Lys Thr Ala Arg Thr Phe Leu Tyr Trp 2315 2320 2325 Arg Leu Arg Arg Leu Leu Leu Glu Asp Gln Val Lys Gln Glu Ile 2330 2335 2340 Leu Gln Ala Ser Gly Glu Leu Ser His Val His Ile Gln Ser Met 2345 2350 2355 Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr 2360 2365 2370 Leu Trp Asp Asn Asn Gln Val Val Val Gln Trp Leu Glu Gln His 2375 2380 2385 Trp Gln Ala Gly Asp Gly Pro Arg Ser Thr Ile Arg Glu Asn Ile 2390 2395 2400 Thr Tyr Leu Lys His Asp Ser Val Leu Lys Thr Ile Arg Gly Leu 2405 2410 2415 Val Glu Glu Asn Pro Glu Val Ala Val Asp Cys Val Ile Tyr Leu 2420 2425 2430 Ser Gln His Ile Ser Pro Ala Glu Arg Ala Gln Val Val His Leu 2435 2440 2445 Leu Ser Thr Met Asp Ser Pro Ala Ser Thr 2450 2455 14 7471 DNA Rattus norvegicus 14 atggtcttgc ttctctttct gacttgcctg gttttctcct gcctgaccat ttcctggtta 60 aaaatctggg ggaagatgac agactcgaag ccgctcagca acagtaaggt ggatgcaagc 120 ctcctttcga gcaaggagga gtccttttca gcctcggacc agtcagagga gcatggcgac 180 tgcagctgtc cgttgacaac tcctgaccag gaggagctgg cctcccacgg aggtcctgta 240 gatgccagtc agcagaggaa ctctgtgcca agctcacacc agaagcctcc gaggaaccca 300 ctatcttcca atgacacctg ttcctcccca gaactccaaa ccaacggggt agcagcccct 360 ggctcagagg ttccagaagc caacgggttg cctttcccag ccaggcctca gacccagaga 420 acgggatccc ccactaggga ggacaagaag caggcacaca tcaagaggca gctgatgacc 480 agctttatcc tgggctccct cgatgacaac tcctctgacg aggaccctag tgctagctcc 540 ttccagacct cctctcggaa gggcagcagg gctagcctgg gcaccctgtc ccaggaggct 600 gcattgaaca cagctgatcc tgagtctcac acacctacta tgaggcccag catgtctgga 660 ctccatctgg tgaagagagg ccgtgaacac aagaaactgg acctgcacag agatttcact 720 gtagcttccc cagccgaatt tgtcacccgc tttggaggca acagggttat cgagacggtg 780 ctcatcgcca ataatggtat cgctgcggtc aagtgtatgc gctccatccg ccgctgggcc 840 tatgagatgt tccgtaatga acgcgccatc cggtttgtgg ttatggtgac acccgaggat 900 cttaaggcca acgcagagta catcaagatg gcggaccagt acgttccggt cccaggagga 960 cccaataata acaactacgc caacgttgag ctgatcatag acattgccaa gagaatccct 1020 gtgcaggccg tgtgggctgg ctggggccac gcttcggaaa accccaaact tccagagcta 1080 ctgtgcaagc acgagattgc tttcctaggt cccccgagtg aggccatgtg ggccctggga 1140 gacaagatct cctccaccat tgtagcccag acattgcaga tcccaactct accctggagc 1200 ggaagcggtc tcacagtgga gtggacggag gacagccagc atcagggcaa atgcatcagc 1260 gtcccggaag acgtttatga acaaggctgt gtgagagatg tggacgaagg cttgcaggca 1320 gcagaaaaag taggatttcc tctgatgatc aaagcctctg aaggtggagg agggaaagga 1380 atccgcaggg ctgagagtgc agaggacttc ccgatgcttt tcagacaggt gcagagtgag 1440 atcccgggct cgcccatctt tctcatgaag ctggcccaga atgctcggca cttggaggtc 1500 caggtcttgg cagatcagta tgggaacgca gtgtccctgt ttggacgaga ctgctccatc 1560 cagaggcggc accagaagat cattgaggag gctccggcca ccatcgctgc tccggctgtg 1620 tttgagttca tggaacagtg tgccgtcctc ctggccaaga ctgtgggtta tgtgagcgcg 1680 ggaaccgtgg agtacctata cagccaggat ggcagctttc acttcttgga gctgaaccca 1740 cgcctgcagg tggaacatcc ctgcactgaa atgatcgcag atgtcaacct gcccgctgca 1800 cagttacaga tcgccatggg cgtgcccctg caccggctga aggacatacg gcttctgtac 1860 ggagagtccc cctggggagt gacccccgtt tcttttgaga cccctttgag ccctcccatt 1920 gcccgaggcc atgtcattgc agccaggatc accagcgaaa acccagacga gggctttaag 1980 ccaagctcag ggacagtgca ggagctgaac ttccgcagca acaagaacgt gtggggttac 2040 ttcagcgtgg ccgctgctgg gggcttgcac gagtttgccg attcccagtt tgggcactgc 2100 ttctcctggg gcgagaaccg tgaagaggct atttcgaaca tggtggtggc tttgaaagaa 2160 ctgtctatcc ggggtgactt ccggaccacc gtggaatatc tcgtcaacct tctggagacg 2220 gagagcttcc agaacaatga tatcgacacg gggtggctgg accacctcat cgctcagcgg 2280 gtgcaggcag agaagccgga catcatgctc ggggtggtgt gtggggcctt gaacgtggca 2340 gacgcgatgt tcagaacctg tatgacggaa ttcctgcatt ccttggaaag gggtcaggtc 2400 ctcccggctg attctctgct gaacatcgtg gacgttgagt tgatttacgg aggcatcaaa 2460 tatgttctca aggtggcccg gcagtccctg accatgtttg tcctcatcat gaatggttgc 2520 cacatcgaga tcgatgccca ccggctgaac gatgggggcc tgctcctgtc ctacaatggt 2580 agcagttaca ctacatacat gaaggaagag gtggacagtt accggatcac tatcggcaat 2640 aagacatgcg tgtttgaaaa ggaaaacgac cccaccgtcc tgagatcccc ctcggctggg 2700 aagctgatgc agtacacggt ggaggatggc cagcacgtgg aagtcgggag cagctatgct 2760 gagatggagg tgatgaagat gatcatgacc ctgaacgtgc aagagagcgg ccgggtgaag 2820 tacatcaagc gaccaggggc ggtattggag gctggctgcg tggtggcaaa gctagaactc 2880 gatgaccctt caaaagtgca cgcggcacag ccgttcacag gggagctccc cgcccagcag 2940 actctgccca tcctcgggga gaggctgcat caggtgttcc acagcgtctt ggaaaatctg 3000 accaatgtca tgaatggcta ctgcctgccc gagcccttct tcagcatgaa gctgaaggac 3060 tgggtggaga agctcatgat gactctccgg catccctccc tacctctgct ggagctgcag 3120 gagatcatga ccagcgtggc aggccgcatc ccggttccgg tggagaaggc agtccgcagg 3180 gtgatggcgc agtacgccag caacatcact tcggtgctct gccagttccc cagccagcag 3240 atagccacca tcctggactg ccacgccgcc accctgcagc gtaaggtgga ccgagaggcc 3300 ttcttcatga acacacagag catcgtgcag ctgatccaga gataccgcag tgggacccgt 3360 ggctacatga aggctgtggt gctagacctc ctgaggagat atctgaacgt ggagcatcat 3420 ttccagcaag cccactatga caagtgtgtg atcaacctga gggagcagtt caagccggac 3480 atgactcggg tgctggactg catcttctca cactcacaag tggccaagaa gaaccagctg 3540 gtgaccatgt tgatagatga gctgtgtggc ccagacccca ccctgtcaga agagctgacc 3600 tccatcctca aggaactcac gcagttgagc aggagtgagc actgcaaggt ggccctcaga 3660 gccaggcagg tcctgattgc ctctcacctc ccctcctacg agctgcggca caaccaggtg 3720 gagtccatct tcctgtcagc cattgacatg tatggccacc agttctgccc ggaaaacctc 3780 aagaaactaa tactttcgga aacgaccata ttcgatgtcc tgcccacttt cttctatcac 3840 gctaacaagg tcgtctgtat ggcgtccctg gaggtttatg tgaggagagg ttacatcgcc 3900 tacgagttaa acagcctaca gcaccgggag ctccctgacg gcacctgcgt ggtggagttc 3960 cagttcatgc tgccgtcttc ccaccccaac cggatggcca tgcccatcaa tgtctctgac 4020 cctgacctgc tgagacacag taaggaactc ttcatggaca gtggcttctc cccactgtgc 4080 cagcggatgg gggccatggt ggccttcagg agatttgagg agttcaccag gaacttcgat 4140 gaagtcatct cctgctttgc caacgtgcct acagacactc ctctcttcag taaggcgtgc 4200 acttccctct actcagagga ggacagcaag agccttcaag aggagcccat ccacatcctg 4260 aatgtggcca tccagtgcgc cgaccacatg gaggacgaga gactggtgcc ggttttccgt 4320 gcctttgtac agtccaagaa acacatcctt gtggattacg gactgcgaag aatcacattc 4380 cttatcgccc aagagagaga atttcccaag ttcttcacgt tcagagcgag agatgagttt 4440 gcagaagacc ggatttaccg ccacttggag ccggccctgg ccttccagct ggagctgagc 4500 cggatgcgca actttgacct gacggccgtg ccctgtgcca accataagat gcatctttac 4560 ctgggagccg ccaaggtgaa ggaagggctg gaggtgactg accacaggtt cttcatccga 4620 gccatcataa ggcactcaga cctgatcacc aaggaagcct ccttcgagta cctgcagaat 4680 gaaggggagc ggctgctgct ggaagccatg gacgagctgg aggtggcgtt caacaacacc 4740 agcgtgcgca ctgactgcaa ccacatcttc ctcaacttcg tgcccacggt catcatggac 4800 ccactcaaga tcgaggagtc ggtgcgtgcc atggtcatgc gttacggcag tcggctgtgg 4860 aagctccgtg tgctgcaggc agaagttaag atcaacatcc gtcagacgac ctcggactgc 4920 gccgtcccca ttcgcctctt catcaccaac gagtccggct actacctgga catcagcctc 4980 tacaaagaag tgaccgactc cagatccgga aacatcatgt ttcattcctt cggcaacaaa 5040 caagggagcc tgcacgggat gctgatcaac acgccctacg tcaccaagga tctgctccaa 5100 gccaagcgat tccaggcgca gtccctgggg accacctatg tgtacgactt cccagagatg 5160 ttcaggcagg ctctctttaa attgtggggc tccccagaga agtaccccaa agatatcctg 5220 acatacacag agctggtgtt ggactcccag ggccagctgg tggagatgaa ccggcttcct 5280 ggttgtaacg aggtgggcat ggtggttttc aaaatgaggt tcaagacccc ggagtatcca 5340 gaaggccggg acactatcgt catcggcaac gacattacct tccaaatcgg ctctttcggc 5400 ataggagagg acttcctgta tctacgggca tcggagatgg cccggacaga gggcatcccc 5460 caaatctatc tggcagccaa cagcggggcc cgtatgggcc tgtccgagga gatcaagcag 5520 atattccaag tggcatgggt ggaccctgag gatccctaca aaggatttag atacctgtac 5580 ctgacgcccc aagactacac ccagatcagc tcccagaact ccgtgcactg caaacacatc 5640 gaggacgaag gcgagtccag gtatgtcatc gttgatgtca tcgggaagga cagcagcctg 5700 ggtgtggaga acctgcgggg ctcgggcatg attgcaggag aggcttctct ggcttacgaa 5760 aaaaatgtca ccatcagcat ggtgacctgc cgcgccatcg gaatcggggc ttacctggtg 5820 aggctgggcc agcgggtgat ccaggtggaa aactcccaca tcatcctcac gggagccggt 