Novel human protocadherin proteins and polynucleotides encoding the same

Abstract

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

Description

[0001] The present application claims the benefit of U.S. Provisional Application No. 60/257,257 which was filed on Dec. 20, 2000 and is herein incorporated by reference in its entirety.

1. INTRODUCTION

[0002] The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins that share sequence similarity with mammalian cadherins. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or overexpress the disclosed genes, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed genes, which can be used for diagnosis, drug screening, clinical trial monitoring, the treatment of diseases and disorders, and cosmetic or nutriceutical applications.

2. BACKGROUND OF THE INVENTION

[0003] Cadherin proteins are membrane proteins that have been linked to a variety of biological processes varying from development, tumor suppression, neural function, and cell communication.

3. SUMMARY OF THE INVENTION

[0004] The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins, and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein share structural similarity with animal protocadherins, and especially the protocadherin FAT.

[0005] The novel human nucleic acid sequences described herein, encode alternative proteins/open reading frames (ORFs) of 4589, 3852, 4585, and 4588 amino acids in length (see respectively SEQ ID NOS: 2, 4, 6, and 8).

[0006] The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPs, or portions thereof, that compete with native NHP, peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and open reading frame or regulatory sequence replacement constructs) or to enhance the expression of the described NHPs (e.g., expression constructs that place the described polynucleotide under the control of a strong promoter system), and transgenic animals that express a NHP sequence, or "knock-outs" (which can be conditional) that do not express a functional NHP. Knock-out mice can be produced in several ways, one of which involves the use of mouse embryonic stem cells ("ES cells") lines that contain gene trap mutations in a murine homolog of at least one of the described NHPs. When the unique NHP sequences described in SEQ ID NOS:1-8 are "knocked-out" they provide a method of identifying phenotypic expression of the particular gene as well as a method of assigning function to previously unknown genes. In addition, animals in which the unique NHP sequences described in SEQ ID NOS:1-8 are "knocked-out" provide a unique source in which to elicit antibodies to homologous and orthologous proteins which would have been previously viewed by the immune system as "self" and therefore would have failed to elicit significant antibody responses.

[0007] Additionally, the unique NHP sequences described in SEQ ID NOS:1-8 are useful for the identification of protein coding sequence and mapping a unique gene to a particular chromosome (the gene encoding the described sequences is apparently encoded on human chromosome 11, see GENBANK accession number AC024231). These sequences identify actual, biologically verified, and therefore relevant, exon splice junctions as opposed to those that may have been bioinformatically predicted from genomic sequence alone. The sequences of the present invention are also useful as additional DNA markers for restriction fragment length polymorphism (RFLP) analysis, and in forensic biology.

[0008] Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

[0009] The Sequence Listing provides the sequences of the NHP ORFs encoding the described NHP amino acid sequences.

5. DETAILED DESCRIPTION OF THE INVENTION

[0010] The NHPs described for the first time herein are novel proteins that may be expressed in, inter alia, human cell lines, fetal brain, brain, pituitary, cerebellum, fetal kidney, fetal lung, and 6- and 9-week embryos.

[0011] The present invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described genes, including the specifically described NHPs, and the NHP products; (b) nucleotides that encode one or more portions of the NHPs that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of the described NHPs in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal (or hydrophobic transmembrane) sequence is deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of an NHP, or one of its domains (e.g., a receptor or ligand binding domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide; or (e) therapeutic or diagnostic derivatives of the described polynucleotides such as oligonucleotides, antisense polynucleotides, ribozymes, dsRNA, or gene therapy constructs comprising a sequence first disclosed in the Sequence Listing.

[0012] As discussed above, the present invention includes: (a) the human DNA sequences presented in the Sequence Listing (and vectors comprising the same) and additionally contemplates any nucleotide sequence encoding a contiguous NHP open reading frame (ORF) that hybridizes to a complement of a DNA sequence presented in the Sequence Listing under highly stringent conditions, e.g., hybridization to filter-bound DNA in 0.5 M NaHPO.sub.4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65.degree. C., and washing in 0.1.times.SSC/0.1% SDS at 68.degree. C. (Ausubel F. M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley & Sons, Inc., NY, at p. 2.10.3) and encodes a functionally equivalent expression product.

[0013] Additionally contemplated are any nucleotide sequences that hybridize to the complement of a DNA sequence that encodes and expresses an amino acid sequence presented in the Sequence Listing under moderately stringent conditions, e.g., washing in 0.2.times.SSC/0.1% SDS at 42.degree. C. (Ausubel et al., 1989, supra), yet still encodes a functionally equivalent NHP product. Functional equivalents of a NHP include naturally occurring NHPs present in other species and mutant NHPs whether naturally occurring or engineered (by site directed mutagenesis, gene shuffling, directed evolution as described in, for example, U.S. Pat. Nos. 5,837,458 and 5,723,323 both of which are herein incorporated by reference in their entirety). The invention also includes degenerate nucleic acid variants of the disclosed NHP polynucleotide sequences.

[0014] Additionally contemplated are polynucleotides encoding NHP ORFs, or their functional equivalents, encoded by polynucleotide sequences that are about 99, 95, 90, or about 85 percent similar or identical to corresponding regions of the nucleotide sequences of the Sequence Listing (as measured by BLAST sequence comparison analysis using, for example, the GCG sequence analysis package using standard default settings).

[0015] The invention also includes nucleic acid molecules, preferably DNA molecules, that hybridize to, and are therefore the complements of, the described NHP gene nucleotide sequences. Such hybridization conditions may be highly stringent or less highly stringent, as described above. In instances where the nucleic acid molecules are deoxyoligonucleotides ("DNA oligos"), such molecules are generally about 16 to about 100 bases long, or about 20 to about 80, or about 34 to about 45 bases long, or any variation or combination of sizes represented therein that incorporate a contiguous region of sequence first disclosed in the Sequence Listing. Such oligonucleotides can be used in conjunction with the polymerase chain reaction (PCR) to screen libraries, isolate clones, and prepare cloning and sequencing templates, etc.

[0016] Alternatively, such NHP oligonucleotides can be used as hybridization probes for screening libraries, and assessing gene expression patterns (particularly using a micro array or high-throughput "chip" format). Additionally, a series of the described NHP oligonucleotide sequences, or the complements thereof, can be used to represent all or a portion of the described NHP sequences. An oligonucleotide or polynucleotide sequence first disclosed in at least a portion of one or more of the sequences of SEQ ID NOS: 1-8 can be used as a hybridization probe in conjunction with a solid support matrix/substrate (resins, beads, membranes, plastics, polymers, metal or metallized substrates, crystalline or polycrystalline substrates, etc.). Of particular note are spatially addressable arrays (i.e., gene chips, microtiter plates, etc.) of oligonucleotides and polynucleotides, or corresponding oligopeptides and polypeptides, wherein at least one of the biopolymers present on the spatially addressable array comprises an oligonucleotide or polynucleotide sequence first disclosed in at least one of the sequences of SEQ ID NOS: 1-8, or an amino acid sequence encoded thereby. Methods for attaching biopolymers to, or synthesizing biopolymers on, solid support matrices, and conducting binding studies thereon are disclosed in, inter alia, U.S. Pat. Nos. 5,700,637, 5,556,752, 5,744,305, 4,631,211, 5,445,934, 5,252,743, 4,713,326, 5,424,186, and 4,689,405 the disclosures of which are herein incorporated by reference in their entirety.

[0017] Addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-8 can be used to identify and characterize the temporal and tissue specific expression of a gene. These addressable arrays incorporate oligonucleotide sequences of sufficient length to confer the required specificity, yet be within the limitations of the production technology. The length of these probes is within a range of between about 8 to about 2000 nucleotides. Preferably the probes consist of 60 nucleotides and more preferably 25 nucleotides from the sequences first disclosed in SEQ ID NOS:1-8.

[0018] For example, a series of the described oligonucleotide sequences, or the complements thereof, can be used in chip format to represent all or a portion of the described sequences. The oligonucleotides, typically between about 16 to about 40 (or any whole number within the stated range) nucleotides in length can partially overlap each other and/or the sequence may be represented using oligonucleotides that do not overlap. Accordingly, the described polynucleotide sequences shall typically comprise at least about two or three distinct oligonucleotide sequences of at least about 8 nucleotides in length that are each first disclosed in the described Sequence Listing. Such oligonucleotide sequences can begin at any nucleotide present within a sequence in the Sequence Listing and proceed in either a sense (5'-to-3') orientation vis-a-vis the described sequence or in an antisense orientation.

[0019] Microarray-based analysis allows the discovery of broad patterns of genetic activity, providing new understanding of gene functions and generating novel and unexpected insight into transcriptional processes and biological mechanisms. The use of addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-8 provides detailed information about transcriptional changes involved in a specific pathway, potentially leading to the identification of novel components or gene functions that manifest themselves as novel phenotypes.

[0020] Probes consisting of sequences first disclosed in SEQ ID NOS:1-8 can also be used in the identification, selection and validation of novel molecular targets for drug discovery. The use of these unique sequences permits the direct confirmation of drug targets and recognition of drug dependent changes in gene expression that are modulated through pathways distinct from the drugs intended target. These unique sequences therefore also have utility in defining and monitoring both drug action and toxicity.

[0021] As an example of utility, the sequences first disclosed in SEQ ID NOS:1-8 can be utilized in microarrays or other assay formats, to screen collections of genetic material from patients who have a particular medical condition. These investigations can also be carried out using the sequences first disclosed in SEQ ID NOS:1-8 in silico and by comparing previously collected genetic databases and the disclosed sequences using computer software known to those in the art.

[0022] Thus the sequences first disclosed in SEQ ID NOS:1-8 can be used to identify mutations associated with a particular disease and also as a diagnostic or prognostic assay.

[0023] Although the presently described sequences have been specifically described using nucleotide sequence, it should be appreciated that each of the sequences can uniquely be described using any of a wide variety of additional structural attributes, or combinations thereof. For example, a given sequence can be described by the net composition of the nucleotides present within a given region of the sequence in conjunction with the presence of one or more specific oligonucleotide sequence(s) first disclosed in the SEQ ID NOS: 1-8. Alternatively, a restriction map specifying the relative positions of restriction endonuclease digestion sites, or various palindromic or other specific oligonucleotide sequences can be used to structurally describe a given sequence. Such restriction maps, which are typically generated by widely available computer programs (e.g., the University of Wisconsin GCG sequence analysis package, SEQUENCHER 3.0, Gene Codes Corp., Ann Arbor, Mich., etc.), can optionally be used in conjunction with one or more discrete nucleotide sequence(s) present in the sequence that can be described by the relative position of the sequence relative to one or more additional sequence(s) or one or more restriction sites present in the disclosed sequence.

[0024] For oligonucleotide probes, highly stringent conditions may refer, e.g., to washing in 6.times.SSC/0.05% sodium pyrophosphate at 37.degree. C. (for 14-base oligos), 48.degree. C. (for 17-base oligos), 55.degree. C. (for 20-base oligos), and 60.degree. C. (for 23-base oligos). These nucleic acid molecules may encode or act as NHP gene antisense molecules, useful, for example, in NHP gene regulation and/or as antisense primers in amplification reactions of NHP gene nucleic acid sequences. With respect to NHP gene regulation, such techniques can be used to regulate biological functions. Further, such sequences may be used as part of ribozyme and/or triple helix sequences that are also useful for NHP gene regulation.

[0025] Inhibitory antisense or double stranded oligonucleotides can additionally comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluraci- l, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-6-isopente- nyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

[0026] The antisense oligonucleotide can also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0027] In yet another embodiment, the antisense oligonucleotide will comprise at least one modified phosphate backbone selected from the group including, but not limited to, a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

[0028] In yet another embodiment, the antisense oligonucleotide is an .alpha.-anomeric oligonucleotide. An .alpha.-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual .beta.-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2'-O-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330). Alternatively, double stranded RNA can be used to disrupt the expression and function of a targeted NHP.

[0029] Oligonucleotides of the invention can be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), and methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

[0030] Low stringency conditions are well-known to those of skill in the art, and will vary predictably depending on the specific organisms from which the library and the labeled sequences are derived. For guidance regarding such conditions see, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual (and periodic updates thereof), Cold Spring Harbor Press, NY; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, NY.

[0031] Alternatively, suitably labeled NHP nucleotide probes can be used to screen a human genomic library using appropriately stringent conditions or by PCR. The identification and characterization of human genomic clones is helpful for identifying polymorphisms (including, but not limited to, nucleotide repeats, microsatellite alleles, single nucleotide polymorphisms, or coding single nucleotide polymorphisms), determining the genomic structure of a given locus/allele, and designing diagnostic tests. For example, sequences derived from regions adjacent to the intron/exon boundaries of the human gene can be used to design primers for use in amplification assays to detect mutations within the exons, introns, splice sites (e.g., splice acceptor and/or donor sites), etc., that can be used in diagnostics and pharmacogenomics.

[0032] For example, the present sequences can be used in restriction fragment length polymorphism (RFLP) analysis to identify specific individuals. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification (as generally described in U.S. Pat. No. 5,272,057, incorporated herein by reference). In addition, the sequences of the present invention can be used to provide polynucleotide reagents, e.g., PCR primers, targeted to specific loci in the human genome, which can enhance the reliability of DNA-based forensic identifications by, for example, providing another "identification marker" (i.e., another DNA sequence that is unique to a particular individual). Actual base sequence information can be used for identification as an accurate alternative to patterns formed by restriction enzyme generated fragments.

[0033] Further, a NHP gene homolog can be isolated from nucleic acid from an organism of interest by performing PCR using two degenerate or "wobble" oligonucleotide primer pools designed on the basis of amino acid sequences within the NHP products disclosed herein. The template for the reaction may be total RNA, mRNA, and/or cDNA obtained by reverse transcription of mRNA prepared from human or non-human cell lines or tissue known or suspected to express an allele of a NHP gene. The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequence of the desired NHP gene. The PCR fragment can then be used to isolate a full length cDNA clone by a variety of methods. For example, the amplified fragment can be labeled and used to screen a cDNA library, such as a bacteriophage cDNA library. Alternatively, the labeled fragment can be used to isolate genomic clones via the screening of a genomic library.

[0034] PCR technology can also be used to isolate full length cDNA sequences. For example, RNA can be isolated, following standard procedures, from an appropriate cellular or tissue source (i.e., one known, or suspected, to express a NHP gene). A reverse transcription (RT) reaction can be performed on the RNA using an oligonucleotide primer specific for the most 5' end of the amplified fragment for the priming of first strand synthesis. The resulting RNA/DNA hybrid may then be "tailed" using a standard terminal transferase reaction, the hybrid may be digested with RNase H, and second strand synthesis may then be primed with a complementary primer. Thus, cDNA sequences upstream of the amplified fragment can be isolated. For a review of cloning strategies that can be used, see e.g., Sambrook et al., 1989, supra.

[0035] A cDNA encoding a mutant NHP sequence can be isolated, for example, by using PCR. In this case, the first cDNA strand may be synthesized by hybridizing an oligo-dT oligonucleotide to mRNA isolated from tissue known or suspected to be expressed in an individual putatively carrying a mutant NHP allele, and by extending the new strand with reverse transcriptase. The second strand of the cDNA is then synthesized using an oligonucleotide that hybridizes specifically to the 5' end of the normal sequence. Using these two primers, the product is then amplified via PCR, optionally cloned into a suitable vector, and subjected to DNA sequence analysis through methods well-known to those of skill in the art. By comparing the DNA sequence of the mutant NHP allele to that of a corresponding normal NHP allele, the mutation(s) responsible for the loss or alteration of function of the mutant NHP gene product can be ascertained.

[0036] Alternatively, a genomic library can be constructed using DNA obtained from an individual suspected of or known to carry a mutant NHP allele (e.g., a person manifesting a NHP-associated phenotype such as, for example, obesity, high blood pressure, connective tissue disorders, infertility, etc.), or a cDNA library can be constructed using RNA from a tissue known, or suspected, to express a mutant NHP allele. A normal NHP gene, or any suitable fragment thereof, can then be labeled and used as a probe to identify the corresponding mutant NHP allele in such libraries. Clones containing mutant NHP sequences can then be purified and subjected to sequence analysis according to methods well-known to those skilled in the art.