5880 gctctcaaca aggtcctggg aagagaggtc tacacatcca acaaccaact gggcggtgtg 5940 cagatcatgc acaccaacgg ggtctcccac gtcacggtgc cagatgactt cgagggggtc 6000 tgcaccattc tggaatggct gtcatatata ccaaaggaca atcaaagccc agtccccatc 6060 atcactcctt ctgaccccat cgacagggaa attgaattca ccccaaccaa agctccctat 6120 gaccccaggt ggctgctggc agggaggcct cacccaactc tgaaggggac ctggcagagt 6180 ggattcttcg accatggcag tttcaaggaa atcatggcac cctgggccca gactgtggtg 6240 actggacgag caaggctggg gggcatccct gtaggggtga ttgccgtgga gactcggtct 6300 gtggaggtgg ctgtccctgc tgaccctgcc aacttggatt ctgaggccaa gatcatccag 6360 caggcaggcc aggtgtggtt cccggactct gccttcaaga cggctcaggt catcagggac 6420 ttcaaccagg agcatctgcc tctcatgatc tttgctaact ggagaggctt ctcgggcggc 6480 atgaaagaca tgtacgagca gatgctgaag tttggcgcct acatcgtgga cagtctccgt 6540 ctgttcaagc agccagttct catctatatc cctcccggtg ccgaactccg agggggcgcc 6600 tgggttgtcc tcgactccag catcaacccc ctgtgcatag agatgtacgc agacaaagag 6660 agcagggggg gtgtcctgga gcccgagggc actgtggaga ttaagttccg gaagaaagat 6720 ttggtgaaga ccataaggag gattgaccca gtgtgcaaga aactcctggg gcagctgggg 6780 acagcccagc tccctgacaa ggaccggaaa gagctggaga gccagctgaa ggcccgggag 6840 gacctgctgc tccccatcta ccaccaggtg gcagtgcagt tcgccgacct gcatgacacg 6900 ccgggccaca tgctggagaa gggaatcatt tctgatgtgc tggagtggaa gaccacacgt 6960 acctacttct actggaggct gcgccggctg ctgctggagg cacaggtgaa gcaggagatt 7020 ctgcgagcca gccctgagct gagccatgag cacacgcagt ccatgctgcg acgctggttt 7080 gtggagaccg agggcgccgt caaggcctac ctgtgggaca gcaaccaggt ggtagtccag 7140 tggctggaac agcactggtc agccagggac aacctgcgtt ccactatccg agagaacatc 7200 aattatctga agcgggactc tgtcctcaag accatccaaa gcctagttca agaacaccca 7260 gaggcgacca tggactgtgt ggcatacctg agccagcacc tcacgcccgc tgagcagatg 7320 caggtggttc agctgctgtc taccacggag agcccagctt cccactgagc aaccctggcc 7380 atccccagga ccctggacgg tgggaatggc cgcgcagcag gccttcgcag tacgccagga 7440 ctaattttgg gaaaactgga gctacagcgg c 7471 15 7388 DNA Rattus norvegicus CDS (21)..(7388) 15 tcccttgaca ggttgtctga atg gtc ttg ctt ctc ttt ctg act tgc ctg gtt 53 Met Val Leu Leu Leu Phe Leu Thr Cys Leu Val 1 5 10 ttc tcc tgc ctg acc att tcc tgg tta aaa atc tgg ggg aag atg aca 101 Phe Ser Cys Leu Thr Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr 15 20 25 gac tcg aag ccg ctc agc aac agt aag gtg gat gca agc ctc ctt tcg 149 Asp Ser Lys Pro Leu Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Ser 30 35 40 agc aag gag gag tcc ttt tca gcc tcg gac cag tca gag gag cat ggc 197 Ser Lys Glu Glu Ser Phe Ser Ala Ser Asp Gln Ser Glu Glu His Gly 45 50 55 gac tgc agc tgt ccg ttg aca act cct gac cag gag gag ctg gcc tcc 245 Asp Cys Ser Cys Pro Leu Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser 60 65 70 75 cac gga ggt cct gta gat gcc agt cag cag agg aac tct gtg cca agc 293 His Gly Gly Pro Val Asp Ala Ser Gln Gln Arg Asn Ser Val Pro Ser 80 85 90 tca cac cag aag cct ccg agg aac cca cta tct tcc aat gac acc tgt 341 Ser His Gln Lys Pro Pro Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys 95 100 105 tcc tcc cca gaa ctc caa acc aac ggg gta gca gcc cct ggc tca gag 389 Ser Ser Pro Glu Leu Gln Thr Asn Gly Val Ala Ala Pro Gly Ser Glu 110 115 120 gtt cca gaa gcc aac ggg ttg cct ttc cca gcc agg cct cag acc cag 437 Val Pro Glu Ala Asn Gly Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln 125 130 135 aga acg gga tcc ccc act agg gag gac aag aag cag gca cac atc aag 485 Arg Thr Gly Ser Pro Thr Arg Glu Asp Lys Lys Gln Ala His Ile Lys 140 145 150 155 agg cag ctg atg acc agc ttt atc ctg ggc tcc ctc gat gac aac tcc 533 Arg Gln Leu Met Thr Ser Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser 160 165 170 tct gac gag gac cct agt gct agc tcc ttc cag acc tcc tct cgg aag 581 Ser Asp Glu Asp Pro Ser Ala Ser Ser Phe Gln Thr Ser Ser Arg Lys 175 180 185 ggc agc agg gct agc ctg ggc acc ctg tcc cag gag gct gca ttg aac 629 Gly Ser Arg Ala Ser Leu Gly Thr Leu Ser Gln Glu Ala Ala Leu Asn 190 195 200 aca gct gat cct gag tct cac aca cct act atg agg ccc agc atg tct 677 Thr Ala Asp Pro Glu Ser His Thr Pro Thr Met Arg Pro Ser Met Ser 205 210 215 gga ctc cat ctg gtg aag aga ggc cgt gaa cac aag aaa ctg gac ctg 725 Gly Leu His Leu Val Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu 220 225 230 235 cac aga gat ttc act gta gct tcc cca gcc gaa ttt gtc acc cgc ttt 773 His Arg Asp Phe Thr Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe 240 245 250 gga ggc aac agg gtt atc gag acg gtg ctc atc gcc aat aat ggt atc 821 Gly Gly Asn Arg Val Ile Glu Thr Val Leu Ile Ala Asn Asn Gly Ile 255 260 265 gct gcg gtc aag tgt atg cgc tcc atc cgc cgc tgg gcc tat gag atg 869 Ala Ala Val Lys Cys Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met 270 275 280 ttc cgt aat gaa cgc gcc atc cgg ttt gtg gtt atg gtg aca ccc gag 917 Phe Arg Asn Glu Arg Ala Ile Arg Phe Val Val Met Val Thr Pro Glu 285 290 295 gat ctt aag gcc aac gca gag tac atc aag atg gcg gac cag tac gtt 965 Asp Leu Lys Ala Asn Ala Glu Tyr Ile Lys Met Ala Asp Gln Tyr Val 300 305 310 315 ccg gtc cca gga gga ccc aat aat aac aac tac gcc aac gtt gag ctg 1013 Pro Val Pro Gly Gly Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu 320 325 330 atc ata gac att gcc aag aga atc cct gtg cag gcc gtg tgg gct ggc 1061 Ile Ile Asp Ile Ala Lys Arg Ile Pro Val Gln Ala Val Trp Ala Gly 335 340 345 tgg ggc cac gct tcg gaa aac ccc aaa ctt cca gag cta ctg tgc aag 1109 Trp Gly His Ala Ser Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys 350 355 360 cac gag att gct ttc cta ggt ccc ccg agt gag gcc atg tgg gcc ctg 1157 His Glu Ile Ala Phe Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu 365 370 375 gga gac aag atc tcc tcc acc att gta gcc cag aca ttg cag atc cca 1205 Gly Asp Lys Ile Ser Ser Thr Ile Val Ala Gln Thr Leu Gln Ile Pro 380 385 390 395 act cta ccc tgg agc gga agc ggt ctc aca gtg gag tgg acg gag gac 1253 Thr Leu Pro Trp Ser Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp 400 405 410 agc cag cat cag ggc aaa tgc atc agc gtc ccg gaa gac gtt tat gaa 1301 Ser Gln His Gln Gly Lys Cys Ile Ser Val Pro Glu Asp Val Tyr Glu 415 420 425 caa ggc tgt gtg aga gat gtg gac gaa ggc ttg cag gca gca gaa aaa 1349 Gln Gly Cys Val Arg Asp Val Asp Glu Gly Leu Gln Ala Ala Glu Lys 430 435 440 gta gga ttt cct ctg atg atc aaa gcc tct gaa ggt gga gga ggg aaa 1397 Val Gly Phe Pro Leu Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys 445 450 455 gga atc cgc agg gct gag agt gca gag gac ttc ccg atg ctt ttc aga 1445 Gly Ile Arg Arg Ala Glu Ser Ala Glu Asp Phe Pro Met Leu Phe Arg 460 465 470 475 cag gtg cag agt gag atc ccg ggc tcg ccc atc ttt ctc atg aag ctg 1493 Gln Val Gln Ser Glu Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu 480 485 490 gcc cag aat gct cgg cac ttg gag gtc cag gtc ttg gca gat cag tat 1541 Ala Gln Asn Ala Arg His Leu Glu Val Gln Val Leu Ala Asp Gln Tyr 495 500 505 ggg aac gca gtg tcc ctg ttt gga cga gac tgc tcc atc cag agg cgg 1589 Gly Asn Ala Val Ser Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg 510 515 520 cac cag aag atc att gag gag gct ccg gcc acc atc gct gct ccg gct 1637 His Gln Lys Ile Ile Glu Glu Ala Pro Ala Thr Ile Ala Ala Pro Ala 525 530 535 gtg ttt gag ttc atg gaa cag tgt gcc gtc ctc ctg gcc aag act gtg 1685 Val Phe Glu Phe Met Glu Gln Cys Ala Val Leu Leu Ala Lys Thr Val 540 545 550 555 ggt tat gtg agc gcg gga acc gtg gag tac cta tac agc cag gat ggc 1733 Gly Tyr Val Ser Ala Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly 560 565 570 agc ttt cac ttc ttg gag ctg aac cca cgc ctg cag gtg gaa cat ccc 1781 Ser Phe His Phe Leu Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro 575 580 585 tgc act gaa atg atc gca gat gtc aac ctg ccc gct gca cag tta cag 1829 Cys Thr Glu Met Ile Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln 590 595 600 atc gcc atg ggc gtg ccc ctg

cac cgg ctg aag gac ata cgg ctt ctg 1877 Ile Ala Met Gly Val Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu 605 610 615 tac gga gag tcc ccc tgg gga gtg acc ccc gtt tct ttt gag acc cct 1925 Tyr Gly Glu Ser Pro Trp Gly Val Thr Pro Val Ser Phe Glu Thr Pro 620 625 630 635 ttg agc cct ccc att gcc cga ggc cat gtc att gca gcc agg atc acc 1973 Leu Ser Pro Pro Ile Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr 640 645 650 agc gaa aac cca gac gag ggc ttt aag cca agc tca ggg aca gtg cag 2021 Ser Glu Asn Pro Asp Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln 655 660 665 gag ctg aac ttc cgc agc aac aag aac gtg tgg ggt tac ttc agc gtg 2069 Glu Leu Asn Phe Arg Ser Asn Lys Asn Val Trp Gly Tyr Phe Ser Val 670 675 680 gcc gct gct ggg ggc ttg cac gag ttt gcc gat tcc cag ttt ggg cac 2117 Ala Ala Ala Gly Gly Leu His Glu Phe Ala Asp Ser Gln Phe Gly His 685 690 695 tgc ttc tcc tgg ggc gag aac cgt gaa gag gct att tcg aac atg gtg 2165 Cys Phe Ser Trp Gly Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val 700 705 710 715 gtg gct ttg aaa gaa ctg tct atc cgg ggt gac ttc cgg acc acc gtg 2213 Val Ala Leu Lys Glu Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val 720 725 730 gaa tat ctc gtc aac ctt ctg gag acg gag agc ttc cag aac aat gat 2261 Glu Tyr Leu Val Asn Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp 735 740 745 atc gac acg ggg tgg ctg gac cac ctc atc gct cag cgg gtg cag gca 2309 Ile Asp Thr Gly Trp Leu Asp His Leu Ile Ala Gln Arg Val Gln Ala 750 755 760 gag aag ccg gac atc atg ctc ggg gtg gtg tgt ggg gcc ttg aac gtg 2357 Glu Lys Pro Asp Ile Met Leu Gly Val Val Cys Gly Ala Leu Asn Val 765 770 775 gca gac gcg atg ttc aga acc tgt atg acg gaa ttc ctg cat tcc ttg 2405 Ala Asp Ala Met Phe Arg Thr Cys Met Thr Glu Phe Leu His Ser Leu 780 785 790 795 gaa agg ggt cag gtc ctc ccg gct gat tct ctg ctg aac atc gtg gac 2453 Glu Arg Gly Gln Val Leu Pro Ala Asp Ser Leu Leu Asn Ile Val Asp 800 805 810 gtt gag ttg att tac gga ggc atc aaa tat gtt ctc aag gtg gcc cgg 2501 Val Glu Leu Ile Tyr Gly Gly Ile Lys Tyr Val Leu Lys Val Ala Arg 815 820 825 cag tcc ctg acc atg ttt gtc ctc atc atg aat ggt tgc cac atc gag 2549 Gln Ser Leu Thr Met Phe Val Leu Ile Met Asn Gly Cys His Ile Glu 830 835 840 atc gat gcc cac cgg ctg aac gat ggg ggc ctg ctc ctg tcc tac aat 2597 Ile Asp Ala His Arg Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn 845 850 855 ggt agc agt tac act aca tac atg aag gaa gag gtg gac agt tac cgg 2645 Gly Ser Ser Tyr Thr Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg 860 865 870 875 atc act atc ggc aat aag aca tgc gtg ttt gaa aag gaa aac gac ccc 2693 Ile Thr Ile Gly Asn Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro 880 885 890 acc gtc ctg aga tcc ccc tcg gct ggg aag ctg atg cag tac acg gtg 2741 Thr Val Leu Arg Ser Pro Ser Ala Gly Lys Leu Met Gln Tyr Thr Val 895 900 905 gag gat ggc cag cac gtg gaa gtc ggg agc agc tat gct gag atg gag 2789 Glu Asp Gly Gln His Val Glu Val Gly Ser Ser Tyr Ala Glu Met Glu 910 915 920 gtg atg aag atg atc atg acc ctg aac gtg caa gag agc ggc cgg gtg 2837 Val Met Lys Met Ile Met Thr Leu Asn Val Gln Glu Ser Gly Arg Val 925 930 935 aag tac atc aag cga cca ggg gcg gta ttg gag gct ggc tgc gtg gtg 2885 Lys Tyr Ile Lys Arg Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val 940 945 950 955 gca aag cta gaa ctc gat gac cct tca aaa gtg cac gcg gca cag ccg 2933 Ala Lys Leu Glu Leu Asp Asp Pro Ser Lys Val His Ala Ala Gln Pro 960 965 970 ttc aca ggg gag ctc ccc gcc cag cag act ctg ccc atc ctc ggg gag 2981 Phe Thr Gly Glu Leu Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu 975 980 985 agg ctg cat cag gtg ttc cac agc gtc ttg gaa aat ctg acc aat gtc 3029 Arg Leu His Gln Val Phe His Ser Val Leu Glu Asn Leu Thr Asn Val 990 995 1000 atg aat ggc tac tgc ctg ccc gag ccc ttc ttc agc atg aag ctg 3074 Met Asn Gly Tyr Cys Leu Pro Glu Pro Phe Phe Ser Met Lys Leu 1005 1010 1015 aag gac tgg gtg gag aag ctc atg atg act ctc cgg cat ccc tcc 3119 Lys Asp Trp Val Glu Lys Leu Met Met Thr Leu Arg His Pro Ser 1020 1025 1030 cta cct ctg ctg gag ctg cag gag atc atg acc agc gtg gca ggc 3164 Leu Pro Leu Leu Glu Leu Gln Glu Ile Met Thr Ser Val Ala Gly 1035 1040 1045 cgc atc ccg gtt ccg gtg gag aag gca gtc cgc agg gtg atg gcg 3209 Arg Ile Pro Val Pro Val Glu Lys Ala Val Arg Arg Val Met Ala 1050 1055 1060 cag tac gcc agc aac atc act tcg gtg ctc tgc cag ttc ccc agc 3254 Gln Tyr Ala Ser Asn Ile Thr Ser Val Leu Cys Gln Phe Pro Ser 1065 1070 1075 cag cag ata gcc acc atc ctg gac tgc cac gcc gcc acc ctg cag 3299 Gln Gln Ile Ala Thr Ile Leu Asp Cys His Ala Ala Thr Leu Gln 1080 1085 1090 cgt aag gtg gac cga gag gcc ttc ttc atg aac aca cag agc atc 3344 Arg Lys Val Asp Arg Glu Ala Phe Phe Met Asn Thr Gln Ser Ile 1095 1100 1105 gtg cag ctg atc cag aga tac cgc agt ggg acc cgt ggc tac atg 3389 Val Gln Leu Ile Gln Arg Tyr Arg Ser Gly Thr Arg Gly Tyr Met 1110 1115 1120 aag gct gtg gtg cta gac ctc ctg agg aga tat ctg aac gtg gag 3434 Lys Ala Val Val Leu Asp Leu Leu Arg Arg Tyr Leu Asn Val Glu 1125 1130 1135 cat cat ttc cag caa gcc cac tat gac aag tgt gtg atc aac ctg 3479 His His Phe Gln Gln Ala His Tyr Asp Lys Cys Val Ile Asn Leu 1140 1145 1150 agg gag cag ttc aag ccg gac atg act cgg gtg ctg gac tgc atc 3524 Arg Glu Gln Phe Lys Pro Asp Met Thr Arg Val Leu Asp Cys Ile 1155 1160 1165 ttc tca cac tca caa gtg gcc aag aag aac cag ctg gtg acc atg 3569 Phe Ser His Ser Gln Val Ala Lys Lys Asn Gln Leu Val Thr Met 1170 1175 1180 ttg ata gat gag ctg tgt ggc cca gac ccc acc ctg tca gaa gag 3614 Leu Ile Asp Glu Leu Cys Gly Pro Asp Pro Thr Leu Ser Glu Glu 1185 1190 1195 ctg acc tcc atc ctc aag gaa ctc acg cag ttg agc agg agt gag 3659 Leu Thr Ser Ile Leu Lys Glu Leu Thr Gln Leu Ser Arg Ser Glu 1200 1205 1210 cac tgc aag gtg gcc ctc aga gcc agg cag gtc ctg att gcc tct 3704 His Cys Lys Val Ala Leu Arg Ala Arg Gln Val Leu Ile Ala Ser 1215 1220 1225 cac ctc ccc tcc tac gag ctg cgg cac aac cag gtg gag tcc atc 3749 His Leu Pro Ser Tyr Glu Leu Arg His Asn Gln Val Glu Ser Ile 1230 1235 1240 ttc ctg tca gcc att gac atg tat ggc cac cag ttc tgc ccg gaa 3794 Phe Leu Ser Ala Ile Asp Met Tyr Gly His Gln Phe Cys Pro Glu 1245 1250 1255 aac ctc aag aaa cta ata ctt tcg gaa acg acc ata ttc gat gtc 3839 Asn Leu Lys Lys Leu Ile Leu Ser Glu Thr Thr Ile Phe Asp Val 1260 1265 1270 ctg ccc act ttc ttc tat cac gct aac aag gtc gtc tgt atg gcg 3884 Leu Pro Thr Phe Phe Tyr His Ala Asn Lys Val Val Cys Met Ala 1275 1280 1285 tcc ctg gag gtt tat gtg agg aga ggt tac atc gcc tac gag tta 3929 Ser Leu Glu Val Tyr Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu 1290 1295 1300 aac agc cta cag cac cgg gag ctc cct gac ggc acc tgc gtg gtg 3974 Asn Ser Leu Gln His Arg Glu Leu Pro Asp Gly Thr Cys Val Val 1305 1310 1315 gag ttc cag ttc atg ctg ccg tct tcc cac ccc aac cgg atg gcc 4019 Glu Phe Gln Phe Met Leu Pro Ser Ser His Pro Asn Arg Met Ala 1320 1325 1330 atg ccc atc aat gtc tct gac cct gac ctg ctg aga cac agt aag 4064 Met Pro Ile Asn Val Ser Asp Pro Asp Leu Leu Arg His Ser Lys 1335 1340 1345 gaa ctc ttc atg gac agt ggc ttc tcc cca ctg tgc cag cgg atg 4109 Glu Leu Phe Met