[0037] Additionally, an expression library can be constructed utilizing cDNA synthesized from, for example, RNA isolated from a tissue known, or suspected, to express a mutant NHP allele in an individual suspected of or known to carry such a mutant allele. In this manner, gene products made by the putatively mutant tissue can be expressed and screened using standard antibody screening techniques in conjunction with antibodies raised against a normal NHP product, as described below. For screening techniques, see, for example, Harlow, E. and Lane, eds., 1988, "Antibodies: A Laboratory Manual", Cold Spring Harbor Press, Cold Spring Harbor, N.Y.

[0038] Additionally, screening can be accomplished by screening with labeled NHP fusion proteins, such as, for example, alkaline phosphatase-NHP or NHP-alkaline phosphatase fusion proteins. In cases where a NHP mutation results in an expression product with altered function (e.g., as a result of a missense or a frameshift mutation), polyclonal antibodies to NHP are likely to cross-react with a corresponding mutant NHP expression product. Library clones detected via their reaction with such labeled antibodies can be purified and subjected to sequence analysis according to methods well-known in the art.

[0039] The invention also encompasses (a) DNA vectors that contain any of the foregoing NHP coding sequences and/or their complements (i.e., antisense); (b) DNA expression vectors that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences (for example, baculovirus as described in U.S. Pat. No. 5,869,336 herein incorporated by reference); (c) genetically engineered host cells that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences in the host cell; and (d) genetically engineered host cells that express an endogenous NHP sequence under the control of an exogenously introduced regulatory element (i.e., gene activation). As used herein, regulatory elements include, but are not limited to, inducible and non-inducible promoters, enhancers, operators and other elements known to those skilled in the art that drive and regulate expression. Such regulatory elements include but are not limited to the cytomegalovirus (hCMV) immediate early gene, regulatable, viral elements (particularly retroviral LTR promoters), the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase (PGK), the promoters of acid phosphatase, and the promoters of the yeast .alpha.-mating factors.

[0040] The present invention also encompasses antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists and agonists of a NHP, as well as compounds or nucleotide constructs that inhibit expression of a NHP sequence (transcription factor inhibitors, antisense and ribozyme molecules, or open reading frame sequence or regulatory sequence replacement constructs), or promote the expression of a NHP (e.g., expression constructs in which NHP coding sequences are operatively associated with expression control elements such as promoters, promoter/enhancers, etc.).

[0041] The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences, antibodies, antagonists and agonists can be useful for the detection of mutant NHPs or inappropriately expressed NHPs for the diagnosis of disease. The NHP proteins or peptides, NHP fusion proteins, NHP nucleotide sequences, host cell expression systems, antibodies, antagonists, agonists and genetically engineered cells and animals can be used for screening for drugs (or high throughput screening of combinatorial libraries) effective in the treatment of the symptomatic or phenotypic manifestations of perturbing the normal function of NHP in the body. The use of engineered host cells and/or animals may offer an advantage in that such systems allow not only for the identification of compounds that bind to the endogenous receptor for an NHP, but can also identify compounds that trigger NHP-mediated activities or pathways.

[0042] Finally, the NHP products can be used as therapeutics. For example, soluble derivatives such as NHP peptides/domains corresponding to NHPs, NHP fusion protein products (especially NHP-Ig fusion proteins, i.e., fusions of a NHP, or a domain of a NHP, to an IgFc), NHP antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists or agonists (including compounds that modulate or act on downstream targets in a NHP-mediated pathway) can be used to directly treat diseases or disorders. For instance, the administration of an effective amount of soluble NHP, or a NHP-IgFc fusion protein or an anti-idiotypic antibody (or its Fab) that mimics the NHP could activate or effectively antagonize the endogenous NHP receptor. Nucleotide constructs encoding such NHP products can be used to genetically engineer host cells to express such products in vivo; these genetically engineered cells function as "bioreactors" in the body delivering a continuous supply of a NHP, a NHP peptide, or a NHP fusion protein to the body. Nucleotide constructs encoding functional NHPs, mutant NHPs, as well as antisense and ribozyme molecules can also be used in "gene therapy" approaches for the modulation of NHP expression. Thus, the invention also encompasses pharmaceutical formulations and methods for treating biological disorders.

[0043] Various aspects of the invention are described in greater detail in the subsections below.

5.1 The NHP Sequences

[0044] The cDNA sequences and the corresponding deduced amino acid sequences of the described NHPs are presented in the Sequence Listing. The NHP nucleotides were obtained from clustered human ESTs, and cDNAs made from brain mRNA (Edge Biosystems, Gaithersburg, Md.).

[0045] Several polymorphisms were identified including an A/T polymorphism at the nucleotide position represented by, for example, position 4543 of SEQ ID NO:1 (which can result in a thr or ser at the region corresponding to amino acid (aa) position 1515 of, for example, SEQ ID NO:2), an A/G polymorphism at nucleotide position 4775 (which can result in an asp or gly at aa position 1592), an A/G polymorphism at the nucleotide position represented by, for example, position 6878 of SEQ ID NO:1 (which can result in an asn or ser at the region corresponding to amino acid (aa) position 2293 of, for example, SEQ ID NO:2), a G/C polymorphism at nucleotide position 7227 (which can result in an arg or pro at aa position 2409), a G/A polymorphism at the nucleotide position represented by, for example, position 8263 of SEQ ID NO:1 (which can result in a val or ile at the region corresponding to amino acid (aa) position 2755 of, for example, SEQ ID NO:2), a G/A polymorphism at nucleotide position 10552 (which can result in val or leu at aa position 3518 of, for example, SEQ ID NO:2), a G/A polymorphism at nucleotide position 11434 (which can result in a gly or ser at aa position 3812), a C/A polymorphism at the nucleotide position represented by, for example, position 12691 of SEQ ID NO:1 (which can result in a pro or thr at the region corresponding to amino acid (aa) position 4231 of, for example, SEQ ID NO:2), a G/A polymorphism at nucleotide position 12770 (which can result in a gly or glu at aa position 4257 of, for example, SEQ ID NO:2), and a C/G polymorphism at the nucleotide position represented by, for example, position 12820 of SEQ ID NO:1 (which can result in a leu or val at the region corresponding to amino acid (aa) position 4274 of, for example, SEQ ID NO:2).

[0046] The disclosed NHPs are apparently encoded on human chromosome 11 (or possibly human chromosome 8).

[0047] The described novel human polynucleotide sequences can be used, among other things, in the molecular mutagenesis/evolution of proteins that are at least partially encoded by the described novel sequences using, for example, polynucleotide shuffling or related methodologies. Such approaches are described in U.S. Pat. Nos. 5,830,721 and 5,837,458 which are herein incorporated by reference in their entirety.

[0048] NHP gene products can also be expressed in transgenic animals. Animals of any species, including, but not limited to, worms, mice, rats, rabbits, guinea pigs, pigs, micro-pigs, birds, goats, and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate NHP transgenic animals.

[0049] Any technique known in the art may be used to introduce a NHP transgene into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to pronuclear microinjection (Hoppe, P. C. and Wagner, T. E., 1989, U.S. Pat. No. 4,873,191); retrovirus-mediated gene transfer into germ lines (Van der Putten et al., 1985, Proc. Natl. Acad. Sci., USA 82:6148-6152); gene targeting in embryonic stem cells (Thompson et al., 1989, Cell 56:313-321); electroporation of embryos (Lo, 1983, Mol Cell. Biol. 3:1803-1814); and sperm-mediated gene transfer (Lavitrano et al., 1989, Cell 57:717-723); etc. For a review of such techniques, see Gordon, 1989, Transgenic Animals, Intl. Rev. Cytol. 115:171-229, which is incorporated by reference herein in its entirety.

[0050] The present invention provides for transgenic animals that carry the NHP transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or somatic cell transgenic animals. The transgene may be integrated as a single transgene or in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell-type by following, for example, the teaching of Lasko et al., 1992, Proc. Natl. Acad. Sci. USA 89:6232-6236. The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell-type of interest, and will be apparent to those of skill in the art.

[0051] When it is desired that a NHP transgene be integrated into the chromosomal site of the endogenous NHP gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous NHP gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous NHP gene (i.e., "knockout" animals).

[0052] The transgene can also be selectively introduced into a particular cell-type, thus inactivating the endogenous NHP gene in only that cell-type, by following, for example, the teaching of Gu et al., 1994, Science, 265:103-106. The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell-type of interest, and will be apparent to those of skill in the art.

[0053] Once transgenic animals have been generated, the expression of the recombinant NHP gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to assay whether integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include but are not limited to Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and RT-PCR. Samples of NHP gene-expressing tissue, may also be evaluated immunocytochemically using antibodies specific for the NHP transgene product.

[0054] The present invention provides for "knockin" animals. Knockin animals are those in which a gene that the animal does not naturally have in its genome, is inserted. For example, when a human gene is used to replace its murine ortholog in the mouse. Such knockin animals are useful for the in vivo study, testing and validation of, intra alia, numan drug targets as well as for compounds that are directed at the same.

5.2 NHPS and NHP Polypeptides

[0055] NHPs, polypeptides, peptide fragments, mutated, truncated, or deleted forms of the NHPs, and/or NHP fusion proteins can be prepared for a variety of uses. These uses include but are not limited to the generation of antibodies, as reagents in diagnostic assays, the identification of other cellular gene products related to a NHP, as reagents in assays for screening for compounds that can be used as pharmaceutical reagents useful in the therapeutic treatment of mental, biological, or medical disorders and diseases. Given the similarity information and expression data, the described NHPs can be targeted (by drugs, oligos, antibodies, etc,) in order to treat disease, or to therapeutically augment the efficacy of, for example, chemotherapeutic agents used in the treatment of cancer.

[0056] The Sequence Listing discloses the amino acid sequences encoded by the described NHP genes. The NHPs typically display initiator methionines in DNA sequence contexts consistent with a translation initiation site, and a signal like sequences near their N-terminal ends as typical of many other membrane proteins.

[0057] The NHP amino acid sequences of the invention include the amino acid sequence presented in the Sequence Listing as well as analogues and derivatives thereof. Further, corresponding NHP homologues from other species are encompassed by the invention. In fact, any NHP protein encoded by the NHP nucleotide sequences described above are within the scope of the invention, as are any novel polynucleotide sequences encoding all or any novel portion of an amino acid sequence presented in the Sequence Listing. The degenerate nature of the genetic code is well-known, and, accordingly, each amino acid presented in the Sequence Listing, is generically representative of the well-known nucleic acid "triplet" codon, or in many cases codons, that can encode the amino acid. As such, as contemplated herein, the amino acid sequences presented in the Sequence Listing, when taken together with the genetic code (see, for example, Table 4-1 at page 109 of "Molecular Cell Biology", 1986, J. Darnell et al. eds., Scientific American Books, New York, N.Y., herein incorporated by reference) are generically representative of all the various permutations and combinations of nucleic acid sequences that can encode such amino acid sequences.

[0058] The invention also encompasses proteins that are functionally equivalent to the NHPs encoded by the presently described nucleotide sequences as judged by any of a number of criteria, including, but not limited to, the ability to bind and cleave a substrate of a NHP, or the ability to effect an identical or complementary downstream pathway, or a change in cellular metabolism (e.g., proteolytic activity, ion flux, tyrosine phosphorylation, etc.). Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.

[0059] A variety of host-expression vector systems can be used to express the NHP nucleotide sequences of the invention. Where, as in the present instance, the NHP peptide or polypeptide is thought to be membrane protein, the hydrophobic regions of the protein can be excised and the resulting soluble peptide or polypeptide can be recovered from the culture media. Such expression systems also encompass engineered host cells that express a NHP, or functional equivalent, in situ. Purification or enrichment of a NHP from such expression systems can be accomplished using appropriate detergents and lipid micelles and methods well-known to those skilled in the art. However, such engineered host cells themselves may be used in situations where it is important not only to retain the structural and functional characteristics of the NHP, but to assess biological activity, e.g., in certain drug screening assays.

[0060] The expression systems that may be used for purposes of the invention 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 NHP nucleotide sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing NHP nucleotide sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing NHP nucleotide 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 NHP nucleotide sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing NHP nucleotide sequences and 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).

[0061] In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the NHP product being expressed. For example, when a large quantity of such a protein is to be produced for the generation of pharmaceutical compositions of or containing NHP, or for raising antibodies to a NHP, vectors that direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequence may be ligated individually into the vector in frame with the lacZ coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like. PGEX vectors (Pharmacia or American Type Culture Collection) 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 to 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 expression product can be released from the GST moiety.

[0062] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign polynucleotide sequences. The virus grows in Spodoptera frugiperda cells. A NHP coding sequence can 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). Successful insertion of NHP coding sequence will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted sequence is expressed (e.g., see Smith et al., 1983, J. Virol. 46: 584; Smith, U.S. Pat. No. 4,215,051).

[0063] In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the NHP nucleotide sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric sequence may 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 a NHP product in infected hosts (e.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:3655-3659). Specific initiation signals may also be required for efficient translation of inserted NHP nucleotide sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where an entire NHP gene or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where only a portion of a NHP coding sequence is inserted, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided. 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 of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bitter et al., 1987, Methods in Enzymol. 153:516-544).

[0064] In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the expression product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may 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 expression 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 which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the expression product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and in particular, human cell lines.

[0065] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the NHP sequences described above can be engineered. Rather than using expression vectors which 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 may 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 which express the NHP product. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of the NHP product.

[0066] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska and Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adenine phosphoribosyltransferase (Lowy et al., 1980, Cell 22:817) genes, which can be employed in tk.sup.-, hgprt.sup.- or aprt.sup.- cells, respectively. Also, antimetabolite 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. USA 77:3567; O'Hare et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan and Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Colberre-Garapin et al., 1981, J. Mol. Biol. 150:1); and hygro, which confers resistance to hygromycin (Santerre et al., 1984, Gene 30:147).

[0067] Alternatively, any fusion protein can be readily purified by utilizing an antibody specific for the fusion protein being expressed. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-8976). In this system, the sequence of interest is subcloned into a vaccinia recombination plasmid such that the sequence's open reading frame is translationally fused to an amino-terminal tag consisting of six histidine residues. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni.sup.2+-nitriloacetic acid-agarose columns and histidine-tagged proteins are selectively eluted with imidazole-containing buffers.

[0068] Also encompassed by the present invention are fusion proteins that direct the NHP to a target organ and/or facilitate transport across the membrane into the cytosol. Conjugation of NHPs to antibody molecules or their Fab fragments could be used to target cells bearing a particular epitope. Attaching the appropriate signal sequence to the NHP would also transport the NHP to the desired location within the cell. Alternatively targeting of NHP or its nucleic acid sequence might be achieved using liposome or lipid complex based delivery systems. Such technologies are described in "Liposomes: A Practical Approach", New, R.R.C., ed., Oxford University Press, New York and in U.S. Pat. Nos. 4,594,595, 5,459,127, 5,948,767 and 6,110,490 and their respective disclosures which are herein incorporated by reference in their entirety. Additionally embodied are novel protein constructs engineered in such a way that they facilitate transport of the NHP to the target site or desired organ, where they cross the cell membrane and/or the nucleus where the NHP can exert its functional activity. This goal may be achieved by coupling of the NHP to a cytokine or other ligand that provides targeting specificity, and/or to a protein transducing domain (see generally U.S. applications Ser. Nos. 60/111,701 and 60/056,713, both of which are herein incorporated by reference, for examples of such transducing sequences) to facilitate passage across cellular membranes and can optionally be engineered to include nuclear localization.

5.3 Antibodies to NHP Products

[0069] Antibodies that specifically recognize one or more epitopes of a NHP, or epitopes of conserved variants of a NHP, or peptide fragments of a NHP are also encompassed by the invention. Such antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab').sub.2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.

[0070] The antibodies of the invention may be used, for example, in the detection of NHP in a biological sample and may, therefore, be utilized as part of a diagnostic or prognostic technique whereby patients may be tested for abnormal amounts of NHP. Such antibodies may also be utilized in conjunction with, for example, compound screening schemes for the evaluation of the effect of test compounds on expression and/or activity of a NHP expression product. Additionally, such antibodies can be used in conjunction gene therapy to, for example, evaluate the normal and/or engineered NHP-expressing cells prior to their introduction into the patient. Such antibodies may additionally be used as a method for the inhibition of abnormal NHP activity. Thus, such antibodies may, therefore, be utilized as part of treatment methods.

[0071] For the production of antibodies, various host animals may be immunized by injection with a NHP, an NHP peptide (e.g., one corresponding to a functional domain of an NHP), truncated NHP polypeptides (NHP in which one or more domains have been deleted), functional equivalents of the NHP or mutated variant of the NHP. Such host animals may include but are not limited to pigs, rabbits, mice, goats, and rats, to name but a few. Various adjuvants may be used to increase the immunological response, depending on the host species, including, but not limited to, Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, chitosan, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum. Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diphtheria toxoid, ovalbumin, cholera toxin or fragments thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.

[0072] Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Pat. No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc. Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production.

[0073] In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984, Proc. Natl. Acad. Sci. USA, 81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda et al., 1985, Nature, 314:452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin Such technologies are described in U.S. Pat. Nos. 6,075,181 and 5,877,397 and their respective disclosures which are herein incorporated by reference in their entirety. Also encompassed by the present invention is the use of fully humanized monoclonal antibodies as described in U.S. Pat. No. 6,150,584 and respective disclosures which are herein incorporated by reference in their entirety.

[0074] Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 341:544-546) can be adapted to produce single chain antibodies against NHP expression products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.

[0075] Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include, but are not limited to: the F(ab').sub.2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab').sub.2 fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.

[0076] Antibodies to a NHP can, in turn, be utilized to generate anti-idiotype antibodies that "mimic" a given NHP, using techniques well-known to those skilled in the art. (See, e.g., Greenspan & Bona, 1993, FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). For example antibodies which bind to a NHP domain and competitively inhibit the binding of NHP to its cognate receptor can be used to generate anti-idiotypes that "mimic" the NHP and, therefore, bind and activate or neutralize a receptor. Such anti-idiotypic antibodies or Fab fragments of such anti-idiotypes can be used in therapeutic regimens involving a NHP-mediated pathway.

[0077] Additionally given the high degree of relatedness of mammalian NHPs, the presently described knock-out mice (having never seen NHP, and thus never been tolerized to NHP) have a unique utility, as they can be advantageously applied to the generation of antibodies against the disclosed mammalian NHP (i.e., NHP will be immunogenic in NHP knock-out animals).

[0078] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All cited publications, patents, and patent applications are herein incorporated by reference in their entirety.

Sequence CWU 1

1

8 1 13770 DNA homo sapiens 1 atggatataa ttatgggaca ctgtgtgggc acacggcctc ctgcttgttg cctcatcctc 60 ctgcttttca agcttttggc cactgtctcc caggggctgc cagggactgg acccctgggc 120 ttccacttca cacattccat ttataatgct accgtgtatg agaactcagc agcaaggacc 180 tacgtcaaca gccagagtag aatgggcatc accttaatag atctatcctg ggatatcaaa 240 tacagaatag tgtccggaga cgaggaaggc tttttcaaag cagaggaagt catcattgca 300 gatttctgtt ttctcagaat aagaactaaa ggtggcaatt ctgccatatt aaatagggaa 360 atccaggata attatttatt gatagtaaaa ggttctgtca gaggagagga tttggaagca 420 tggaccaaag tgaatataca ggttttagat atgaatgatc tgagaccttt gttttcaccc 480 acaacatact ctgttaccat agcagaaagc acacctctaa ggactagtgt tgcccaggtg 540 actgcaacag acgcagatat tggttccaat ggagaattct actactactt taaaaataaa 600 gttgatctct tttcagttca ccccacgagt ggtgtcatct ccttaagtgg tcgattaaat 660 tatgatgaaa agaataggta tgatctggaa attttggctg tggaccgggg aatgaaactg 720 tatgggaaca atggagtgag cagtactgca aagctttatg ttcacattga gcgcataaat 780 gaacatgccc caacaatcca tgtagtcact catgttcctt tctcgttgga aaaagagcca 840 acatatgcag tggtgacagt tgatgactta gatgatggag cgaatggaga gatcgaatct 900 gtttccattg tggctgggga tcctttagat cagttcttcc tggctaagga aggaaagtgg 960 ttgaatgagt acaagattaa ggagaggaag cagattgact gggagagctt tccctatggc 1020 tacaatctca ctcttcaagc aaaagacaag ggatctcctc aaaaatgttc agcattaaag 1080 gcagtctaca ttggcaaccc cacaagagac actgtcccca ttagatttga aaaagaagtg 1140 tacgatgtga gcataagtga attttcccct cctggtgtcg tggttgctat agtaaaatta 1200 agtcctgaac cgatagatgt ggaatacaaa ttatctcctg gtgaggatgc agtgtacttt 1260 aaaattaatc ctcggtcggg tctgattgtt acagcacggc cactgaatac tgttaagaag 1320 gaggtttata aactggaggt gacaaacaag gaaggagatt taaaagcaca ggtcaccatc 1380 agcatagaag atgcaaatga ccacacccca gaatttcagc aaccactgta tgatgcttat 1440 gtgaatgaaa gtgtcccagt gggaaccagc gttctaacag tttcagcttc tgataaggat 1500 aaaggagaaa atgggtacat cacctatagt atcgctagcc tgaatttgtt accatttgtc 1560 attaatcagt ttacaggtgt tattagcaca actgaagaac tggattttga atcctcccca 1620 gaaatttaca gattcattgt tagagcctct gactggggtt caccataccg ccatgaaagt 1680 gaggtcaatg tgactattcg aataggaaat gtcaacgaca acagccctct ctttgaaaaa 1740 gtggcttgcc agggagttat ttcatatgac tttccagttg gtggtcacat cacagcagtc 1800 tcagcgatcg atatcgatga acttgaactt gtaaagtaca aaatcatttc tggaaatgaa 1860 cttggcttct tttatttaaa cccagattct ggtgttttac agcttaaaaa atcactgaca 1920 aattctggca ttaaaaatgg caattttgcc ctcagaatta cagcaactga tggagagaat 1980 cttgcagacc ccatgtctat taacatttca gtcctacatg ggaaagtgtc ttcaaagagc 2040 ttcagttgca gagaaactcg tgtggctcaa aagctggcag agaaactact cattaaggca 2100 aaagcaaatg ggaaactgaa tctggaagat ggatttcttg acttttattc aattaataga 2160 cagggaccat attttgacaa gtcttttcct tctgatgtgg ctgtaaagga ggatctgcca 2220 gttggtgcta acattctgaa gattaaagcc tatgatgccg actctggctt caatggaaaa 2280 gtgctattta caatatcaga tggaaatacg gatagttgct ttaatattga tatggagact 2340 gggcagctta aagtccttat gcccatggat cgagaacaca cagacctcta tctccttaat 2400 atcaccatct atgacttagg taatccacag aaatcgtcat ggagactgct gaccatcaat 2460 gtggaggatg ctaatgacaa tagcccagtt tttattcaag acagttactc agttaacatt 2520 cttgaaagtt caggcattgg tactgaaatc attcaagtgg aagccagaga caaagactta 2580 ggttctaatg gtgaagtgac ttactcagtc ttgacagata cacagcagtt tgccatcaat 2640 agctcaactg gaatcgttta tgtagccgac cagttggacc gggaatccaa agccaattat 2700 tctttgaaaa tagaagccag ggacaaggca gagagtggtc agcagctgtt ttcagttgtc 2760 actcttaaag tttttttaga tgatgtcaat gactgctccc cagctttcat tcccagtagc 2820 tatagtgtga aggttcttga agatctccct gttggcactg tcattgcttg gcttgagacc 2880 catgatccag atcttggact ggggggtcaa gtgcgctatt ctttggtcaa tgactataat 2940 gggagatttg aaatagataa agcaagtggt gccatccgct tgagcaaaga gcttgattat 3000 gagaaacagc agttctataa ccttactgtg cgggccaaag acaaagggcg gcctgtctct 3060 ctgtcatctg tttcctttgt tgaggtggaa gtggtggatg tcaatgaaaa cctccacact 3120 ccctatttcc cagactttgc tgttgttgga tctgtaaagg aaaactcacg cattggaaca 3180 agcgtgctgc aggtgactgc tcgagatgaa gactccggaa gggatggaga gatccagtac 3240 tccatcaggg atggcagtgg tcttggaagg ttcagtatag acgacgagag tggggtcatc 3300 actgccgcag acattcttga tcgggagaca atggggtcat actggctaac agtgtatgcc 3360 acagacaggg gcgttgttcc actctactcc accattgagg tctacattga agttgaagat 3420 gtgaatgaca atgccccgct gacctcagaa cctatatatt atcctgttgt catggaaaac 3480 tctccaaagg acgtatctgt cattcagatc caggctgaag atcctgactc cagttccaat 3540 gaaaaactga catacaggat tacaagtgga aatcctcaga atttttttgc catcaatatc 3600 aaaacaggtc tgattacaac aacttcaagg aaattggatc gagaacagca ggcagaacat 3660 tttctggagg tgactgtgac agatggtggt ccctctccaa aacagtcaac catttgggtg 3720 gtggttcagg ttctagatga aaatgacaac aagccccagt tcccagagaa ggtctaccag 3780 atcaagctgc cagaacgtga ccgaaagaag agaggagaac cgatttacag ggcttttgca 3840 tttgatagag atgagggccc caacgcagaa atctcctaca gtattgtgga tgggaatgat 3900 gacggaaagt tctttattga ccctaaaact gggatggttt cttctagaaa gcagtttaca 3960 gcaggcagtt atgacatcct aacgataaag gcagtggaca atgggcgccc acagaaatcc 4020 tccacggccc gcctccacat tgaatggatt aagaaaccac ccccttcacc tataccattg 4080 accttcgatg agccgtttta taacttcaca gtcatggaaa gtgatagagt gactgaaatt 4140 gtaggggtgg tgtctgtgca gccagctaac acccctctgt ggtttgacat agttgggggg 4200 aattttgaca gcgcttttga tgcagagaag ggtgttggga caattgtcat cgcaaaacct 4260 ttggatgcag agcagaggtc catctataat atgagtgtgg aagtcaccga tgggacaaat 4320 gttgctgtta ctcaggtatt tatcaaagtg ctggataata atgataatgg cccagaattc 4380 tctcagccga attacgatgt gacaatttcc gaggatgtgc ttccagacac ggagatcctg 4440 cagattgaag ccacagatag agatgagaag cacaagctga gctacactgt tcatagcagc 4500 atcgactcca tcagcatgag aaaattccgg attgacccta gcactggcgt gctctatact 4560 gccgagaggc tggaccatga ggcccaggac aagcacattc tcaacataat ggtcagagat 4620 caggagtttc cttatcgaag aaacttggcc cgagtcattg tgaatgtgga ggatgctaat 4680 gatcacagtc cttattttac caacccactg tatgaagcgt ctgtgtttga atctgctgct 4740 ctgggatcag ctgttctgca agtgacggct ctggacaaag acaaaggaga aaatgcagaa 4800 ctcatatata ccatagaagc agggaacact gggaacatgt ttaagatcga accggtccta 4860 ggcatcatca ccatttgcaa agaaccagac atgacgacga tgggtcagtt tgtcctatcc 4920 atcaaagtca cagatcaggg atccccgcca atgtctgcta ctgcaattgt gcgcatttcc 4980 gtcaccatgt ctgacaattc tcaccccaag ttcattcaca aagactacca agcagaagta 5040 aatgaaaatg ttgacattgg aacatcagtc attctaatct ctgccatcag tcaatctacc 5100 ctcatttatg aagtcaaaga tggagacatt aatgggatct ttaccataaa tccatattct 5160 ggagtcatca ccactcagaa ggccctggat tatgagcgca catcctctta tcaactcatc 5220 attcaggcca ccaatatggc aggaatggct tccaatgcta cagtcaatat tcagattgtt 5280 gatgaaaatg ataatgcccc agtttttctc ttttctcaat actcaggcag cctaagtgag 5340 gctgccccaa ttaatagcat tgtcaggagc ttggataaca gcccactggt gattcgagcc 5400 acagatgctg acagcaaccg gaatgctctg cttgtgtatc agattgtgga gtcaacagca 5460 aaaaagtttt tcacggtgga ctccagtaca ggtgcaatca gaacaattgc caacctggac 5520 catgaaacca ttgcccattt ccattttcat gtgcatgtga gagacagtgg