Asp Ser Gly Phe Ser Pro Leu Cys Gln Arg Met 1350 1355 1360 ggg gcc atg gtg gcc ttc agg aga ttt gag gag ttc acc agg aac 4154 Gly Ala Met Val Ala Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn 1365 1370 1375 ttc gat gaa gtc atc tcc tgc ttt gcc aac gtg cct aca gac act 4199 Phe Asp Glu Val Ile Ser Cys Phe Ala Asn Val Pro Thr Asp Thr 1380 1385 1390 cct ctc ttc agt aag gcg tgc act tcc ctc tac tca gag gag gac 4244 Pro Leu Phe Ser Lys Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp 1395 1400 1405 agc aag agc ctt caa gag gag ccc atc cac atc ctg aat gtg gcc 4289 Ser Lys Ser Leu Gln Glu Glu Pro Ile His Ile Leu Asn Val Ala 1410 1415 1420 atc cag tgc gcc gac cac atg gag gac gag aga ctg gtg ccg gtt 4334 Ile Gln Cys Ala Asp His Met Glu Asp Glu Arg Leu Val Pro Val 1425 1430 1435 ttc cgt gcc ttt gta cag tcc aag aaa cac atc ctt gtg gat tac 4379 Phe Arg Ala Phe Val Gln Ser Lys Lys His Ile Leu Val Asp Tyr 1440 1445 1450 gga ctg cga aga atc aca ttc ctt atc gcc caa gag aga gaa ttt 4424 Gly Leu Arg Arg Ile Thr Phe Leu Ile Ala Gln Glu Arg Glu Phe 1455 1460 1465 ccc aag ttc ttc acg ttc aga gcg aga gat gag ttt gca gaa gac 4469 Pro Lys Phe Phe Thr Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp 1470 1475 1480 cgg att tac cgc cac ttg gag ccg gcc ctg gcc ttc cag ctg gag 4514 Arg Ile Tyr Arg His Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu 1485 1490 1495 ctg agc cgg atg cgc aac ttt gac ctg acg gcc gtg ccc tgt gcc 4559 Leu Ser Arg Met Arg Asn Phe Asp Leu Thr Ala Val Pro Cys Ala 1500 1505 1510 aac cat aag atg cat ctt tac ctg gga gcc gcc aag gtg aag gaa 4604 Asn His Lys Met His Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu 1515 1520 1525 ggg ctg gag gtg act gac cac agg ttc ttc atc cga gcc atc ata 4649 Gly Leu Glu Val Thr Asp His Arg Phe Phe Ile Arg Ala Ile Ile 1530 1535 1540 agg cac tca gac ctg atc acc aag gaa gcc tcc ttc gag tac ctg 4694 Arg His Ser Asp Leu Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu 1545 1550 1555 cag aat gaa ggg gag cgg ctg ctg ctg gaa gcc atg gat gag ctg 4739 Gln Asn Glu Gly Glu Arg Leu Leu Leu Glu Ala Met Asp Glu Leu 1560 1565 1570 gag gtg gcg ttc aac aac acc agc gtg cgc act gac tgc aac cac 4784 Glu Val Ala Phe Asn Asn Thr Ser Val Arg Thr Asp Cys Asn His 1575 1580 1585 atc ttc ctc aac ttc gtg ccc acg gtc atc atg gac cca ctc aag 4829 Ile Phe Leu Asn Phe Val Pro Thr Val Ile Met Asp Pro Leu Lys 1590 1595 1600 atc gag gag tcg gtg cgt gcc atg gtc atg cgt tac ggc agt cgg 4874 Ile Glu Glu Ser Val Arg Ala Met Val Met Arg Tyr Gly Ser Arg 1605 1610 1615 ctg tgg aag ctc cgt gtg ctg cag gca gaa gtt aag atc aac atc 4919 Leu Trp Lys Leu Arg Val Leu Gln Ala Glu Val Lys Ile Asn Ile 1620 1625 1630 cgt cag acg acc tcg gac tgc gcc gtc ccc att cgc ctc ttc atc 4964 Arg Gln Thr Thr Ser Asp Cys Ala Val Pro Ile Arg Leu Phe Ile 1635 1640 1645 acc aac gag tcc ggc tac tac ctg gac atc agc ctc tac aaa gaa 5009 Thr Asn Glu Ser Gly Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu 1650 1655 1660 gtg acc gac tcc aga tcc gga aac atc atg ttt cat tcc ttc ggc 5054 Val Thr Asp Ser Arg Ser Gly Asn Ile Met Phe His Ser Phe Gly 1665 1670 1675 aac aaa caa ggg agc ctg cac ggg atg ctg atc aac acg ccc tac 5099 Asn Lys Gln Gly Ser Leu His Gly Met Leu Ile Asn Thr Pro Tyr 1680 1685 1690 gtc acc aag gat ctg ctc caa gcc aag cga ttc cag gcg cag tcc 5144 Val Thr Lys Asp Leu Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser 1695 1700 1705 ctg ggg acc acc tat gtg tac gac ttc cca gag atg ttc agg cag 5189 Leu Gly Thr Thr Tyr Val Tyr Asp Phe Pro Glu Met Phe Arg Gln 1710 1715 1720 gct ctc ttt aaa ttg tgg ggc tcc cca gag aag tac ccc aaa gat 5234 Ala Leu Phe Lys Leu Trp Gly Ser Pro Glu Lys Tyr Pro Lys Asp 1725 1730 1735 atc ctg aca tac aca gag ctg gtg ttg gac tcc cag ggc cag ctg 5279 Ile Leu Thr Tyr Thr Glu Leu Val Leu Asp Ser Gln Gly Gln Leu 1740 1745 1750 gtg gag atg aac cgg ctt cct ggt tgt aac gag gtg ggc atg gtg 5324 Val Glu Met Asn Arg Leu Pro Gly Cys Asn Glu Val Gly Met Val 1755 1760 1765 gtt ttc aaa atg agg ttc aag acc ccg gag tat cca gaa ggc cgg 5369 Val Phe Lys Met Arg Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg 1770 1775 1780 gac act atc gtc atc ggc aac gac att acc ttc caa atc ggc tct 5414 Asp Thr Ile Val Ile Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser 1785 1790 1795 ttc ggc ata gga gag gac ttc ctg tat cta cgg gca tcg gag atg 5459 Phe Gly Ile Gly Glu Asp Phe Leu Tyr Leu Arg Ala Ser Glu Met 1800 1805 1810 gcc cgg aca gag ggc atc ccc caa atc tat ctg gca gcc aac agc 5504 Ala Arg Thr Glu Gly Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser 1815 1820 1825 ggg gcc cgt atg ggc ctg tcc gag gag atc aag cag ata ttc caa 5549 Gly Ala Arg Met Gly Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln 1830 1835 1840 gtg gca tgg gtg gac cct gag gat ccc tac aaa gga ttt aga tac 5594 Val Ala Trp Val Asp Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr 1845 1850 1855 ctg tac ctg acg ccc caa gac tac acc cag atc agc tcc cag aac 5639 Leu Tyr Leu Thr Pro Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn 1860 1865 1870 tcc gtg cac tgc aaa cac atc gag gac gaa ggc gag tcc agg tat 5684 Ser Val His Cys Lys His Ile Glu Asp Glu Gly Glu Ser Arg Tyr 1875 1880 1885 gtc atc gtt gat gtc atc ggg aag gac agc agc ctg ggt gtg gag 5729 Val Ile Val Asp Val Ile Gly Lys Asp Ser Ser Leu Gly Val Glu 1890 1895 1900 aac ctg cgg ggc tcg ggc atg att gca gga gag gct tct ctg gct 5774 Asn Leu Arg Gly Ser Gly Met Ile Ala Gly Glu Ala Ser Leu Ala 1905 1910 1915 tac gaa aaa aat gtc acc atc agc atg gtg acc tgc cgc gcc atc 5819 Tyr Glu Lys Asn Val Thr Ile Ser Met Val Thr Cys Arg Ala Ile 1920 1925 1930 gga atc ggg gct tac ctg gtg agg ctg ggc cag cgg gtg atc cag 5864 Gly Ile Gly Ala Tyr Leu Val Arg Leu Gly Gln Arg Val Ile Gln 1935 1940 1945 gtg gaa aac tcc cac atc atc ctc acg gga gcc ggt gct ctc aac 5909 Val Glu Asn Ser His Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn 1950 1955 1960 aag gtc ctg gga aga gag gtc tac aca tcc aac aac caa ctg ggc 5954 Lys Val Leu Gly Arg Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly 1965 1970 1975 ggt gtg cag atc atg cac acc aac ggg gtc tcc cac gtc acg gtg 5999 Gly Val Gln Ile Met His Thr Asn Gly Val Ser His Val Thr Val 1980 1985 1990 cca gat gac ttc gag ggg gtc tgc acc att ctg gaa tgg ctg tca 6044 Pro Asp Asp Phe Glu Gly Val Cys Thr Ile Leu Glu Trp Leu Ser 1995 2000 2005 tat ata cca aag gac aat caa agc cca gtc ccc atc atc act cct 6089 Tyr Ile Pro Lys Asp Asn Gln Ser Pro Val Pro Ile Ile Thr Pro 2010 2015 2020 tct gac ccc atc gac agg gaa att gaa ttc acc cca acc aaa gct 6134 Ser Asp Pro Ile Asp Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala 2025 2030 2035 ccc tat gac ccc agg tgg ctg ctt gca ggg agg cct cac cca act 6179 Pro Tyr Asp Pro Arg Trp Leu Leu Ala Gly Arg Pro His Pro Thr 2040 2045 2050 ctg aag ggg acc tgg cag agt gga ttc ttc gac cat ggc agt ttc 6224 Leu Lys Gly Thr Trp Gln Ser Gly Phe Phe Asp His Gly Ser Phe 2055 2060 2065 aag gaa atc atg gca ccc tgg gcc cag acc gtg gtg act gga cga 6269 Lys Glu Ile Met Ala Pro Trp Ala Gln Thr Val Val Thr Gly Arg 2070 2075 2080 gca agg ctg ggg ggc atc