tagcccccaa 5580 ctgactgcag agagtcccgt tgaagtcaac attgaggtga cagatgtgaa tgataaccca 5640 cctgttttta ctcaggctgt gtttgagact atcttacttc tacctaccta tgttggagtg 5700 gaggttctga aagttagtgc cacagatcct gactctgagg taccccctga actgacatac 5760 agcctaatgg aaggcagttt ggatcatttt ttaattgact caaacagtgg agtacttacc 5820 ataaaaaaca acaacctctc caaggatcac tacatgctga tagttaaggt gtctgatgga 5880 aagttctaca gtacctccat ggtcaccatc atggttaaag aagccatgga cagcggcctc 5940 cactttacac aaagcttcta ttccacctca atctcagaga acaacactaa cataaccaaa 6000 gttgctattg tcaatgcagt tggaaatcgc cttaatgagc ccttaaaata cagcatctta 6060 aacccaggaa ataagttcaa gataaaatct acctcagggg tcattcagac gactggagtc 6120 ccctttgacc gtgaagaaca agagttatat gagctggtgg tagaagccag ccgtgagctg 6180 gaccatctgc gtgtggccag agtggtggtc agggttaaca ttgaagacat aaatgacaat 6240 tctccagtct ttgtgggcct cccatactat gctgctgttc aagtggatgc ggaacccggg 6300 actctgattt atcaggtgac agccattgac aaagataaag gtccaaatgg agaagtgacc 6360 tatgtcctgc aggatgacta tggccacttt gaaattaacc ctaattcagg gaatgttatt 6420 ttaaaggaag cattcaactc tgacttgtcc aacattgagt atggagtcac catcctagcc 6480 aaggatggcg gaaaaccttc tttgtctaca tctgtggagc ttcccatcac tattgtcaac 6540 aaagcaatgc ctgtgtttga taagcccttt tatacagcat ctgtcaatga agacatcaga 6600 atgaacacac ccatcctaag catcaatgcc accagtccag aaggccaagg catcatatat 6660 atcattatcg atggggaccc ttttaaacag tttaacattg actttgacac tggggtcctg 6720 aaagttgtta gccctttgga ttatgaagtt acatctgctt acaagctgac aataagagcc 6780 agcgacgccc ttactggtgc tagggctgaa gtcactgttg acttgctagt taatgatgta 6840 aatgacaacc cccctatttt cgatcagcct acatacaata caacactatc agaagcatct 6900 cttattggga cacctgtttt acaagttgtc tctattgatg cagactcaga aaacaataaa 6960 atggtacatt atcagattgt ccaggatacc tacaatagca cagattattt tcacatagat 7020 agctcaagtg gcttaatcct gacagcacga atgctggacc atgagttagt acaacactgc 7080 actttgaaag tcagatcaat agatagtggc ttcccatcac tgagcagtga ggttctcgtt 7140 catatctaca tctctgatgt aaatgacaac cctccagttt ttaatcagct catttatgag 7200 tcatatgtga gtgaattagc cccccggggc cattttgtaa cctgtgtaca agcctctgat 7260 gcagacagct ctgattttga ccggttggaa tatagcattt tatctgggaa tgaccggacg 7320 agctttctga tggacagcaa gagtggagtt atcacattgt ccaaccatcg gaagcagcgg 7380 atggagcctc tgtacagtct caatgtgtct gtctctgatg ggttgttcac cagcactgca 7440 caggtgcata ttagggtact tggggctaac ttgtacagcc ctgccttttc acaaagcaca 7500 tacgtagctg aggtgagaga gaacgtggct gcaggaacaa aggtaattca tgttcgagcc 7560 acagatggtg atccagggac ttatgggcag atcagctatg ccatcatcaa tgactttgcc 7620 aaggatcgat tcctcataga cagcaatggg caggtcatca ccacagaaag gctagaccgg 7680 gaaaaccctc tagaagggga tgttagtatt tttgtgaggg cccttgatgg tggagggaga 7740 acaactttct gcactgtgag agtgattgtt gtggatgaaa atgacaatgc tccccagttc 7800 atgacagtgg aatatagagc cagtgtcagg gcagatgttg gaaggggcca cttggtcact 7860 caagttcaag ccatagatcc cgatgatgga gcaaattcaa ggattactta ttccctctat 7920 agcgaggcct ctgtttcagt ggccgacctc ctggaaatcg atcctgacaa tggctggatg 7980 gtcacaaagg gtaattttaa ccagctgaaa aatacagtgc tttcgttctt tgtcaaagca 8040 gtagatgggg gcatcccagt aaagcactcc ctcattcctg tctatatcca cgtcttgccc 8100 cctgaaacgt tcttgccatc attcacccag tctcagtatt cctttaccat tgcagaagat 8160 acagccattg ggagtacagt ggacaccctg aggattttgc ccagtcagaa tgtctggttc 8220 agcacagtta atggggaacg gccagaaaat aacaaagggg gcgtattcgt catagaacag 8280 gaaacaggca ctattaagct tgacaaacgc cttgaccgtg aaaccagccc agctttccac 8340 tttaaagtag cagccactat acccctggac aaagtagaca ttgtgtttac tgtggatgta 8400 gatatcaagg tattggattt gaatgacaac aagccagtct ttgaaacttc aagctatgac 8460 accattataa tggaagggat gcctgttggc accaaactca cacaagtgag agctattgat 8520 atggactggg gagccaatgg acaagtcact tactccctcc actcggattc ccagcccgaa 8580 aaggtaatgg aagcattcaa tattgacagc aacacgggct ggatcagtac cttgaaggac 8640 ctagatcacg agacagaccc cacattcacc ttctctgtgg tggcctctga ccttggagag 8700 gcattctctc tttcctccac ggccttggtc tctgtcagag tgacagatat aaatgacaat 8760 gcaccagtct tcgcgcagga agtgtaccga gggaatgtga aggagagcga cccaccgggc 8820 gaggtggtag ccgtcctcag cacctgggac agagacacat ccgacgttaa tcgccaagtg 8880 agctaccata ttacaggagg aaaccctcga ggaaggtttg ctctgggcct ggtgcaaagt 8940 gagtggaagg tctatgtgaa gaggcctcta gacagagaag aacaggacat ttactttctc 9000 aatatcactg ccactgatgg gctttttgtc acacaggcca tggtggaagt gagcgtcagt 9060 gatgtgaatg acaatagccc agtgtgtgat caggttgcat atacagcatt acttcctgaa 9120 gacattccat caaataaaat catcctgaaa gtcagtgcaa aggatgctga tattggatcc 9180 aatggatata tacgatactc actctatgga tctggaaaca gtgaattttt tctagatcca 9240 gaaagtggcg agttaaaaac cttggctctg ttggaccggg agaggatccc cgtgtacagc 9300 ctgatggcca aggccactga cgggggtggc aggttctgcc agtccaacat ccacctaatc 9360 ctggaggatg tgaatgataa cccccctgtg ttttcttctg accactacaa cacctgtgtc 9420 tatgagaaca cagccaccaa ggctctgttg accagagttc aagccgtgga ccccgacatt 9480 ggcatcaata ggaaggtcgt gtactccctg gcagactcag ctggtggggt cttctccatt 9540 gacagctcat ctggcatcat catcctggag cagccactgg accgtgagca gcagtcttcg 9600 tacaacatca gcgtgcgggc cactgaccag agtcctggac agtccctgtc ctctctcact 9660 actgtcacca tcaccgttct ggacattaat gacaaccccc ctgtgtttga gaggagggac 9720 tacctggtga cggtgcctga ggacacctcc cctggcaccc aagtccttgc tgtttttgcc 9780 accagcaaag atattggcac aaatgctgag atcacttatc tcatccggtc tgggaacgaa 9840 caagggaaat ttaagatcaa ccccaagaca gggggtattt ctgtctctga agtcctggac 9900 tatgaattat gcaaaaggtt ttacctggta gtggaagcca aagatggggg caccccagct 9960 ctcagcgctg tggccactgt caacatcaac ctcacagatg ttaatgacaa ccctcccaag 10020 ttcagccaag acgtctacag tgcggttatc agtgaagacg ccttggtggg agactctgtc 10080 attttgctaa tagcagaaga tgtagacagc cagcccaacg gacagattca tttttccatt 10140 gtgaatggag atcgggacaa tgaatttact gtagatcctg tcttgggact tgtgaaagtt 10200 aagaagaaat tggaccggga acgggtgtct ggatactctc tgcttgtcca ggccgtagac 10260 agtggcattc ctgcaatgtc atcaactgca actgtcaaca ttgatatttc tgatgtgaat 10320 gacaacagcc cggtgtttac acctgccaac tatactgctg tgattcagga aaataagcca 10380 gtgggcacca gcatcttgca gctggtggtg acagacagag actcctttca caatgggcct 10440 cccttttcat tctctatttt gtcgggaaat gaagaggagg agtttgtgtt ggaccctcat 10500 gggatcttgc ggtcggctgt ggtcttccag cacacagagt ctctggaata cgtgttgtgt 10560 gtccaggcaa aggattcagg caaaccccag caagtttctc acacttacat ccgcgtgcga 10620 gtcattgagg aaagcaccca caagcccaca gccattcccc tggaaatttt cattgtcacc 10680 atggaggatg actttcctgg tggggtcatt gggaagattc atgccacaga tcaagacatg 10740 tatgatgtgc tcacatttgc cctgaaatcg gagcagaaaa gcttatttaa agtgaacagt 10800 cacgatggga aaatcatcgc cctgggaggc ctggacagcg gcaagtatgt cctgaatgtg 10860 tctgtgagtg atggtcgctt ccaggtaccc attgatgtgg tcgtgcatgt ggagcagttg 10920 gtgcatgaga tgctgcagaa cactgtcacc atccgctttg aaaatgtgtc ccctgaggac 10980 ttcgtggggc tgcacatgca tgggttccgg cgcaccctgc ggaatgcagt cctcacccag 11040 aagcaggaca gcctgcgcat catcagcatc cagcccgtgg caggcaccaa ccaactggac 11100 atgctgtttg cggtggagat gcacagcagc gagttctaca agccagccta cctgatccag 11160 aagctgtcca atgctagaag acacctggag aatatcatgc gcatctcagc catcttggag 11220 aagaactgct cagggctgga ctgtcaggaa cagcattgtg agcaaggctt gtcactcgat 11280 tcccacgcgc tcatgaccta cagcacggct cgcatcagct ttgtgtgtcc gcgtttctac 11340 aggaacgtgc gttgcacctg caatggagga ctgtgtccgg ggtccaacga tccttgtgtg 11400 gagaagccgt gtccagggga catgcagtgt gtcggttatg aagccagcag gagaccgttc 11460 ctctgccagt gtccaccagg gaagctcgga gagtgctcag ggcacacttc tctcagcttt 11520 gctggaaaca gttacatcaa atatcggctt tctgaaaata gcaaagaaga ggatttcaaa 11580 ctagctctgc gtcttcgaac actgcaaagc aatgggatta taatgtacac cagagcaaat 11640 ccctgcataa ttctgaagat tgtggatggc aagctgtggt tccagctgga ctgcggcagc 11700 ggccctggaa tcttgggcat ctcgggccgt gctgtcaacg acgggagctg gcactcggtc 11760 ttcctggagc tcaaccgcaa tttcacgagc ctgtccctgg atgacagcta cgtggagcgg 11820 cgccgggcgc ccctctactt ccagacgctg agcactgaga gtagcatcta cttcggcgcc 11880 ctggtgcaag cggataacat ccgcagcctg actgacacgc gggtcacgca ggtgctcagc 11940 ggcttccagg gctgcctgga ctcggtgata ctgaataaca atgagctgcc gctgcagaac 12000 aagcgcagca gcttcgcgga ggtggtgggc ctgacggagc tgaagctggg ctgcgtgctc 12060 tatcccgacg cctgcaagcg cagcccgtgc cagcacgggg gcagctgcac tggcctgcca 12120 tcggggggct atcagtgtac ctgtctctca cagtttacgg ggagaaactg tgaatctgag 12180 attacagcct gcttcccaaa cccctgccgg aatggaggat cctgcgatcc aataggaaac 12240 actttcatct gcaattgtaa agctgggctc actggagtca cgtgtgagga ggacatcaat 12300 gagtgcgaac gagaggagtg tgagaacgga ggctcctgcg tgaacgtgtt cggctccttc 12360 ctctgcaact gcacgccggg ctacgtgggc cagtactgcg ggctgcgccc cgtggtggta 12420 cccaatatcc aggctggcca ctcctacgtg gggaaggagg agctcatcgg catcgccgtg 12480 gtcctcttcg tcatcttcat cctggtggtt ctcttcatag tcttccgcaa gaaggtcttc 12540 cgcaagaact actcccgcaa caacatcacg ctagtgcagg acccggccac cgccgccctg 12600 cttaacaaga gcaatggcat cccgttccgg aacctgcgcg gcagtgggga cggccgcaac 12660 gtctaccagg aggtggggcc cccgcaggtc cccgtgcgcc ccatggccta cacaccctgc 12720 ttccagagtg actccaggag caacctggat aagatcgtgg acgggctggg aggcgagcac 12780 caggaaatga ccacgtttca ccctgagtcg ccccgcatcc tgacagcccg gcggggcgtg 12840 gtcgtgtgca gtgtggcccc caacctcccc gccgtgtcac cctgccgctc cgactgcgac 12900 tccatccgga agaatggctg ggacgcggga actgagaaca aaggggttga tgacccggga 12960 gaagtgacct gctttgcagg tagtaataaa ggcagcaact ctgaagttca gtccctcagc 13020 tccttccagt cagattctgg tgacgacaat gcctccatag tgactgtcat tcagcttgtc 13080 aacaatgtag ttgacactat agagaatgaa gtgtctgtca tggaccaagg acagaactac 13140 aaccgagcct atcactggga cacctctgat tggatgccag gggcccgcct gtcggacata 13200 gaggaagtgc ccaactatga gaaccaggat ggagggtctg cacaccaggg gagcacacgg 13260 gagctggaga gcgattacta cctgggtggt tatgacattg acagtgaata cccaccccct 13320 catgaagagg agttcttgag tcaggaccag ctgcctcctc ctctcccgga ggacttccca 13380 gaccaatatg aggccctgcc accctcccag cctgtctccc tggccagcac actgagccca 13440 gactgcagga gaaggcccca gtttcatcct agccagtatc tccctcctca cccattcccc 13500 aacgaaacgg atttggtggg cccgcctgcc agctgtgaat ttagtacttt tgctgtgagc 13560 atgaaccagg gcacagagcc cacaggccca gcagacagcg tgtctctgtc cttgcacaat 13620 tccagaggca cctcatcctc ggatgtgtct gccaactgcg gctttgacga ttccgaagta 13680 gccatgagtg actacgagag cgtgggagag ctcagcctcg ccagccttca cattcccttt 13740 gtggagactc agcatcagac tcaagtgtag 13770 2 4589 PRT homo sapiens 2 Met Asp Ile Ile Met Gly His Cys Val Gly Thr Arg Pro Pro Ala Cys 1 5 10 15 Cys Leu Ile Leu Leu Leu Phe Lys Leu Leu Ala Thr Val Ser Gln Gly 20 25 30 Leu Pro Gly Thr Gly Pro Leu Gly Phe His Phe Thr His Ser Ile Tyr 35 40 45 Asn Ala Thr Val Tyr Glu Asn Ser Ala Ala Arg Thr Tyr Val Asn Ser 50 55 60 Gln Ser Arg Met Gly Ile Thr Leu Ile Asp Leu Ser Trp Asp Ile Lys 65 70 75 80 Tyr Arg Ile Val Ser Gly Asp Glu Glu Gly Phe Phe Lys Ala Glu Glu 85 90 95 Val Ile Ile Ala Asp Phe Cys Phe Leu Arg Ile Arg Thr Lys Gly Gly 100 105 110 Asn Ser Ala Ile Leu Asn Arg Glu Ile Gln Asp Asn Tyr Leu Leu Ile 115 120 125 Val Lys Gly Ser Val Arg Gly Glu Asp Leu Glu Ala Trp Thr Lys Val 130 135 140 Asn Ile Gln Val Leu Asp Met Asn Asp Leu Arg Pro Leu Phe Ser Pro 145 150 155 160 Thr Thr Tyr Ser Val Thr Ile Ala Glu Ser Thr Pro Leu Arg Thr Ser 165 170 175 Val Ala Gln Val Thr Ala Thr Asp Ala Asp Ile Gly Ser Asn Gly Glu 180 185 190 Phe Tyr Tyr Tyr Phe Lys Asn Lys Val Asp Leu