cct gta ggg gtg att gcc gtg gag act 6314 Ala Arg Leu Gly Gly Ile Pro Val Gly Val Ile Ala Val Glu Thr 2085 2090 2095 cgg tct gtg gag gtg gct gtc cct gct gac cct gcc aac ttg gat 6359 Arg Ser Val Glu Val Ala Val Pro Ala Asp Pro Ala Asn Leu Asp 2100 2105 2110 tct gag gcc aag atc atc cag cag gca ggc cag gtg tgg ttc ccg 6404 Ser Glu Ala Lys Ile Ile Gln Gln Ala Gly Gln Val Trp Phe Pro 2115 2120 2125 gac tct gcc ttc aag acg gct cag gtc atc agg gac ttc aac cag 6449 Asp Ser Ala Phe Lys Thr Ala Gln Val Ile Arg Asp Phe Asn Gln 2130 2135 2140 gag cat ctg cct ctc atg atc ttt gcc aac tgg aga ggc ttc tcg 6494 Glu His Leu Pro Leu Met Ile Phe Ala Asn Trp Arg Gly Phe Ser 2145 2150 2155 ggt ggc atg aaa gac atg tac gag cag atg ctg aag ttt ggc gcc 6539 Gly Gly Met Lys Asp Met Tyr Glu Gln Met Leu Lys Phe Gly Ala 2160 2165 2170 tac atc gtg gac agt ctc cgt ctg ttc aag cag cca gtt ctc atc 6584 Tyr Ile Val Asp Ser Leu Arg Leu Phe Lys Gln Pro Val Leu Ile 2175 2180 2185 tat atc cct cct ggt gcc gaa ctc cga ggg ggc gcc tgg gtt gtc 6629 Tyr Ile Pro Pro Gly Ala Glu Leu Arg Gly Gly Ala Trp Val Val 2190 2195 2200 ctc gac tcc agc atc aac ccc ctg tgc ata gag atg tac gca gac 6674 Leu Asp Ser Ser Ile Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp 2205 2210 2215 aaa gag agc agg ggg ggt gtc ctg gag ccc gag ggc act gtg gag 6719 Lys Glu Ser Arg Gly Gly Val Leu Glu Pro Glu Gly Thr Val Glu 2220 2225 2230 att aag ttc cgg aag aaa gat ttg gtg aag acc ata agg agg att 6764 Ile Lys Phe Arg Lys Lys Asp Leu Val Lys Thr Ile Arg Arg Ile 2235 2240 2245 gac cca gtg tgc aag aaa ctc ctg ggg cag ctg ggg aca gcc cag 6809 Asp Pro Val Cys Lys Lys Leu Leu Gly Gln Leu Gly Thr Ala Gln 2250 2255 2260 ctc cct gac aag gac cgg aaa gag ctg gag agc cag ctg aag gcc 6854 Leu Pro Asp Lys Asp Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala 2265 2270 2275 cgg gag gac ctg ctg ctc ccc atc tac cac cag gtg gca gtg cag 6899 Arg Glu Asp Leu Leu Leu Pro Ile Tyr His Gln Val Ala Val Gln 2280 2285 2290 ttc gcc gac ctg cat gac acg ccg ggc cac atg ctg gag aag gga 6944 Phe Ala Asp Leu His Asp Thr Pro Gly His Met Leu Glu Lys Gly 2295 2300 2305 atc att tct gat gtg ctg gag tgg aag acc aca cgt acc tac ttc 6989 Ile Ile Ser Asp Val Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe 2310 2315 2320 tac tgg agg ctg cgc cgg ctg ctg ctg gag gca cag gtg aag cag 7034 Tyr Trp Arg Leu Arg Arg Leu Leu Leu Glu Ala Gln Val Lys Gln 2325 2330 2335 gag att ctg cga gcc agc cct gag ctg agc cat gag cac acg cag 7079 Glu Ile Leu Arg Ala Ser Pro Glu Leu Ser His Glu His Thr Gln 2340 2345 2350 tcc atg ctg cga cgc tgg ttt gtg gag acc gag ggc gcc gtc aag 7124 Ser Met Leu Arg Arg Trp Phe Val Glu Thr Glu Gly Ala Val Lys 2355 2360 2365 gcc tac ctg tgg gac agc aac cag gtg gta gtc cag tgg ctg gaa 7169 Ala Tyr Leu Trp Asp Ser Asn Gln Val Val Val Gln Trp Leu Glu 2370 2375 2380 cag cac tgg tca gcc agg gac aac ctg cgt tcc act atc cga gag 7214 Gln His Trp Ser Ala Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu 2385 2390 2395 aac atc aat tat ctg aag cgg gac tct gtc ctc aag acc atc caa 7259 Asn Ile Asn Tyr Leu Lys Arg Asp Ser Val Leu Lys Thr Ile Gln 2400 2405 2410 agc cta gtt caa gaa cac cca gag gcg acc atg gac tgt gtg gca 7304 Ser Leu Val Gln Glu His Pro Glu Ala Thr Met Asp Cys Val Ala 2415 2420 2425 tac ctg agc cag cac ctc acg ccc gct gag cag atg cag gtg gtt 7349 Tyr Leu Ser Gln His Leu Thr Pro Ala Glu Gln Met Gln Val Val 2430 2435 2440 cag ctg ctg tct acc acg gag agc cca gct tcc cac tga 7388 Gln Leu Leu Ser Thr Thr Glu Ser Pro Ala Ser His 2445 2450 2455 16 2455 PRT Rattus norvegicus 16 Met Val Leu Leu Leu Phe Leu Thr Cys Leu Val Phe Ser Cys Leu Thr 1 5 10 15 Ile Ser Trp Leu Lys Ile Trp Gly Lys Met Thr Asp Ser Lys Pro Leu 20 25 30 Ser Asn Ser Lys Val Asp Ala Ser Leu Leu Ser Ser Lys Glu Glu Ser 35 40 45 Phe Ser Ala Ser Asp Gln Ser Glu Glu His Gly Asp Cys Ser Cys Pro 50 55 60 Leu Thr Thr Pro Asp Gln Glu Glu Leu Ala Ser His Gly Gly Pro Val 65 70 75 80 Asp Ala Ser Gln Gln Arg Asn Ser Val Pro Ser Ser His Gln Lys Pro 85 90 95 Pro Arg Asn Pro Leu Ser Ser Asn Asp Thr Cys Ser Ser Pro Glu Leu 100 105 110 Gln Thr Asn Gly Val Ala Ala Pro Gly Ser Glu Val Pro Glu Ala Asn 115 120 125 Gly Leu Pro Phe Pro Ala Arg Pro Gln Thr Gln Arg Thr Gly Ser Pro 130 135 140 Thr Arg Glu Asp Lys Lys Gln Ala His Ile Lys Arg Gln Leu Met Thr 145 150 155 160 Ser Phe Ile Leu Gly Ser Leu Asp Asp Asn Ser Ser Asp Glu Asp Pro 165 170 175 Ser Ala Ser Ser Phe Gln Thr Ser Ser Arg Lys Gly Ser Arg Ala Ser 180 185 190 Leu Gly Thr Leu Ser Gln Glu Ala Ala Leu Asn Thr Ala Asp Pro Glu 195 200 205 Ser His Thr Pro Thr Met Arg Pro Ser Met Ser Gly Leu His Leu Val 210 215 220 Lys Arg Gly Arg Glu His Lys Lys Leu Asp Leu His Arg Asp Phe Thr 225 230 235 240 Val Ala Ser Pro Ala Glu Phe Val Thr Arg Phe Gly Gly Asn Arg Val 245 250 255 Ile Glu Thr Val Leu Ile Ala Asn Asn Gly Ile Ala Ala Val Lys Cys 260 265 270 Met Arg Ser Ile Arg Arg Trp Ala Tyr Glu Met Phe Arg Asn Glu Arg 275 280 285 Ala Ile Arg Phe Val Val Met Val Thr Pro Glu Asp Leu Lys Ala Asn 290 295 300 Ala Glu Tyr Ile Lys Met Ala Asp Gln Tyr Val Pro Val Pro Gly Gly 305 310 315 320 Pro Asn Asn Asn Asn Tyr Ala Asn Val Glu Leu Ile Ile Asp Ile Ala 325 330 335 Lys Arg Ile Pro Val Gln Ala Val Trp Ala Gly Trp Gly His Ala Ser 340 345 350 Glu Asn Pro Lys Leu Pro Glu Leu Leu Cys Lys His Glu Ile Ala Phe 355 360 365 Leu Gly Pro Pro Ser Glu Ala Met Trp Ala Leu Gly Asp Lys Ile Ser 370 375 380 Ser Thr Ile Val Ala Gln Thr Leu Gln Ile Pro Thr Leu Pro Trp Ser 385 390 395 400 Gly Ser Gly Leu Thr Val Glu Trp Thr Glu Asp Ser Gln His Gln Gly 405 410 415 Lys Cys Ile Ser Val Pro Glu Asp Val Tyr Glu Gln Gly Cys Val Arg 420 425 430 Asp Val Asp Glu Gly Leu Gln Ala Ala Glu Lys Val Gly Phe Pro Leu 435 440 445 Met Ile Lys Ala Ser Glu Gly Gly Gly Gly Lys Gly Ile Arg Arg Ala 450 455 460 Glu Ser Ala Glu Asp Phe Pro Met Leu Phe Arg Gln Val Gln Ser Glu 465 470 475 480 Ile Pro Gly Ser Pro Ile Phe Leu Met Lys Leu Ala Gln Asn Ala Arg 485 490 495 His Leu Glu Val Gln Val Leu Ala Asp Gln Tyr Gly Asn Ala Val Ser 500 505 510 Leu Phe Gly Arg Asp Cys Ser Ile Gln Arg Arg His Gln Lys Ile Ile 515 520 525 Glu Glu Ala Pro Ala Thr Ile Ala Ala Pro Ala Val Phe Glu Phe Met 530 535 540 Glu Gln Cys Ala Val Leu Leu Ala Lys Thr Val Gly Tyr Val Ser Ala 545 550 555 560 Gly Thr Val Glu Tyr Leu Tyr Ser Gln Asp Gly Ser Phe His Phe Leu 565 570 575 Glu Leu Asn Pro Arg Leu Gln Val Glu His Pro Cys Thr Glu Met Ile 580 585 590 Ala Asp Val Asn Leu Pro Ala Ala Gln Leu Gln Ile Ala Met Gly Val 595 600 605 Pro Leu His Arg Leu Lys Asp Ile Arg Leu Leu Tyr Gly Glu Ser Pro 610 615 620 Trp Gly Val Thr Pro Val Ser Phe Glu Thr Pro Leu Ser Pro Pro Ile 625 630 635 640 Ala Arg Gly His Val Ile Ala Ala Arg Ile Thr Ser Glu Asn Pro Asp 645 650 655 Glu Gly Phe Lys Pro Ser Ser Gly Thr Val Gln Glu Leu Asn Phe Arg 660 665 670 Ser Asn Lys Asn Val Trp Gly Tyr Phe Ser Val Ala Ala Ala Gly Gly 675 680 685 Leu His Glu Phe Ala Asp Ser Gln Phe Gly His Cys Phe Ser Trp Gly 690 695 700 Glu Asn Arg Glu Glu Ala Ile Ser Asn Met Val Val Ala Leu Lys Glu 705 710 715 720 Leu Ser Ile Arg Gly Asp Phe Arg Thr Thr Val Glu Tyr Leu Val Asn 725 730 735 Leu Leu Glu Thr Glu Ser Phe Gln Asn Asn Asp Ile Asp Thr Gly Trp 740 745 750 Leu Asp His Leu Ile Ala Gln Arg Val Gln Ala Glu Lys Pro Asp Ile 755 760 765 Met Leu Gly Val Val Cys Gly Ala Leu Asn Val Ala Asp Ala Met Phe 770 775 780 Arg Thr Cys Met Thr Glu Phe Leu His Ser Leu Glu Arg Gly Gln Val 785 790 795 800 Leu Pro Ala Asp Ser Leu Leu Asn Ile Val Asp Val Glu Leu Ile Tyr 805 810 815 Gly Gly Ile Lys Tyr Val Leu Lys Val Ala Arg Gln Ser Leu Thr Met 820 825 830 Phe Val Leu Ile Met Asn Gly Cys His Ile Glu Ile Asp Ala His Arg 835 840 845 Leu Asn Asp Gly Gly Leu Leu Leu Ser Tyr Asn Gly Ser Ser Tyr Thr 850 855 860 Thr Tyr Met Lys Glu Glu Val Asp Ser Tyr Arg Ile Thr Ile Gly Asn 865 870 875 880 Lys Thr Cys Val Phe Glu Lys Glu Asn Asp Pro Thr Val Leu Arg Ser 885 890 895 Pro Ser Ala Gly Lys Leu Met Gln Tyr Thr Val Glu Asp Gly Gln His 900 905 910 Val Glu Val Gly Ser Ser Tyr Ala Glu Met Glu Val Met Lys Met Ile 915 920 925 Met Thr Leu Asn Val Gln Glu Ser Gly Arg Val Lys Tyr Ile Lys Arg 930 935 940 Pro Gly Ala Val Leu Glu Ala Gly Cys Val Val Ala Lys Leu Glu Leu 945 950 955 960 Asp Asp Pro Ser Lys Val His Ala Ala Gln Pro Phe Thr Gly Glu Leu 965 970 975 Pro Ala Gln Gln Thr Leu Pro Ile Leu Gly Glu Arg Leu His Gln Val 980 985 990 Phe His Ser Val Leu Glu Asn Leu Thr Asn Val Met Asn Gly Tyr Cys 995 1000 1005 Leu Pro Glu Pro Phe Phe Ser Met Lys Leu Lys Asp Trp Val Glu 1010 1015 1020 Lys Leu Met Met Thr Leu Arg His Pro Ser Leu Pro Leu Leu Glu 1025 1030 1035 Leu Gln Glu Ile Met Thr Ser Val Ala Gly Arg Ile Pro Val Pro 1040 1045 1050 Val Glu Lys Ala Val Arg Arg Val Met Ala Gln Tyr Ala Ser Asn 1055 1060 1065 Ile Thr Ser Val Leu Cys Gln Phe Pro Ser Gln Gln Ile Ala Thr 1070 1075 1080 Ile Leu Asp Cys His Ala Ala Thr Leu Gln Arg Lys Val Asp Arg 1085 1090 1095 Glu Ala Phe Phe Met Asn Thr Gln Ser Ile Val Gln Leu Ile Gln 1100 1105 1110 Arg Tyr Arg Ser Gly Thr Arg Gly Tyr Met Lys Ala Val Val Leu 1115 1120 1125 Asp Leu Leu Arg Arg Tyr Leu Asn Val Glu His His Phe Gln Gln 1130 1135 1140 Ala His Tyr Asp Lys Cys Val Ile Asn Leu Arg Glu Gln Phe Lys 1145 1150 1155 Pro Asp Met Thr Arg Val Leu Asp Cys Ile Phe Ser His Ser Gln 1160 1165 1170 Val Ala Lys Lys Asn Gln Leu Val Thr Met Leu Ile Asp Glu Leu 1175 1180 1185 Cys Gly Pro Asp Pro Thr Leu Ser Glu Glu Leu Thr Ser Ile Leu 1190 1195 1200 Lys Glu Leu Thr Gln Leu Ser Arg Ser Glu His Cys Lys Val Ala 1205 1210 1215 Leu Arg Ala Arg Gln Val Leu Ile Ala Ser His Leu Pro Ser Tyr 1220 1225 1230 Glu Leu Arg His Asn Gln Val Glu Ser Ile Phe Leu Ser Ala Ile 1235 1240 1245 Asp Met Tyr Gly His Gln Phe Cys Pro Glu Asn Leu Lys Lys Leu 1250 1255 1260 Ile Leu Ser Glu Thr Thr Ile Phe Asp Val Leu Pro Thr Phe Phe 1265 1270 1275 Tyr His Ala Asn Lys Val Val Cys Met Ala Ser Leu Glu Val Tyr 1280 1285 1290 Val Arg Arg Gly Tyr Ile Ala Tyr Glu Leu Asn Ser Leu Gln His 1295 1300 1305 Arg Glu Leu Pro Asp Gly Thr Cys Val Val Glu Phe Gln Phe Met 1310 1315 1320 Leu Pro Ser Ser His Pro Asn Arg Met Ala Met Pro Ile Asn Val 1325 1330 1335 Ser Asp Pro Asp Leu Leu Arg His Ser Lys Glu Leu Phe Met Asp 1340 1345 1350 Ser Gly Phe Ser Pro Leu Cys Gln Arg Met Gly Ala Met Val Ala 1355 1360 1365 Phe Arg Arg Phe Glu Glu Phe Thr Arg Asn Phe Asp Glu Val Ile 1370 1375 1380 Ser Cys Phe Ala Asn Val Pro Thr Asp Thr Pro Leu Phe Ser Lys 1385 1390 1395 Ala Cys Thr Ser Leu Tyr Ser Glu Glu Asp Ser Lys Ser Leu Gln 1400 1405 1410 Glu Glu Pro Ile His Ile Leu Asn Val Ala Ile Gln Cys Ala Asp 1415 1420 1425 His Met Glu Asp Glu Arg Leu Val Pro Val Phe Arg Ala Phe Val 1430 1435 1440 Gln Ser Lys Lys His Ile Leu Val Asp Tyr Gly Leu Arg Arg Ile 1445 1450 1455 Thr Phe Leu Ile Ala Gln Glu Arg Glu Phe Pro Lys Phe Phe Thr 1460 1465 1470 Phe Arg Ala Arg Asp Glu Phe Ala Glu Asp Arg Ile Tyr Arg His 1475 1480 1485 Leu Glu Pro Ala Leu Ala Phe Gln Leu Glu Leu Ser Arg Met Arg 1490 1495 1500 Asn Phe Asp Leu Thr Ala Val Pro Cys Ala Asn His Lys Met His 1505 1510 1515 Leu Tyr Leu Gly Ala Ala Lys Val Lys Glu Gly Leu Glu Val Thr 1520 1525 1530 Asp His Arg Phe Phe Ile Arg Ala Ile Ile Arg His Ser Asp Leu 1535 1540 1545 Ile Thr Lys Glu Ala Ser Phe Glu Tyr Leu Gln Asn Glu Gly Glu 1550 1555 1560 Arg Leu Leu Leu Glu Ala Met Asp Glu Leu Glu Val Ala Phe Asn 1565 1570 1575 Asn Thr Ser Val Arg Thr Asp Cys Asn His Ile Phe Leu Asn Phe 1580 1585 1590 Val Pro Thr Val Ile Met Asp Pro Leu Lys Ile Glu Glu Ser Val 1595 1600 1605 Arg Ala Met Val Met Arg Tyr Gly Ser Arg Leu Trp Lys Leu Arg 1610 1615 1620 Val Leu Gln Ala Glu Val Lys Ile Asn Ile Arg Gln Thr Thr Ser 1625 1630 1635 Asp Cys Ala Val Pro Ile Arg Leu Phe Ile Thr Asn Glu Ser Gly 1640 1645 1650 Tyr Tyr Leu Asp Ile Ser Leu Tyr Lys Glu Val Thr Asp Ser Arg 1655 1660 1665 Ser Gly Asn Ile Met Phe His Ser Phe Gly Asn Lys Gln Gly Ser 1670 1675 1680 Leu His Gly Met Leu Ile Asn Thr Pro Tyr Val Thr Lys Asp Leu 1685 1690 1695 Leu Gln Ala Lys Arg Phe Gln Ala Gln Ser Leu Gly Thr Thr Tyr 1700 1705 1710 Val Tyr Asp Phe Pro Glu Met Phe Arg Gln Ala Leu Phe Lys Leu 1715 1720 1725 Trp Gly Ser Pro Glu Lys Tyr Pro Lys Asp Ile Leu Thr Tyr Thr 1730 1735 1740 Glu Leu Val Leu Asp Ser Gln Gly Gln Leu Val Glu Met Asn Arg 1745 1750 1755 Leu Pro Gly Cys Asn Glu Val Gly Met Val Val Phe Lys Met Arg 1760 1765 1770 Phe Lys Thr Pro Glu Tyr Pro Glu Gly Arg Asp Thr Ile Val Ile 1775 1780 1785 Gly Asn Asp Ile Thr Phe Gln Ile Gly Ser Phe Gly Ile Gly Glu 1790 1795 1800 Asp