Phe Ser Val His Pro 195 200 205 Thr Ser Gly Val Ile Ser Leu Ser Gly Arg Leu Asn Tyr Asp Glu Lys 210 215 220 Asn Arg Tyr Asp Leu Glu Ile Leu Ala Val Asp Arg Gly Met Lys Leu 225 230 235 240 Tyr Gly Asn Asn Gly Val Ser Ser Thr Ala Lys Leu Tyr Val His Ile 245 250 255 Glu Arg Ile Asn Glu His Ala Pro Thr Ile His Val Val Thr His Val 260 265 270 Pro Phe Ser Leu Glu Lys Glu Pro Thr Tyr Ala Val Val Thr Val Asp 275 280 285 Asp Leu Asp Asp Gly Ala Asn Gly Glu Ile Glu Ser Val Ser Ile Val 290 295 300 Ala Gly Asp Pro Leu Asp Gln Phe Phe Leu Ala Lys Glu Gly Lys Trp 305 310 315 320 Leu Asn Glu Tyr Lys Ile Lys Glu Arg Lys Gln Ile Asp Trp Glu Ser 325 330 335 Phe Pro Tyr Gly Tyr Asn Leu Thr Leu Gln Ala Lys Asp Lys Gly Ser 340 345 350 Pro Gln Lys Cys Ser Ala Leu Lys Ala Val Tyr Ile Gly Asn Pro Thr 355 360 365 Arg Asp Thr Val Pro Ile Arg Phe Glu Lys Glu Val Tyr Asp Val Ser 370 375 380 Ile Ser Glu Phe Ser Pro Pro Gly Val Val Val Ala Ile Val Lys Leu 385 390 395 400 Ser Pro Glu Pro Ile Asp Val Glu Tyr Lys Leu Ser Pro Gly Glu Asp 405 410 415 Ala Val Tyr Phe Lys Ile Asn Pro Arg Ser Gly Leu Ile Val Thr Ala 420 425 430 Arg Pro Leu Asn Thr Val Lys Lys Glu Val Tyr Lys Leu Glu Val Thr 435 440 445 Asn Lys Glu Gly Asp Leu Lys Ala Gln Val Thr Ile Ser Ile Glu Asp 450 455 460 Ala Asn Asp His Thr Pro Glu Phe Gln Gln Pro Leu Tyr Asp Ala Tyr 465 470 475 480 Val Asn Glu Ser Val Pro Val Gly Thr Ser Val Leu Thr Val Ser Ala 485 490 495 Ser Asp Lys Asp Lys Gly Glu Asn Gly Tyr Ile Thr Tyr Ser Ile Ala 500 505 510 Ser Leu Asn Leu Leu Pro Phe Val Ile Asn Gln Phe Thr Gly Val Ile 515 520 525 Ser Thr Thr Glu Glu Leu Asp Phe Glu Ser Ser Pro Glu Ile Tyr Arg 530 535 540 Phe Ile Val Arg Ala Ser Asp Trp Gly Ser Pro Tyr Arg His Glu Ser 545 550 555 560 Glu Val Asn Val Thr Ile Arg Ile Gly Asn Val Asn Asp Asn Ser Pro 565 570 575 Leu Phe Glu Lys Val Ala Cys Gln Gly Val Ile Ser Tyr Asp Phe Pro 580 585 590 Val Gly Gly His Ile Thr Ala Val Ser Ala Ile Asp Ile Asp Glu Leu 595 600 605 Glu Leu Val Lys Tyr Lys Ile Ile Ser Gly Asn Glu Leu Gly Phe Phe 610 615 620 Tyr Leu Asn Pro Asp Ser Gly Val Leu Gln Leu Lys Lys Ser Leu Thr 625 630 635 640 Asn Ser Gly Ile Lys Asn Gly Asn Phe Ala Leu Arg Ile Thr Ala Thr 645 650 655 Asp Gly Glu Asn Leu Ala Asp Pro Met Ser Ile Asn Ile Ser Val Leu 660 665 670 His Gly Lys Val Ser Ser Lys Ser Phe Ser Cys Arg Glu Thr Arg Val 675 680 685 Ala Gln Lys Leu Ala Glu Lys Leu Leu Ile Lys Ala Lys Ala Asn Gly 690 695 700 Lys Leu Asn Leu Glu Asp Gly Phe Leu Asp Phe Tyr Ser Ile Asn Arg 705 710 715 720 Gln Gly Pro Tyr Phe Asp Lys Ser Phe Pro Ser Asp Val Ala Val Lys 725 730 735 Glu Asp Leu Pro Val Gly Ala Asn Ile Leu Lys Ile Lys Ala Tyr Asp 740 745 750 Ala Asp Ser Gly Phe Asn Gly Lys Val Leu Phe Thr Ile Ser Asp Gly 755 760 765 Asn Thr Asp Ser Cys Phe Asn Ile Asp Met Glu Thr Gly Gln Leu Lys 770 775 780 Val Leu Met Pro Met Asp Arg Glu His Thr Asp Leu Tyr Leu Leu Asn 785 790 795 800 Ile Thr Ile Tyr Asp Leu Gly Asn Pro Gln Lys Ser Ser Trp Arg Leu 805 810 815 Leu Thr Ile Asn Val Glu Asp Ala Asn Asp Asn Ser Pro Val Phe Ile 820 825 830 Gln Asp Ser Tyr Ser Val Asn Ile Leu Glu Ser Ser Gly Ile Gly Thr 835 840 845 Glu Ile Ile Gln Val Glu Ala Arg Asp Lys Asp Leu Gly Ser Asn Gly 850 855 860 Glu Val Thr Tyr Ser Val Leu Thr Asp Thr Gln Gln Phe Ala Ile Asn 865 870 875 880 Ser Ser Thr Gly Ile Val Tyr Val Ala Asp Gln Leu Asp Arg Glu Ser 885 890 895 Lys Ala Asn Tyr Ser Leu Lys Ile Glu Ala Arg Asp Lys Ala Glu Ser 900 905 910 Gly Gln Gln Leu Phe Ser Val Val Thr Leu Lys Val Phe Leu Asp Asp 915 920 925 Val Asn Asp Cys Ser Pro Ala Phe Ile Pro Ser Ser Tyr Ser Val Lys 930 935 940 Val Leu Glu Asp Leu Pro Val Gly Thr Val Ile Ala Trp Leu Glu Thr 945 950 955 960 His Asp Pro Asp Leu Gly Leu Gly Gly Gln Val Arg Tyr Ser Leu Val 965 970 975 Asn Asp Tyr Asn Gly Arg Phe Glu Ile Asp Lys Ala Ser Gly Ala Ile 980 985 990 Arg Leu Ser Lys Glu Leu Asp Tyr Glu Lys Gln Gln Phe Tyr Asn Leu 995 1000 1005 Thr Val Arg Ala Lys Asp Lys Gly Arg Pro Val Ser Leu Ser Ser Val 1010 1015 1020 Ser Phe Val Glu Val Glu Val Val Asp Val Asn Glu Asn Leu His Thr 1025 1030 1035 1040 Pro Tyr Phe Pro Asp Phe Ala Val Val Gly Ser Val Lys Glu Asn Ser 1045 1050 1055 Arg Ile Gly Thr Ser Val Leu Gln Val Thr Ala Arg Asp Glu Asp Ser 1060 1065 1070 Gly Arg Asp Gly Glu Ile Gln Tyr Ser Ile Arg Asp Gly Ser Gly Leu 1075 1080 1085 Gly Arg Phe Ser Ile Asp Asp Glu Ser Gly Val Ile Thr Ala Ala Asp 1090 1095 1100 Ile Leu Asp Arg Glu Thr Met Gly Ser Tyr Trp Leu Thr Val Tyr Ala 1105 1110 1115 1120 Thr Asp Arg Gly Val Val Pro Leu Tyr Ser Thr Ile Glu Val Tyr Ile 1125 1130 1135 Glu Val Glu Asp Val Asn Asp Asn Ala Pro Leu Thr Ser Glu Pro Ile 1140 1145 1150 Tyr Tyr Pro Val Val Met Glu Asn Ser Pro Lys Asp Val Ser Val Ile 1155 1160 1165 Gln Ile Gln Ala Glu Asp Pro Asp Ser Ser Ser Asn Glu Lys Leu Thr 1170 1175 1180 Tyr Arg Ile Thr Ser Gly Asn Pro Gln Asn Phe Phe Ala Ile Asn Ile 1185 1190 1195 1200 Lys Thr Gly Leu Ile Thr Thr Thr Ser Arg Lys Leu Asp Arg Glu Gln 1205 1210 1215 Gln Ala Glu His Phe Leu Glu Val Thr Val Thr Asp Gly Gly Pro Ser 1220 1225 1230 Pro Lys Gln Ser Thr Ile Trp Val Val Val Gln Val Leu Asp Glu Asn 1235 1240 1245 Asp Asn Lys Pro Gln Phe Pro Glu Lys Val Tyr Gln Ile Lys Leu Pro 1250 1255 1260 Glu Arg Asp Arg Lys Lys Arg Gly Glu Pro Ile Tyr Arg Ala Phe Ala 1265 1270 1275 1280 Phe Asp Arg Asp Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Val 1285 1290 1295 Asp Gly Asn Asp Asp Gly Lys Phe Phe Ile Asp Pro Lys Thr Gly Met 1300 1305 1310 Val Ser Ser Arg Lys Gln Phe Thr Ala Gly Ser Tyr Asp Ile Leu Thr 1315 1320 1325 Ile Lys Ala Val Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr Ala Arg 1330 1335 1340 Leu His Ile Glu Trp Ile Lys Lys Pro Pro Pro Ser Pro Ile Pro Leu 1345 1350 1355 1360 Thr Phe Asp Glu Pro Phe Tyr Asn Phe Thr Val Met Glu Ser Asp Arg 1365 1370 1375 Val Thr Glu Ile Val Gly Val Val Ser Val Gln Pro Ala Asn Thr Pro 1380 1385 1390 Leu Trp Phe Asp Ile Val Gly Gly Asn Phe Asp Ser Ala Phe Asp Ala 1395 1400 1405 Glu Lys Gly Val Gly Thr Ile Val Ile Ala Lys Pro Leu Asp Ala Glu 1410 1415 1420 Gln Arg Ser Ile Tyr Asn Met Ser Val Glu Val Thr Asp Gly Thr Asn 1425 1430 1435 1440 Val Ala Val Thr Gln Val Phe Ile Lys Val Leu Asp Asn Asn Asp Asn 1445 1450 1455 Gly Pro Glu Phe Ser Gln Pro Asn Tyr Asp Val Thr Ile Ser Glu Asp 1460 1465 1470 Val Leu Pro Asp Thr Glu Ile Leu Gln Ile Glu Ala Thr Asp Arg Asp 1475 1480 1485 Glu Lys His Lys Leu Ser Tyr Thr Val His Ser Ser Ile Asp Ser Ile 1490 1495 1500 Ser Met Arg Lys Phe Arg Ile Asp Pro Ser Thr Gly Val Leu Tyr Thr 1505 1510 1515 1520 Ala Glu Arg Leu Asp His Glu Ala Gln Asp Lys His Ile Leu Asn Ile 1525 1530 1535 Met Val Arg Asp Gln Glu Phe Pro Tyr Arg Arg Asn Leu Ala Arg Val 1540 1545 1550 Ile Val Asn Val Glu Asp Ala Asn Asp His Ser Pro Tyr Phe Thr Asn 1555 1560 1565 Pro Leu Tyr Glu Ala Ser Val Phe Glu Ser Ala Ala Leu Gly Ser Ala 1570 1575 1580 Val Leu Gln Val Thr Ala Leu Asp Lys Asp Lys Gly Glu Asn Ala Glu 1585 1590 1595 1600 Leu Ile Tyr Thr Ile Glu Ala Gly Asn Thr Gly Asn Met Phe Lys Ile 1605 1610 1615 Glu Pro Val Leu Gly Ile Ile Thr Ile Cys Lys Glu Pro Asp Met Thr 1620 1625 1630 Thr Met Gly Gln Phe Val Leu Ser Ile Lys Val Thr Asp Gln Gly Ser 1635 1640 1645 Pro Pro Met Ser Ala Thr Ala Ile Val Arg Ile Ser Val Thr Met Ser 1650 1655 1660 Asp Asn Ser His Pro Lys Phe Ile His Lys Asp Tyr Gln Ala Glu Val 1665 1670 1675 1680 Asn Glu Asn Val Asp Ile Gly Thr Ser Val Ile Leu Ile Ser Ala Ile 1685 1690 1695 Ser Gln Ser Thr Leu Ile Tyr Glu Val Lys Asp Gly Asp Ile Asn Gly 1700 1705 1710 Ile Phe Thr Ile Asn Pro Tyr Ser Gly Val Ile Thr Thr Gln Lys Ala 1715 1720 1725 Leu Asp Tyr Glu Arg Thr Ser Ser Tyr Gln Leu Ile Ile Gln Ala Thr 1730 1735 1740 Asn Met Ala Gly Met Ala Ser Asn Ala Thr Val Asn Ile Gln Ile Val 1745 1750 1755 1760 Asp Glu Asn Asp Asn Ala Pro Val Phe Leu Phe Ser Gln Tyr Ser Gly 1765 1770 1775 Ser Leu Ser Glu Ala Ala Pro Ile Asn Ser Ile Val Arg Ser Leu Asp 1780 1785 1790 Asn Ser Pro Leu Val Ile Arg Ala Thr Asp Ala Asp Ser Asn Arg Asn 1795 1800 1805 Ala Leu Leu Val Tyr Gln Ile Val Glu Ser Thr Ala Lys Lys Phe Phe 1810 1815 1820 Thr Val Asp Ser Ser Thr Gly Ala Ile Arg Thr Ile Ala Asn Leu Asp 1825 1830 1835 1840 His Glu Thr Ile Ala His Phe His Phe His Val His Val Arg Asp Ser 1845 1850 1855 Gly Ser Pro Gln Leu Thr Ala Glu Ser Pro Val Glu Val Asn Ile Glu 1860 1865 1870 Val Thr Asp Val Asn Asp Asn Pro Pro Val Phe Thr Gln Ala Val Phe 1875 1880 1885 Glu Thr Ile Leu Leu Leu Pro Thr Tyr Val Gly Val Glu Val Leu Lys 1890 1895 1900 Val Ser Ala Thr Asp Pro Asp Ser Glu Val Pro Pro Glu Leu Thr Tyr 1905 1910 1915 1920 Ser Leu Met Glu Gly Ser Leu Asp His Phe Leu Ile Asp Ser Asn Ser 1925 1930 1935 Gly Val Leu Thr Ile Lys Asn Asn Asn Leu Ser Lys Asp His Tyr Met 1940 1945 1950 Leu Ile Val Lys Val Ser Asp Gly Lys Phe Tyr Ser Thr Ser Met Val 1955 1960 1965 Thr Ile Met Val Lys Glu Ala Met Asp Ser Gly Leu His Phe Thr Gln 1970 1975 1980 Ser Phe Tyr Ser Thr Ser Ile Ser Glu Asn Asn Thr Asn Ile Thr Lys 1985 1990 1995 2000 Val Ala Ile Val Asn Ala Val Gly Asn Arg Leu Asn Glu Pro Leu Lys 2005 2010 2015 Tyr Ser Ile Leu Asn Pro Gly Asn Lys Phe Lys Ile Lys Ser Thr Ser 2020 2025 2030 Gly Val Ile Gln Thr Thr Gly Val Pro Phe Asp Arg Glu Glu Gln Glu 2035 2040 2045 Leu Tyr Glu Leu Val Val Glu Ala Ser Arg Glu Leu Asp His Leu Arg 2050 2055 2060 Val Ala Arg Val Val Val Arg Val Asn Ile Glu Asp Ile Asn Asp Asn 2065 2070 2075 2080 Ser Pro Val Phe Val Gly Leu Pro Tyr Tyr Ala Ala Val Gln Val Asp 2085 2090 2095 Ala Glu Pro Gly Thr Leu Ile Tyr Gln Val Thr Ala Ile Asp Lys Asp 2100 2105 2110 Lys Gly Pro Asn Gly Glu Val Thr Tyr Val Leu Gln Asp Asp Tyr Gly 2115 2120 2125 His Phe Glu Ile Asn Pro Asn Ser Gly Asn Val Ile Leu Lys Glu Ala 2130 2135 2140 Phe Asn Ser Asp Leu Ser Asn Ile Glu Tyr Gly Val Thr Ile Leu Ala 2145 2150 2155 2160 Lys Asp Gly Gly Lys Pro Ser Leu Ser Thr Ser Val Glu Leu Pro Ile 2165 2170 2175 Thr Ile Val Asn Lys Ala Met Pro Val Phe Asp Lys Pro Phe Tyr Thr 2180 2185 2190 Ala Ser Val Asn Glu Asp Ile Arg Met Asn Thr Pro Ile Leu Ser Ile 2195 2200 2205 Asn Ala Thr Ser Pro Glu Gly Gln Gly Ile Ile Tyr Ile Ile Ile Asp 2210 2215 2220 Gly Asp Pro Phe Lys Gln Phe Asn Ile Asp Phe Asp Thr Gly Val Leu 2225 2230 2235 2240 Lys Val Val Ser Pro Leu Asp Tyr Glu Val Thr Ser Ala Tyr Lys Leu 2245 2250 2255 Thr Ile Arg Ala Ser Asp Ala Leu Thr Gly Ala Arg Ala Glu Val Thr 2260 2265 2270 Val Asp Leu Leu Val Asn Asp Val Asn Asp Asn Pro Pro Ile Phe Asp 2275 2280 2285 Gln Pro Thr Tyr Asn Thr Thr Leu Ser Glu Ala Ser Leu Ile Gly Thr 2290 2295 2300 Pro Val Leu Gln Val Val Ser Ile Asp Ala Asp Ser Glu Asn Asn Lys 2305 2310 2315 2320 Met Val His Tyr Gln Ile Val Gln Asp Thr Tyr Asn Ser Thr Asp Tyr 2325 2330 2335 Phe His Ile Asp Ser Ser Ser Gly Leu Ile Leu Thr Ala Arg Met Leu 2340 2345 2350 Asp His Glu Leu Val Gln His Cys Thr Leu Lys Val Arg Ser Ile Asp 2355 2360 2365 Ser Gly Phe Pro Ser Leu Ser Ser Glu Val Leu Val His Ile Tyr Ile 2370 2375 2380 Ser Asp Val Asn Asp Asn Pro Pro Val Phe Asn Gln Leu Ile Tyr Glu 2385 2390 2395 2400 Ser Tyr Val Ser Glu Leu Ala Pro Arg Gly His Phe Val Thr Cys Val 2405 2410 2415 Gln Ala Ser Asp Ala Asp Ser Ser Asp Phe Asp Arg Leu Glu Tyr Ser 2420 2425 2430 Ile Leu Ser Gly Asn Asp Arg Thr Ser Phe Leu Met Asp Ser Lys Ser 2435 2440 2445 Gly Val Ile Thr Leu Ser Asn His Arg Lys Gln Arg Met Glu Pro Leu 2450 2455 2460 Tyr Ser Leu Asn Val Ser Val Ser Asp Gly Leu Phe Thr Ser Thr Ala 2465 2470 2475 2480 Gln Val His Ile Arg Val Leu Gly Ala Asn Leu Tyr Ser Pro Ala Phe 2485 2490 2495 Ser Gln Ser Thr Tyr Val Ala Glu Val Arg Glu Asn Val Ala Ala Gly 2500 2505 2510 Thr Lys Val Ile His Val Arg Ala Thr Asp Gly Asp Pro Gly Thr Tyr 2515 2520 2525 Gly Gln Ile Ser Tyr Ala Ile Ile Asn Asp Phe Ala Lys Asp Arg Phe 2530 2535 2540 Leu Ile Asp Ser Asn Gly Gln Val Ile Thr Thr Glu Arg Leu Asp Arg 2545 2550 2555 2560 Glu Asn Pro Leu Glu Gly Asp Val Ser Ile Phe Val Arg Ala Leu Asp 2565 2570 2575 Gly Gly Gly Arg Thr Thr Phe Cys Thr Val Arg Val Ile Val Val Asp 2580 2585 2590 Glu Asn Asp Asn Ala Pro Gln Phe Met Thr Val Glu Tyr Arg Ala Ser 2595 2600 2605 Val Arg Ala Asp Val Gly Arg Gly His Leu Val Thr Gln Val Gln Ala 2610 2615

2620 Ile Asp Pro Asp Asp Gly Ala Asn Ser Arg Ile Thr Tyr Ser Leu Tyr 2625 2630 2635 2640 Ser Glu Ala Ser Val Ser Val Ala Asp Leu Leu Glu Ile Asp Pro Asp 2645 2650 2655 Asn Gly Trp Met Val Thr Lys Gly Asn Phe Asn Gln Leu Lys Asn Thr 2660 2665 2670 Val Leu Ser Phe Phe Val Lys Ala Val Asp Gly Gly Ile Pro Val Lys 2675 2680 2685 His Ser Leu Ile Pro Val Tyr Ile His Val Leu Pro Pro Glu Thr Phe 2690 2695 2700 Leu Pro Ser Phe Thr Gln Ser Gln Tyr Ser Phe Thr Ile Ala Glu Asp 2705 2710 2715 2720 Thr Ala Ile Gly Ser Thr Val Asp Thr Leu Arg Ile Leu Pro Ser Gln 2725 2730 2735 Asn Val Trp Phe Ser Thr Val Asn Gly Glu Arg Pro Glu Asn Asn Lys 2740 2745 2750 Gly Gly Val Phe Val Ile Glu Gln Glu Thr Gly Thr Ile Lys Leu Asp 2755 2760 2765 Lys Arg Leu Asp Arg Glu Thr Ser Pro Ala Phe His Phe Lys Val Ala 2770 2775 2780 Ala Thr Ile Pro Leu Asp Lys Val Asp Ile Val Phe Thr Val Asp Val 2785 2790 2795 2800 Asp Ile Lys Val Leu Asp Leu Asn Asp Asn Lys Pro Val Phe Glu Thr 2805 2810 2815 Ser Ser Tyr Asp Thr Ile Ile Met Glu Gly Met Pro Val Gly Thr Lys 2820 2825 2830 Leu Thr Gln Val Arg Ala Ile Asp Met Asp Trp Gly Ala Asn Gly Gln 2835 2840 2845 Val Thr Tyr Ser Leu His Ser Asp Ser Gln Pro Glu Lys Val Met Glu 2850 2855 2860 Ala Phe Asn Ile Asp Ser Asn Thr Gly Trp Ile Ser Thr Leu Lys Asp 2865 2870 2875 2880 Leu Asp His Glu Thr Asp Pro Thr Phe Thr Phe Ser Val Val Ala Ser 2885 2890 2895 Asp Leu Gly Glu Ala Phe Ser Leu Ser Ser Thr Ala Leu Val Ser Val 2900 2905 2910 Arg Val Thr Asp Ile Asn Asp Asn Ala Pro Val Phe Ala Gln Glu Val 2915 2920 2925 Tyr Arg Gly Asn Val Lys Glu Ser Asp Pro Pro Gly Glu Val Val Ala 2930 2935 2940 Val Leu Ser Thr Trp Asp Arg Asp Thr Ser Asp Val Asn Arg Gln Val 2945 2950 2955 2960 Ser Tyr His Ile Thr Gly Gly Asn Pro Arg Gly Arg Phe Ala Leu Gly 2965 2970 2975 Leu Val Gln Ser Glu Trp Lys Val Tyr Val Lys Arg Pro Leu Asp Arg 2980 2985 2990 Glu Glu Gln Asp Ile Tyr Phe Leu Asn Ile Thr Ala Thr Asp Gly Leu 2995 3000 3005 Phe Val Thr Gln Ala Met Val Glu Val Ser Val Ser Asp Val Asn Asp 3010 3015 3020 Asn Ser Pro Val Cys Asp Gln Val Ala Tyr Thr Ala Leu Leu Pro Glu 3025 3030 3035 3040 Asp Ile Pro Ser Asn Lys Ile Ile Leu Lys Val Ser Ala Lys Asp Ala 3045 3050 3055 Asp Ile Gly Ser Asn Gly Tyr Ile Arg Tyr Ser Leu Tyr Gly Ser Gly 3060 3065 3070 Asn Ser Glu Phe Phe Leu Asp Pro Glu Ser Gly Glu Leu Lys Thr Leu 3075 3080 3085 Ala Leu Leu Asp Arg Glu Arg Ile Pro Val Tyr Ser Leu Met Ala Lys 3090 3095 3100 Ala Thr Asp Gly Gly Gly Arg Phe Cys Gln Ser Asn Ile His Leu Ile 3105 3110 3115 3120 Leu Glu Asp Val Asn Asp Asn Pro Pro Val Phe Ser Ser Asp His Tyr 3125 3130 3135 Asn Thr Cys Val Tyr Glu Asn Thr Ala Thr Lys Ala Leu Leu Thr Arg 3140 3145 3150 Val Gln Ala Val Asp Pro Asp Ile Gly Ile Asn Arg Lys Val Val Tyr 3155 3160 3165 Ser Leu Ala Asp Ser Ala Gly Gly Val Phe Ser Ile Asp Ser Ser Ser 3170 3175 3180 Gly Ile Ile Ile Leu Glu Gln Pro Leu Asp Arg Glu Gln Gln Ser Ser 3185 3190 3195 3200 Tyr Asn Ile Ser Val Arg Ala Thr Asp Gln Ser Pro Gly Gln Ser Leu 3205 3210 3215 Ser Ser Leu Thr Thr Val Thr Ile Thr Val Leu Asp Ile Asn Asp Asn 3220 3225 3230 Pro Pro Val Phe Glu Arg Arg Asp Tyr Leu Val Thr Val Pro Glu Asp 3235 3240 3245 Thr Ser Pro Gly Thr Gln Val Leu Ala Val Phe Ala Thr Ser Lys Asp 3250 3255 3260 Ile Gly Thr Asn Ala Glu Ile Thr Tyr Leu Ile Arg Ser Gly Asn Glu 3265 3270 3275 3280 Gln Gly Lys Phe Lys Ile Asn Pro Lys Thr Gly Gly Ile Ser Val Ser 3285 3290 3295 Glu Val Leu Asp Tyr Glu Leu Cys Lys Arg Phe Tyr Leu Val Val Glu 3300 3305 3310 Ala Lys Asp Gly Gly Thr Pro Ala Leu Ser Ala Val Ala Thr Val Asn 3315 3320 3325 Ile Asn Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Ser Gln Asp 3330 3335 3340 Val Tyr Ser Ala Val Ile Ser Glu Asp Ala Leu Val Gly Asp Ser Val 3345 3350 3355 3360 Ile Leu Leu Ile Ala Glu Asp Val Asp Ser Gln Pro Asn Gly Gln Ile 3365 3370 3375 His Phe Ser Ile Val Asn Gly Asp Arg Asp Asn Glu Phe Thr Val Asp 3380 3385 3390 Pro Val Leu Gly Leu Val Lys Val Lys Lys Lys Leu Asp Arg Glu Arg 3395 3400 3405 Val Ser Gly Tyr Ser Leu Leu Val Gln Ala Val Asp Ser Gly Ile Pro 3410 3415 3420 Ala Met Ser Ser Thr Ala Thr Val Asn Ile Asp Ile Ser Asp Val Asn 3425 3430 3435 3440 Asp Asn Ser Pro Val Phe Thr Pro Ala Asn Tyr Thr Ala Val Ile Gln 3445 3450 3455 Glu Asn Lys Pro Val Gly Thr Ser Ile Leu Gln Leu Val Val Thr Asp 3460 3465 3470 Arg Asp Ser Phe His Asn Gly Pro Pro Phe Ser Phe Ser Ile Leu Ser 3475 3480 3485 Gly Asn Glu Glu Glu Glu Phe Val Leu Asp Pro His Gly Ile Leu Arg 3490 3495 3500 Ser Ala Val Val Phe Gln His Thr Glu Ser Leu Glu Tyr Val Leu Cys 3505 3510 3515 3520 Val Gln Ala Lys Asp Ser Gly Lys Pro Gln Gln Val Ser His Thr Tyr 3525 3530 3535 Ile Arg Val Arg Val Ile Glu Glu Ser Thr His Lys Pro Thr Ala Ile 3540 3545 3550 Pro Leu Glu Ile Phe Ile Val Thr Met Glu Asp Asp Phe Pro Gly Gly 3555 3560 3565 Val Ile Gly Lys Ile His Ala Thr Asp Gln Asp Met Tyr Asp Val Leu 3570 3575 3580 Thr Phe Ala Leu Lys Ser Glu Gln Lys Ser Leu Phe Lys Val Asn Ser 3585 3590 3595 3600 His Asp Gly Lys Ile Ile Ala Leu Gly Gly Leu Asp Ser Gly Lys Tyr 3605 3610 3615 Val Leu Asn Val Ser Val Ser Asp Gly Arg Phe Gln Val Pro Ile Asp 3620 3625 3630 Val Val Val His Val Glu Gln Leu Val His Glu Met Leu Gln Asn Thr 3635 3640 3645 Val Thr Ile Arg Phe Glu Asn Val Ser Pro Glu Asp Phe Val Gly Leu 3650 3655 3660 His Met His Gly Phe Arg Arg Thr Leu Arg Asn Ala Val Leu Thr Gln 3665 3670 3675 3680 Lys Gln Asp Ser Leu Arg Ile Ile Ser Ile Gln Pro Val Ala Gly Thr 3685 3690 3695 Asn Gln Leu Asp Met Leu Phe Ala Val Glu Met His Ser Ser Glu Phe 3700 3705 3710 Tyr Lys Pro Ala Tyr Leu Ile Gln Lys Leu Ser Asn Ala Arg Arg His 3715 3720 3725 Leu Glu Asn Ile Met Arg Ile Ser Ala Ile Leu Glu Lys Asn Cys Ser 3730 3735 3740 Gly Leu Asp Cys Gln Glu Gln His Cys Glu Gln Gly Leu Ser Leu Asp 3745 3750 3755 3760 Ser His Ala Leu Met Thr Tyr Ser Thr Ala Arg Ile Ser Phe Val Cys 3765 3770 3775 Pro Arg Phe Tyr Arg Asn Val Arg Cys Thr Cys Asn Gly Gly Leu Cys 3780 3785 3790 Pro Gly Ser Asn Asp Pro Cys Val Glu Lys Pro Cys Pro Gly Asp Met 3795 3800 3805 Gln Cys Val Gly Tyr Glu Ala Ser Arg Arg Pro Phe Leu Cys Gln Cys 3810 3815 3820 Pro Pro Gly Lys Leu Gly Glu Cys Ser Gly His Thr Ser Leu Ser Phe 3825 3830 3835 3840 Ala Gly Asn Ser Tyr Ile Lys Tyr Arg Leu Ser Glu Asn Ser Lys Glu 3845 3850 3855 Glu Asp Phe Lys Leu Ala Leu Arg Leu Arg Thr Leu Gln Ser Asn Gly 3860 3865 3870 Ile Ile Met Tyr Thr Arg Ala Asn Pro Cys Ile Ile Leu Lys Ile Val 3875 3880 3885 Asp Gly Lys Leu Trp Phe Gln Leu Asp Cys Gly Ser Gly Pro Gly Ile 3890 3895 3900 Leu Gly Ile Ser Gly Arg Ala Val Asn Asp Gly Ser Trp His Ser Val 3905 3910 3915 3920 Phe Leu Glu Leu Asn Arg Asn Phe Thr Ser Leu Ser Leu Asp Asp Ser 3925 3930 3935 Tyr Val Glu Arg Arg Arg Ala Pro Leu Tyr Phe Gln Thr Leu Ser Thr 3940 3945 3950 Glu Ser Ser Ile Tyr Phe Gly Ala Leu Val Gln Ala Asp Asn Ile Arg 3955 3960 3965 Ser Leu Thr Asp Thr Arg Val Thr Gln Val Leu Ser Gly Phe Gln Gly 3970 3975 3980 Cys Leu Asp Ser Val Ile Leu Asn Asn Asn Glu Leu Pro Leu Gln Asn 3985 3990 3995 4000 Lys Arg Ser Ser Phe Ala Glu Val Val Gly Leu Thr Glu Leu Lys Leu 4005 4010 4015 Gly Cys Val Leu Tyr Pro Asp Ala Cys Lys Arg Ser Pro Cys Gln His 4020 4025 4030 Gly Gly Ser Cys Thr Gly Leu Pro Ser Gly Gly Tyr Gln Cys Thr Cys 4035 4040 4045 Leu Ser Gln Phe Thr Gly Arg Asn Cys Glu Ser Glu Ile Thr Ala Cys 4050 4055 4060 Phe Pro Asn Pro Cys Arg Asn Gly Gly Ser Cys Asp Pro Ile Gly Asn 4065 4070 4075 4080 Thr Phe Ile Cys Asn Cys Lys Ala Gly Leu Thr Gly Val Thr Cys Glu 4085 4090 4095 Glu Asp Ile Asn Glu Cys Glu Arg Glu Glu Cys Glu Asn Gly Gly Ser 4100 4105 4110 Cys Val Asn Val Phe Gly Ser Phe Leu Cys Asn Cys Thr Pro Gly Tyr 4115 4120 4125 Val Gly Gln Tyr Cys Gly Leu Arg Pro Val Val Val Pro Asn Ile Gln 4130 4135 4140 Ala Gly His Ser Tyr Val Gly Lys Glu Glu Leu Ile Gly Ile Ala Val 4145 4150 4155 4160 Val Leu Phe Val Ile Phe Ile Leu Val Val Leu Phe Ile Val Phe Arg 4165 4170 4175 Lys Lys Val Phe Arg Lys Asn Tyr Ser Arg Asn Asn Ile Thr Leu Val 4180 4185 4190 Gln Asp Pro Ala Thr Ala Ala Leu Leu Asn Lys Ser Asn Gly Ile Pro 4195 4200 4205 Phe Arg Asn Leu Arg Gly Ser Gly Asp Gly Arg Asn Val Tyr Gln Glu 4210 4215 4220 Val Gly Pro Pro Gln Val Pro Val Arg Pro Met Ala Tyr Thr Pro Cys 4225 4230 4235 4240 Phe Gln Ser Asp Ser Arg Ser Asn Leu Asp Lys Ile Val Asp Gly Leu 4245 4250 4255 Gly Gly Glu His Gln Glu Met Thr Thr Phe His Pro Glu Ser Pro Arg 4260 4265 4270 Ile Leu Thr Ala Arg Arg Gly Val Val Val Cys Ser Val Ala Pro Asn 4275 4280 4285 Leu Pro Ala Val Ser Pro Cys Arg Ser Asp Cys Asp Ser Ile Arg Lys 4290 4295 4300 Asn Gly Trp Asp Ala Gly Thr Glu Asn Lys Gly Val Asp Asp Pro Gly 4305 4310 4315 4320 Glu Val Thr Cys Phe Ala Gly Ser Asn Lys Gly Ser Asn Ser Glu Val 4325 4330 4335 Gln Ser Leu Ser Ser Phe Gln Ser Asp Ser Gly Asp Asp Asn Ala Ser 4340 4345 4350 Ile Val Thr Val Ile Gln Leu Val Asn Asn Val Val Asp Thr Ile Glu 4355 4360 4365 Asn Glu Val Ser Val Met Asp Gln Gly Gln Asn Tyr Asn Arg Ala Tyr 4370 4375 4380 His Trp Asp Thr Ser Asp Trp Met Pro Gly Ala Arg Leu Ser Asp Ile 4385 4390 4395 4400 Glu Glu Val Pro Asn Tyr Glu Asn Gln Asp Gly Gly Ser Ala His Gln 4405 4410 4415 Gly Ser Thr Arg Glu Leu Glu Ser Asp Tyr Tyr Leu Gly Gly Tyr Asp 4420 4425 4430 Ile Asp Ser Glu Tyr Pro Pro Pro His Glu Glu Glu Phe Leu Ser Gln 4435 4440 4445 Asp Gln Leu Pro Pro Pro Leu Pro Glu Asp Phe Pro Asp Gln Tyr Glu 4450 4455 4460 Ala Leu Pro Pro Ser Gln Pro Val Ser Leu Ala Ser Thr Leu Ser Pro 4465 4470 4475 4480 Asp Cys Arg Arg Arg Pro Gln Phe His Pro Ser Gln Tyr Leu Pro Pro 4485 4490 4495 His Pro Phe Pro Asn Glu Thr Asp Leu Val Gly Pro Pro Ala Ser Cys 4500 4505 4510 Glu Phe Ser Thr Phe Ala Val Ser Met Asn Gln Gly Thr Glu Pro Thr 4515 4520 4525 Gly Pro Ala Asp Ser Val Ser Leu Ser Leu His Asn Ser Arg Gly Thr 4530 4535 4540 Ser Ser Ser Asp Val Ser Ala Asn Cys Gly Phe Asp Asp Ser Glu Val 4545 4550 4555 4560 Ala Met Ser Asp Tyr Glu Ser Val Gly Glu Leu Ser Leu Ala Ser Leu 4565 4570 4575 His Ile Pro Phe Val Glu Thr Gln His Gln Thr Gln Val 4580 4585 3 11559 DNA homo sapiens 3 atggatataa ttatgggaca ctgtgtgggc acacggcctc ctgcttgttg cctcatcctc 60 ctgcttttca agcttttggc cactgtctcc caggggctgc cagggactgg acccctgggc 120 ttccacttca cacattccat ttataatgct accgtgtatg agaactcagc agcaaggacc 180 tacgtcaaca gccagagtag aatgggcatc accttaatag atctatcctg ggatatcaaa 240 tacagaatag tgtccggaga cgaggaaggc tttttcaaag cagaggaagt catcattgca 300 gatttctgtt ttctcagaat aagaactaaa ggtggcaatt ctgccatatt aaatagggaa 360 atccaggata attatttatt gatagtaaaa ggttctgtca gaggagagga tttggaagca 420 tggaccaaag tgaatataca ggttttagat atgaatgatc tgagaccttt gttttcaccc 480 acaacatact ctgttaccat agcagaaagc acacctctaa ggactagtgt tgcccaggtg 540 actgcaacag acgcagatat tggttccaat ggagaattct actactactt taaaaataaa 600 gttgatctct tttcagttca ccccacgagt ggtgtcatct ccttaagtgg tcgattaaat 660 tatgatgaaa agaataggta tgatctggaa attttggctg tggaccgggg aatgaaactg 720 tatgggaaca atggagtgag cagtactgca aagctttatg ttcacattga gcgcataaat 780 gaacatgccc caacaatcca tgtagtcact catgttcctt tctcgttgga aaaagagcca 840 acatatgcag tggtgacagt tgatgactta gatgatggag cgaatggaga gatcgaatct 900 gtttccattg tggctgggga tcctttagat cagttcttcc tggctaagga aggaaagtgg 960 ttgaatgagt acaagattaa ggagaggaag cagattgact gggagagctt tccctatggc 1020 tacaatctca ctcttcaagc aaaagacaag ggatctcctc aaaaatgttc agcattaaag 1080 gcagtctaca ttggcaaccc cacaagagac actgtcccca ttagatttga aaaagaagtg 1140 tacgatgtga gcataagtga attttcccct cctggtgtcg tggttgctat agtaaaatta 1200 agtcctgaac cgatagatgt ggaatacaaa ttatctcctg gtgaggatgc agtgtacttt 1260 aaaattaatc ctcggtcggg tctgattgtt acagcacggc cactgaatac tgttaagaag 1320 gaggtttata aactggaggt gacaaacaag gaaggagatt taaaagcaca ggtcaccatc 1380 agcatagaag atgcaaatga ccacacccca gaatttcagc aaccactgta tgatgcttat 1440 gtgaatgaaa gtgtcccagt gggaaccagc gttctaacag tttcagcttc tgataaggat 1500 aaaggagaaa atgggtacat cacctatagt atcgctagcc tgaatttgtt accatttgtc 1560 attaatcagt ttacaggtgt tattagcaca actgaagaac tggattttga atcctcccca 1620 gaaatttaca gattcattgt tagagcctct gactggggtt caccataccg ccatgaaagt 1680 gaggtcaatg tgactattcg aataggaaat gtcaacgaca acagccctct ctttgaaaaa 1740 gtggcttgcc agggagttat ttcatatgac tttccagttg gtggtcacat cacagcagtc 1800 tcagcgatcg atatcgatga acttgaactt gtaaagtaca aaatcatttc tggaaatgaa 1860 cttggcttct tttatttaaa cccagattct ggtgttttac agcttaaaaa atcactgaca 1920 aattctggca ttaaaaatgg caattttgcc ctcagaatta cagcaactga tggagagaat 1980 cttgcagacc ccatgtctat taacatttca gtcctacatg ggaaagtgtc ttcaaagagc 2040 ttcagttgca gagaaactcg tgtggctcaa aagctggcag agaaactact cattaaggca 2100 aaagcaaatg ggaaactgaa tctggaagat ggatttcttg acttttattc aattaataga 2160 cagggaccat attttgacaa gtcttttcct tctgatgtgg ctgtaaagga ggatctgcca 2220 gttggtgcta acattctgaa gattaaagcc tatgatgccg actctggctt caatggaaaa 2280 gtgctattta caatatcaga tggaaatacg gatagttgct ttaatattga tatggagact 2340 gggcagctta aagtccttat gcccatggat cgagaacaca cagacctcta tctccttaat 2400 atcaccatct atgacttagg taatccacag aaatcgtcat ggagactgct gaccatcaat 2460 gtggaggatg ctaatgacaa tagcccagtt tttattcaag acagttactc agttaacatt 2520 cttgaaagtt caggcattgg tactgaaatc attcaagtgg aagccagaga caaagactta 2580 ggttctaatg gtgaagtgac ttactcagtc ttgacagata cacagcagtt tgccatcaat 2640 agctcaactg gaatcgttta tgtagccgac cagttggacc gggaatccaa agccaattat 2700 tctttgaaaa tagaagccag ggacaaggca gagagtggtc