Phe Leu Tyr Leu Arg Ala Ser Glu Met Ala Arg Thr Glu Gly 1805 1810 1815 Ile Pro Gln Ile Tyr Leu Ala Ala Asn Ser Gly Ala Arg Met Gly 1820 1825 1830 Leu Ser Glu Glu Ile Lys Gln Ile Phe Gln Val Ala Trp Val Asp 1835 1840 1845 Pro Glu Asp Pro Tyr Lys Gly Phe Arg Tyr Leu Tyr Leu Thr Pro 1850 1855 1860 Gln Asp Tyr Thr Gln Ile Ser Ser Gln Asn Ser Val His Cys Lys 1865 1870 1875 His Ile Glu Asp Glu Gly Glu Ser Arg Tyr Val Ile Val Asp Val 1880 1885 1890 Ile Gly Lys Asp Ser Ser Leu Gly Val Glu Asn Leu Arg Gly Ser 1895 1900 1905 Gly Met Ile Ala Gly Glu Ala Ser Leu Ala Tyr Glu Lys Asn Val 1910 1915 1920 Thr Ile Ser Met Val Thr Cys Arg Ala Ile Gly Ile Gly Ala Tyr 1925 1930 1935 Leu Val Arg Leu Gly Gln Arg Val Ile Gln Val Glu Asn Ser His 1940 1945 1950 Ile Ile Leu Thr Gly Ala Gly Ala Leu Asn Lys Val Leu Gly Arg 1955 1960 1965 Glu Val Tyr Thr Ser Asn Asn Gln Leu Gly Gly Val Gln Ile Met 1970 1975 1980 His Thr Asn Gly Val Ser His Val Thr Val Pro Asp Asp Phe Glu 1985 1990 1995 Gly Val Cys Thr Ile Leu Glu Trp Leu Ser Tyr Ile Pro Lys Asp 2000 2005 2010 Asn Gln Ser Pro Val Pro Ile Ile Thr Pro Ser Asp Pro Ile Asp 2015 2020 2025 Arg Glu Ile Glu Phe Thr Pro Thr Lys Ala Pro Tyr Asp Pro Arg 2030 2035 2040 Trp Leu Leu Ala Gly Arg Pro His Pro Thr Leu Lys Gly Thr Trp 2045 2050 2055 Gln Ser Gly Phe Phe Asp His Gly Ser Phe Lys Glu Ile Met Ala 2060 2065 2070 Pro Trp Ala Gln Thr Val Val Thr Gly Arg Ala Arg Leu Gly Gly 2075 2080 2085 Ile Pro Val Gly Val Ile Ala Val Glu Thr Arg Ser Val Glu Val 2090 2095 2100 Ala Val Pro Ala Asp Pro Ala Asn Leu Asp Ser Glu Ala Lys Ile 2105 2110 2115 Ile Gln Gln Ala Gly Gln Val Trp Phe Pro Asp Ser Ala Phe Lys 2120 2125 2130 Thr Ala Gln Val Ile Arg Asp Phe Asn Gln Glu His Leu Pro Leu 2135 2140 2145 Met Ile Phe Ala Asn Trp Arg Gly Phe Ser Gly Gly Met Lys Asp 2150 2155 2160 Met Tyr Glu Gln Met Leu Lys Phe Gly Ala Tyr Ile Val Asp Ser 2165 2170 2175 Leu Arg Leu Phe Lys Gln Pro Val Leu Ile Tyr Ile Pro Pro Gly 2180 2185 2190 Ala Glu Leu Arg Gly Gly Ala Trp Val Val Leu Asp Ser Ser Ile 2195 2200 2205 Asn Pro Leu Cys Ile Glu Met Tyr Ala Asp Lys Glu Ser Arg Gly 2210 2215 2220 Gly Val Leu Glu Pro Glu Gly Thr Val Glu Ile Lys Phe Arg Lys 2225 2230 2235 Lys Asp Leu Val Lys Thr Ile Arg Arg Ile Asp Pro Val Cys Lys 2240 2245 2250 Lys Leu Leu Gly Gln Leu Gly Thr Ala Gln Leu Pro Asp Lys Asp 2255 2260 2265 Arg Lys Glu Leu Glu Ser Gln Leu Lys Ala Arg Glu Asp Leu Leu 2270 2275 2280 Leu Pro Ile Tyr His Gln Val Ala Val Gln Phe Ala Asp Leu His 2285 2290 2295 Asp Thr Pro Gly His Met Leu Glu Lys Gly Ile Ile Ser Asp Val 2300 2305 2310 Leu Glu Trp Lys Thr Thr Arg Thr Tyr Phe Tyr Trp Arg Leu Arg 2315 2320 2325 Arg Leu Leu Leu Glu Ala Gln Val Lys Gln Glu Ile Leu Arg Ala 2330 2335 2340 Ser Pro Glu Leu Ser His Glu His Thr Gln Ser Met Leu Arg Arg 2345 2350 2355 Trp Phe Val Glu Thr Glu Gly Ala Val Lys Ala Tyr Leu Trp Asp 2360 2365 2370 Ser Asn Gln Val Val Val Gln Trp Leu Glu Gln His Trp Ser Ala 2375 2380 2385 Arg Asp Asn Leu Arg Ser Thr Ile Arg Glu Asn Ile Asn Tyr Leu 2390 2395 2400 Lys Arg Asp Ser Val Leu Lys Thr Ile Gln Ser Leu Val Gln Glu 2405 2410 2415 His Pro Glu Ala Thr Met Asp Cys Val Ala Tyr Leu Ser Gln His 2420 2425 2430 Leu Thr Pro Ala Glu Gln Met Gln Val Val Gln Leu Leu Ser Thr 2435 2440 2445 Thr Glu Ser Pro Ala Ser His 2450 2455 17 10 PRT Artificial Synthesized peptide 17 Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 1 5 10 18 23 DNA Artificial Synthesized primer 18 tcctgtattg gcgtctgcgc cgc 23 19 27 DNA Artificial Synthesized primer 19 cgaattcacg gtggaggccg ggctgtc 27 20 64 DNA Artificial Synthesized primer 20 ggccgaagcc ggtaccgcca tgggcaaaga agacaagaag caggcaaaca tcaagaggca 60 gctg 64 21 21 DNA Artificial Synthesized primer 21 cgtctgggcg acaacggtgg a 21 22 23 DNA Artificial Synthesized primer 22 tcctgtattg gcgtctgcgc cgc 23 23 75 DNA Artificial Synthesized primer 23 ggccgaagcc accggtgccc agatcctctt ctgagatgag tttttgttcg cccgtagaat 60 cgagaccgag gagag 75 24 26 DNA Artificial Synthesized Primer 24 cgatcccccc caaagcgtgt gacaaa 26 25 23 DNA Artificial Synthesized primer 25 ccacaccgcc tgcacgggga ttc 23 26 27 DNA Artificial Synthesized primer 26 gaggtattcc actgtccctg cactcac 27 27 29 DNA Artificial Synthesized primer 27 cgatgtggca gccattcatg atgagaacg 29 28 30 DNA Artificial Synthesized primer 28 tgttgatgaa gaagacctct cgatcagcct 30 29 23 DNA Artificial Synthesized primer 29 gttctcgggg cagaactggt ggc 23 30 28 DNA Artificial Synthesized primer 30 ccttcacctt ggcagcaccc aggtaaag 28 31 27 DNA Artificial Synthesized primer 31 gggaagtcat agatgtaggt ggttccc 27 32 4 PRT Artificial Core sequence of commercially available FLAG peptide 32 Asp Tyr Lys Asp 1 33 8 PRT Artificial Commerically available FLAG sequence 33 Asp Tyr Lys Asp Asp Asp Asp Lys 1 5