agcagctgtt ttcagttgtc 2760 actcttaaag tttttttaga tgatgtcaat gactgctccc cagctttcat tcccagtagc 2820 tatagtgtga aggttcttga agatctccct gttggcactg tcattgcttg gcttgagacc 2880 catgatccag atcttggact ggggggtcaa gtgcgctatt ctttggtcaa tgactataat 2940 gggagatttg aaatagataa agcaagtggt gccatccgct tgagcaaaga gcttgattat 3000 gagaaacagc agttctataa ccttactgtg cgggccaaag acaaagggcg gcctgtctct 3060 ctgtcatctg tttcctttgt tgaggtggaa gtggtggatg tcaatgaaaa cctccacact 3120 ccctatttcc cagactttgc tgttgttgga tctgtaaagg aaaactcacg cattggaaca 3180 agcgtgctgc aggtgactgc tcgagatgaa gactccggaa gggatggaga gatccagtac 3240 tccatcaggg atggcagtgg tcttggaagg ttcagtatag acgacgagag tggggtcatc 3300 actgccgcag acattcttga tcgggagaca atggggtcat actggctaac agtgtatgcc 3360 acagacaggg gcgttgttcc actctactcc accattgagg tctacattga agttgaagat 3420 gtgaatgaca atgccccgct gacctcagaa cctatatatt atcctgttgt catggaaaac 3480 tctccaaagg acgtatctgt cattcagatc caggctgaag atcctgactc cagttccaat 3540 gaaaaactga catacaggat tacaagtgga aatcctcaga atttttttgc catcaatatc 3600 aaaacaggtc tgattacaac aacttcaagg aaattggatc gagaacagca ggcagaacat 3660 tttctggagg tgactgtgac agatggtggt ccctctccaa aacagtcaac catttgggtg 3720 gtggttcagg ttctagatga aaatgacaac aagccccagt tcccagagaa ggtctaccag 3780 atcaagctgc cagaacgtga ccgaaagaag agaggagaac cgatttacag ggcttttgca 3840 tttgatagag atgagggccc caacgcagaa atctcctaca gtattgtgga tgggaatgat 3900 gacggaaagt tctttattga ccctaaaact gggatggttt cttctagaaa gcagtttaca 3960 gcaggcagtt atgacatcct aacgataaag gcagtggaca atgggcgccc acagaaatcc 4020 tccacggccc gcctccacat tgaatggatt aagaaaccac ccccttcacc tataccattg 4080 accttcgatg agccgtttta taacttcaca gtcatggaaa gtgatagagt gactgaaatt 4140 gtaggggtgg tgtctgtgca gccagctaac acccctctgt ggtttgacat agttgggggg 4200 aattttgaca gcgcttttga tgcagagaag ggtgttggga caattgtcat cgcaaaacct 4260 ttggatgcag agcagaggtc catctataat atgagtgtgg aagtcaccga tgggacaaat 4320 gttgctgtta ctcaggtatt tatcaaagtg ctggataata atgataatgg cccagaattc 4380 tctcagccga attacgatgt gacaatttcc gaggatgtgc ttccagacac ggagatcctg 4440 cagattgaag ccacagatag agatgagaag cacaagctga gctacactgt tcatagcagc 4500 atcgactcca tcagcatgag aaaattccgg attgacccta gcactggcgt gctctatact 4560 gccgagaggc tggaccatga ggcccaggac aagcacattc tcaacataat ggtcagagat 4620 caggagtttc cttatcgaag aaacttggcc cgagtcattg tgaatgtgga ggatgctaat 4680 gatcacagtc cttattttac caacccactg tatgaagcgt ctgtgtttga atctgctgct 4740 ctgggatcag ctgttctgca agtgacggct ctggacaaag acaaaggaga aaatgcagaa 4800 ctcatatata ccatagaagc agggaacact gggaacatgt ttaagatcga accggtccta 4860 ggcatcatca ccatttgcaa agaaccagac atgacgacga tgggtcagtt tgtcctatcc 4920 atcaaagtca cagatcaggg atccccgcca atgtctgcta ctgcaattgt gcgcatttcc 4980 gtcaccatgt ctgacaattc tcaccccaag ttcattcaca aagactacca agcagaagta 5040 aatgaaaatg ttgacattgg aacatcagtc attctaatct ctgccatcag tcaatctacc 5100 ctcatttatg aagtcaaaga tggagacatt aatgggatct ttaccataaa tccatattct 5160 ggagtcatca ccactcagaa ggccctggat tatgagcgca catcctctta tcaactcatc 5220 attcaggcca ccaatatggc aggaatggct tccaatgcta cagtcaatat tcagattgtt 5280 gatgaaaatg ataatgcccc agtttttctc ttttctcaat actcaggcag cctaagtgag 5340 gctgccccaa ttaatagcat tgtcaggagc ttggataaca gcccactggt gattcgagcc 5400 acagatgctg acagcaaccg gaatgctctg cttgtgtatc agattgtgga gtcaacagca 5460 aaaaagtttt tcacggtgga ctccagtaca ggtgcaatca gaacaattgc caacctggac 5520 catgaaacca ttgcccattt ccattttcat gtgcatgtga gagacagtgg tagcccccaa 5580 ctgactgcag agagtcccgt tgaagtcaac attgaggtga cagatgtgaa tgataaccca 5640 cctgttttta ctcaggctgt gtttgagact atcttacttc tacctaccta tgttggagtg 5700 gaggttctga aagttagtgc cacagatcct gactctgagg taccccctga actgacatac 5760 agcctaatgg aaggcagttt ggatcatttt ttaattgact caaacagtgg agtacttacc 5820 ataaaaaaca acaacctctc caaggatcac tacatgctga tagttaaggt gtctgatgga 5880 aagttctaca gtacctccat ggtcaccatc atggttaaag aagccatgga cagcggcctc 5940 cactttacac aaagcttcta ttccacctca atctcagaga acaacactaa cataaccaaa 6000 gttgctattg tcaatgcagt tggaaatcgc cttaatgagc ccttaaaata cagcatctta 6060 aacccaggaa ataagttcaa gataaaatct acctcagggg tcattcagac gactggagtc 6120 ccctttgacc gtgaagaaca agagttatat gagctggtgg tagaagccag ccgtgagctg 6180 gaccatctgc gtgtggccag agtggtggtc agggttaaca ttgaagacat aaatgacaat 6240 tctccagtct ttgtgggcct cccatactat gctgctgttc aagtggatgc ggaacccggg 6300 actctgattt atcaggtgac agccattgac aaagataaag gtccaaatgg agaagtgacc 6360 tatgtcctgc aggatgacta tggccacttt gaaattaacc ctaattcagg gaatgttatt 6420 ttaaaggaag cattcaactc tgacttgtcc aacattgagt atggagtcac catcctagcc 6480 aaggatggcg gaaaaccttc tttgtctaca tctgtggagc ttcccatcac tattgtcaac 6540 aaagcaatgc ctgtgtttga taagcccttt tatacagcat ctgtcaatga agacatcaga 6600 atgaacacac ccatcctaag catcaatgcc accagtccag aaggccaagg catcatatat 6660 atcattatcg atggggaccc ttttaaacag tttaacattg actttgacac tggggtcctg 6720 aaagttgtta gccctttgga ttatgaagtt acatctgctt acaagctgac aataagagcc 6780 agcgacgccc ttactggtgc tagggctgaa gtcactgttg acttgctagt taatgatgta 6840 aatgacaacc cccctatttt cgatcagcct acatacaata caacactatc agaagcatct 6900 cttattggga cacctgtttt acaagttgtc tctattgatg cagactcaga aaacaataaa 6960 atggtacatt atcagattgt ccaggatacc tacaatagca cagattattt tcacatagat 7020 agctcaagtg gcttaatcct gacagcacga atgctggacc atgagttagt acaacactgc 7080 actttgaaag tcagatcaat agatagtggc ttcccatcac tgagcagtga ggttctcgtt 7140 catatctaca tctctgatgt aaatgacaac cctccagttt ttaatcagct catttatgag 7200 tcatatgtga gtgaattagc cccccggggc cattttgtaa cctgtgtaca agcctctgat 7260 gcagacagct ctgattttga ccggttggaa tatagcattt tatctgggaa tgaccggacg 7320 agctttctga tggacagcaa gagtggagtt atcacattgt ccaaccatcg gaagcagcgg 7380 atggagcctc tgtacagtct caatgtgtct gtctctgatg ggttgttcac cagcactgca 7440 caggtgcata ttagggtact tggggctaac ttgtacagcc ctgccttttc acaaagcaca 7500 tacgtagctg aggtgagaga gaacgtggct gcaggaacaa aggtaattca tgttcgagcc 7560 acagatggtg atccagggac ttatgggcag atcagctatg ccatcatcaa tgactttgcc 7620 aaggatcgat tcctcataga cagcaatggg caggtcatca ccacagaaag gctagaccgg 7680 gaaaaccctc tagaagggga tgttagtatt tttgtgaggg cccttgatgg tggagggaga 7740 acaactttct gcactgtgag agtgattgtt gtggatgaaa atgacaatgc tccccagttc 7800 atgacagtgg aatatagagc cagtgtcagg gcagatgttg gaaggggcca cttggtcact 7860 caagttcaag ccatagatcc cgatgatgga gcaaattcaa ggattactta ttccctctat 7920 agcgaggcct ctgtttcagt ggccgacctc ctggaaatcg atcctgacaa tggctggatg 7980 gtcacaaagg gtaattttaa ccagctgaaa aatacagtgc tttcgttctt tgtcaaagca 8040 gtagatgggg gcatcccagt aaagcactcc ctcattcctg tctatatcca cgtcttgccc 8100 cctgaaacgt tcttgccatc attcacccag tctcagtatt cctttaccat tgcagaagat 8160 acagccattg ggagtacagt ggacaccctg aggattttgc ccagtcagaa tgtctggttc 8220 agcacagtta atggggaacg gccagaaaat aacaaagggg gcgtattcgt catagaacag 8280 gaaacaggca ctattaagct tgacaaacgc cttgaccgtg aaaccagccc agctttccac 8340 tttaaagtag cagccactat acccctggac aaagtagaca ttgtgtttac tgtggatgta 8400 gatatcaagg tattggattt gaatgacaac aagccagtct ttgaaacttc aagctatgac 8460 accattataa tggaagggat gcctgttggc accaaactca cacaagtgag agctattgat 8520 atggactggg gagccaatgg acaagtcact tactccctcc actcggattc ccagcccgaa 8580 aaggtaatgg aagcattcaa tattgacagc aacacgggct ggatcagtac cttgaaggac 8640 ctagatcacg agacagaccc cacattcacc ttctctgtgg tggcctctga ccttggagag 8700 gcattctctc tttcctccac ggccttggtc tctgtcagag tgacagatat aaatgacaat 8760 gcaccagtct tcgcgcagga agtgtaccga gggaatgtga aggagagcga cccaccgggc 8820 gaggtggtag ccgtcctcag cacctgggac agagacacat ccgacgttaa tcgccaagtg 8880 agctaccata ttacaggagg aaaccctcga ggaaggtttg ctctgggcct ggtgcaaagt 8940 gagtggaagg tctatgtgaa gaggcctcta gacagagaag aacaggacat ttactttctc 9000 aatatcactg ccactgatgg gctttttgtc acacaggcca tggtggaagt gagcgtcagt 9060 gatgtgaatg acaatagccc agtgtgtgat caggttgcat atacagcatt acttcctgaa 9120 gacattccat caaataaaat catcctgaaa gtcagtgcaa aggatgctga tattggatcc 9180 aatggatata tacgatactc actctatgga tctggaaaca gtgaattttt tctagatcca 9240 gaaagtggcg agttaaaaac cttggctctg ttggaccggg agaggatccc cgtgtacagc 9300 ctgatggcca aggccactga cgggggtggc aggttctgcc agtccaacat ccacctaatc 9360 ctggaggatg tgaatgataa cccccctgtg ttttcttctg