Claims

1-7. (canceled)

8. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a polypeptide comprising SEQ ID NO:13; (b) a polypeptide comprising amino acids 2 to 2458 of SEQ ID NO:13, wherein amino acids 2 to 2458 comprise a polypeptide of SEQ ID NO:13 minus the start methionine; and (c) a polypeptide comprising amino acids 1 to 2458 of SEQ ID NO:13.

9. The isolated polypeptide of claim 8, wherein the polypeptide comprises two or more sequential amino acid deletions from one or both of: (a) the COOH-terminus of the polypeptide; and (b) the NH.sub.2-terminus of the polypeptide.

10. A method of identifying a compound that modulates the activity of the polypeptide of claim 8, the method comprising: (a) determining the activity of the polypeptide of claim 8 in the absence of a test compound; (b) determining the activity of the polypeptide in the presence of a test compound; and (c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound relative to the activity of the polypeptide in the absence of the test compound indicates that the compound that modulates the activity of the polypeptide.

11. An isolated antibody which specifically binds to the polypeptide of claim 8.

12. The antibody of claim 11, wherein the antibody is selected from the group consisting of a chimeric antibody, a single chain antibody, a Fab fragment, and a humanized antibody.

13. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: (a) a polynucleotide encoding an ACC2 polypeptide comprising SEQ ID NO:16; (b) an isolated polynucleotide encoding a rat ACC2 polypeptide comprising amino acids 2 to 2455 of SEQ ID NO:16 minus the start methionine; (c) an isolated polynucleotide encoding a rat ACC2 polypeptide comprising amino acids 1 to 2455 of SEQ ID NO:16 including the start codon; (d) the cDNA of ATCC Deposit No. PTA-6054; and (e) a polynucleotide capable of hybridizing under stringent conditions to the polynucleotide specified in (a)-(d), wherein the polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

14. The isolated nucleic acid molecule of claim 13, wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO:15.

15. A polynucleotide that is complementary to the isolated nucleic acid molecule of claim 13.

16. A vector comprising the isolated nucleic acid molecule of claim 13.

17. A host cell comprising the vector of claim 16.

18. The host cell of claim 17, wherein the host cell is a mammalian host cell.

19. A method of making an isolated polypeptide comprising: (a) culturing the recombinant host cell of claim 17 under conditions such that the polypeptide is expressed; and (b) recovering the polypeptide.

20. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a polypeptide comprising SEQ ID NO:16; (b) a polypeptide comprising amino acids 2 to 2455 of SEQ ID NO:16, wherein amino acids 2 to 2455 comprise a polypeptide of SEQ ID NO:16 minus the start methionine; and (c) a polypeptide comprising amino acids 1 to 2455 of SEQ ID NO:16.

21. The isolated polypeptide of claim 20, wherein the polypeptide comprises two or more sequential amino acid deletions from one or both of: (a) the C-terminus of the polypeptide; and (b) the N-terminus of the polypeptide.

22. A method of identifying a compound that modulates the activity of the polypeptide of claim 20, the method comprising: (a) determining the activity of the polypeptide of claim 20 in the absence of a test compound; (b) determining the activity of the polypeptide in the presence of a test compound; and (c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound relative to the activity of the polypeptide in the absence of the test compound indicates that the compound that modulates the activity of the polypeptide.

23. An isolated antibody which specifically binds to the polypeptide of claim 20.

24. The antibody of claim 23, wherein the antibody is selected from the group consisting of a chimeric antibody, a single chain antibody, a Fab fragment, and a humanized antibody.

25. A method of isolating an ACC polypeptide comprising: (a) contacting crude lysate derived from a cell or tissue expressing an ACC polypeptide with an antibody to form a complex comprising an antibody and ACC; (b) washing the complex with a buffer comprising 0.5 M NaCl; and (c) contacting the complex with an eluting ligand.

26. The method of claim 25, wherein the antibody comprises an IgG antibody.

27. The method of claim 26, wherein the IgG antibody is a c-Myc-5 IgG antibody and the eluting ligand is a myc peptide.

28. The method of claim 27, wherein the myc peptide comprises the amino acid sequence of SEQ ID NO:17.

29. The method of claim 26, wherein the IgG antibody is an anti-FLAG IgG antibody.

30. The method of claim 25, wherein the antibody is bound to a substrate.

31. The method of claim 25, wherein the ACC polypeptide is an ACC1 polypeptide.

32. The method of claim 25, wherein the ACC polypeptide is an ACC2 polypeptide.

33. The method of claim 25 wherein the ACC polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:13 and 16.

34. A polynucleotide capable of inhibiting the expression of an ACC2 gene comprising a polynucleotide sequence selected from the group consisting of SEQ ID NOs:12 and 15 by antisense inhibition.

35. A method of inhibiting ACC2 gene expression comprising introducing a polynucleotide of claim 34 into a cell or tissue that expresses an ACC2 gene, thereby inhibiting the expression of the gene in the cell or tissue by antisense inhibition.

36. A polynucleotide capable of inhibiting the expression of an ACC2 gene comprising a polynucleotide sequence selected from the group consisting of SEQ ID NOs:12 and 15 by RNA interference.

37. A method of inhibiting ACC2 gene expression comprising introducing a polynucleotide of claim 36 into a cell or tissue that expresses an ACC2 gene, thereby inhibiting the expression of the gene in the cell or tissue by RNA interference.

38. An isolated polypeptide comprising an ACC2 polypeptide encoded by the cDNA deposited as ATCC Accession No. PTA-6054.

39. A method of increasing the activity of a human ACC2 polypeptide, the method comprising generating an enhanced ACC2 polypeptide comprising (a) a phenylalanine residue at position 254, (b) a glutamine residue at position 346, (c) a threonine residue at position 565, (d) an asparagine at position 841, (e) a valine residue at position 1103, (f) a cysteine residue at position 1259, (g) an alanine residue at position 1526, and (h) an isoleucine residue at position 1717, wherein the human ACC2 polypeptide does not comprise SEQ ID NO:13 and wherein the enhanced ACC2 polypeptide has an enzymatic activity level that is greater than the enzymatic activity level of an ACC2 polypeptide that does not contain the indicated residues at the indicated positions.

40. The method of claim 39, wherein the human ACC2 polypeptide sequence is selected from the group consisting of SEQ ID NOs: 2, 4 and 6.