accactacaa cacctgtgtc 9420 tatgagaaca cagccaccaa ggctctgttg accagagttc aagccgtgga ccccgacatt 9480 ggcatcaata ggaaggtcgt gtactccctg gcagactcag ctggtggggt cttctccatt 9540 gacagctcat ctggcatcat catcctggag cagccactgg accgtgagca gcagtcttcg 9600 tacaacatca gcgtgcgggc cactgaccag agtcctggac agtccctgtc ctctctcact 9660 actgtcacca tcaccgttct ggacattaat gacaaccccc ctgtgtttga gaggagggac 9720 tacctggtga cggtgcctga ggacacctcc cctggcaccc aagtccttgc tgtttttgcc 9780 accagcaaag atattggcac aaatgctgag atcacttatc tcatccggtc tgggaacgaa 9840 caagggaaat ttaagatcaa ccccaagaca gggggtattt ctgtctctga agtcctggac 9900 tatgaattat gcaaaaggtt ttacctggta gtggaagcca aagatggggg caccccagct 9960 ctcagcgctg tggccactgt caacatcaac ctcacagatg ttaatgacaa ccctcccaag 10020 ttcagccaag acgtctacag tgcggttatc agtgaagacg ccttggtggg agactctgtc 10080 attttgctaa tagcagaaga tgtagacagc cagcccaacg gacagattca tttttccatt 10140 gtgaatggag atcgggacaa tgaatttact gtagatcctg tcttgggact tgtgaaagtt 10200 aagaagaaat tggaccggga acgggtgtct ggatactctc tgcttgtcca ggccgtagac 10260 agtggcattc ctgcaatgtc atcaactgca actgtcaaca ttgatatttc tgatgtgaat 10320 gacaacagcc cggtgtttac acctgccaac tatactgctg tgattcagga aaataagcca 10380 gtgggcacca gcatcttgca gctggtggtg acagacagag actcctttca caatgggcct 10440 cccttttcat tctctatttt gtcgggaaat gaagaggagg agtttgtgtt ggaccctcat 10500 gggatcttgc ggtcggctgt ggtcttccag cacacagagt ctctggaata cgtgttgtgt 10560 gtccaggcaa aggattcagg caaaccccag caagtttctc acacttacat ccgcgtgcga 10620 gtcattgagg aaagcaccca caagcccaca gccattcccc tggaaatttt cattgtcacc 10680 atggaggatg actttcctgg tggggtcatt gggaagattc atgccacaga tcaagacatg 10740 tatgatgtgc tcacatttgc cctgaaatcg gagcagaaaa gcttatttaa agtgaacagt 10800 cacgatggga aaatcatcgc cctgggaggc ctggacagcg gcaagtatgt cctgaatgtg 10860 tctgtgagtg atggtcgctt ccaggtaccc attgatgtgg tcgtgcatgt ggagcagttg 10920 gtgcatgaga tgctgcagaa cactgtcacc atccgctttg aaaatgtgtc ccctgaggac 10980 ttcgtggggc tgcacatgca tgggttccgg cgcaccctgc ggaatgcagt cctcacccag 11040 aagcaggaca gcctgcgcat catcagcatc cagcccgtgg caggcaccaa ccaactggac 11100 atgctgtttg cggtggagat gcacagcagc gagttctaca agccagccta cctgatccag 11160 aagctgtcca atgctagaag acacctggag aatatcatgc gcatctcagc catcttggag 11220 aagaactgct cagggctgga ctgtcaggaa cagcattgtg agcaaggctt gtcactcgat 11280 tcccacgcgc tcatgaccta cagcacggct cgcatcagct ttgtgtgtcc gcgtttctac 11340 aggaacgtgc gttgcacctg caatggagga ctgtgtccgg ggtccaacga tccttgtgtg 11400 gagaagccgt gtccagggga catgcagtgt gtcggttatg aagccagcag gagaccgttc 11460 ctctgccagt gtccaccagg gaagctcgga gagtgctcag ggcacacttc tctcagcttt 11520 gctggaaaca gttacatcaa atatcggctt tctgaatag 11559 4 3852 PRT homo sapiens 4 Met Asp Ile Ile Met Gly His Cys Val Gly Thr Arg Pro Pro Ala Cys 1 5 10 15 Cys Leu Ile Leu Leu Leu Phe Lys Leu Leu Ala Thr Val Ser Gln Gly 20 25 30 Leu Pro Gly Thr Gly Pro Leu Gly Phe His Phe Thr His Ser Ile Tyr 35 40 45 Asn Ala Thr Val Tyr Glu Asn Ser Ala Ala Arg Thr Tyr Val Asn Ser 50 55 60 Gln Ser Arg Met Gly Ile Thr Leu Ile Asp Leu Ser Trp Asp Ile Lys 65 70 75 80 Tyr Arg Ile Val Ser Gly Asp Glu Glu Gly Phe Phe Lys Ala Glu Glu 85 90 95 Val Ile Ile Ala Asp Phe Cys Phe Leu Arg Ile Arg Thr Lys Gly Gly 100 105 110 Asn Ser Ala Ile Leu Asn Arg Glu Ile Gln Asp Asn Tyr Leu Leu Ile 115 120 125 Val Lys Gly Ser Val Arg Gly Glu Asp Leu Glu Ala Trp Thr Lys Val 130 135 140 Asn Ile Gln Val Leu Asp Met Asn Asp Leu Arg Pro Leu Phe Ser Pro 145 150 155 160 Thr Thr Tyr Ser Val Thr Ile Ala Glu Ser Thr Pro Leu Arg Thr Ser 165 170 175 Val Ala Gln Val Thr Ala Thr Asp Ala Asp Ile Gly Ser Asn Gly Glu 180 185 190 Phe Tyr Tyr Tyr Phe Lys Asn Lys Val Asp Leu Phe Ser Val His Pro 195 200 205 Thr Ser Gly Val Ile Ser Leu Ser Gly Arg Leu Asn Tyr Asp Glu Lys 210 215 220 Asn Arg Tyr Asp Leu Glu Ile Leu Ala Val Asp Arg Gly Met Lys Leu 225 230 235 240 Tyr Gly Asn Asn Gly Val Ser Ser Thr Ala Lys Leu Tyr Val His Ile 245 250 255 Glu Arg Ile Asn Glu His Ala Pro Thr Ile His Val Val Thr His Val 260 265 270 Pro Phe Ser Leu Glu Lys Glu Pro Thr Tyr Ala Val Val Thr Val Asp 275 280 285 Asp Leu Asp Asp Gly Ala Asn Gly Glu Ile Glu Ser Val Ser Ile Val 290 295 300 Ala Gly Asp Pro Leu Asp Gln Phe Phe Leu Ala Lys Glu Gly Lys Trp 305 310 315 320 Leu Asn Glu Tyr Lys Ile Lys Glu Arg Lys Gln Ile Asp Trp Glu Ser 325 330 335 Phe Pro Tyr Gly Tyr Asn Leu Thr Leu Gln Ala Lys Asp Lys Gly Ser 340 345 350 Pro Gln Lys Cys Ser Ala Leu Lys Ala Val Tyr Ile Gly Asn Pro Thr 355 360 365 Arg Asp Thr Val Pro Ile Arg Phe Glu Lys Glu Val Tyr Asp Val Ser 370 375 380 Ile Ser Glu Phe Ser Pro Pro Gly Val Val Val Ala Ile Val Lys Leu 385 390 395 400 Ser Pro Glu Pro Ile Asp Val Glu Tyr Lys Leu Ser Pro Gly Glu Asp 405 410 415 Ala Val Tyr Phe Lys Ile Asn Pro Arg Ser Gly Leu Ile Val Thr Ala 420 425 430 Arg Pro Leu Asn Thr Val Lys Lys Glu Val Tyr Lys Leu Glu Val Thr 435 440 445 Asn Lys Glu Gly Asp Leu Lys Ala Gln Val Thr Ile Ser Ile Glu Asp 450 455 460 Ala Asn Asp His Thr Pro Glu Phe Gln Gln Pro Leu Tyr Asp Ala Tyr 465 470 475 480 Val Asn Glu Ser Val Pro Val Gly Thr Ser Val Leu Thr Val Ser Ala 485 490 495 Ser Asp Lys Asp Lys Gly Glu Asn Gly Tyr Ile Thr Tyr Ser Ile Ala 500 505 510 Ser Leu Asn Leu Leu Pro Phe Val Ile Asn Gln Phe Thr Gly Val Ile 515 520 525 Ser Thr Thr Glu Glu Leu Asp Phe Glu Ser Ser Pro Glu Ile Tyr Arg 530 535 540 Phe Ile Val Arg Ala Ser Asp Trp Gly Ser Pro Tyr Arg His Glu Ser 545 550 555 560 Glu Val Asn Val Thr Ile Arg Ile Gly Asn Val Asn Asp Asn Ser Pro 565 570 575 Leu Phe Glu Lys Val Ala Cys Gln Gly Val Ile Ser Tyr Asp Phe Pro 580 585 590 Val Gly Gly His Ile Thr Ala Val Ser Ala Ile Asp Ile Asp Glu Leu 595 600 605 Glu Leu Val Lys Tyr Lys Ile Ile Ser Gly Asn Glu Leu Gly Phe Phe 610 615 620 Tyr Leu Asn Pro Asp Ser Gly Val Leu Gln Leu Lys Lys Ser Leu Thr 625 630 635 640 Asn Ser Gly Ile Lys Asn Gly Asn Phe Ala Leu Arg Ile Thr Ala Thr 645 650 655 Asp Gly Glu Asn Leu Ala Asp Pro Met Ser Ile Asn Ile Ser Val Leu 660 665 670 His Gly Lys Val Ser Ser Lys Ser Phe Ser Cys Arg Glu Thr Arg Val 675 680 685 Ala Gln Lys Leu Ala Glu Lys Leu Leu Ile Lys Ala Lys Ala Asn Gly 690 695 700 Lys Leu Asn Leu Glu Asp Gly Phe Leu Asp Phe Tyr Ser Ile Asn Arg 705 710 715 720 Gln Gly Pro Tyr Phe Asp Lys Ser Phe Pro Ser Asp Val Ala Val Lys 725 730 735 Glu Asp Leu Pro Val Gly Ala Asn Ile Leu Lys Ile Lys Ala Tyr Asp 740 745 750 Ala Asp Ser Gly Phe Asn Gly Lys Val Leu Phe Thr Ile Ser Asp Gly 755 760 765 Asn Thr Asp Ser Cys Phe Asn Ile Asp Met Glu Thr Gly Gln Leu Lys 770 775 780 Val Leu Met Pro Met Asp Arg Glu His Thr Asp Leu Tyr Leu Leu Asn 785 790 795 800 Ile Thr Ile Tyr Asp Leu Gly Asn Pro Gln Lys Ser Ser Trp Arg Leu 805 810 815 Leu Thr Ile Asn Val Glu Asp Ala Asn Asp Asn Ser Pro Val Phe Ile 820 825 830 Gln Asp Ser Tyr Ser Val Asn Ile Leu Glu Ser Ser Gly Ile Gly Thr 835 840 845 Glu Ile Ile Gln Val Glu Ala Arg Asp Lys Asp Leu Gly Ser Asn Gly 850 855 860 Glu Val Thr Tyr Ser Val Leu Thr Asp Thr Gln Gln Phe Ala Ile Asn 865 870 875 880 Ser Ser Thr Gly Ile Val Tyr Val Ala Asp Gln Leu Asp Arg Glu Ser 885 890 895 Lys Ala Asn Tyr Ser Leu Lys Ile Glu Ala Arg Asp Lys Ala Glu Ser 900 905 910 Gly Gln Gln Leu Phe Ser Val Val Thr Leu Lys Val Phe Leu Asp Asp 915 920 925 Val Asn Asp Cys Ser Pro Ala Phe Ile Pro Ser Ser Tyr Ser Val Lys 930 935 940 Val Leu Glu Asp Leu Pro Val Gly Thr Val Ile Ala Trp Leu Glu Thr 945 950 955 960 His Asp Pro Asp Leu Gly Leu Gly Gly Gln Val Arg Tyr Ser Leu Val 965 970 975 Asn Asp Tyr Asn Gly Arg Phe Glu Ile Asp Lys Ala Ser Gly Ala Ile 980 985 990 Arg Leu Ser Lys Glu Leu Asp Tyr Glu Lys Gln Gln Phe Tyr Asn Leu 995 1000 1005

Thr Val Arg Ala Lys Asp Lys Gly Arg Pro Val Ser Leu Ser Ser Val 1010 1015 1020 Ser Phe Val Glu Val Glu Val Val Asp Val Asn Glu Asn Leu His Thr 1025 1030 1035 1040 Pro Tyr Phe Pro Asp Phe Ala Val Val Gly Ser Val Lys Glu Asn Ser 1045 1050 1055 Arg Ile Gly Thr Ser Val Leu Gln Val Thr Ala Arg Asp Glu Asp Ser 1060 1065 1070 Gly Arg Asp Gly Glu Ile Gln Tyr Ser Ile Arg Asp Gly Ser Gly Leu 1075 1080 1085 Gly Arg Phe Ser Ile Asp Asp Glu Ser Gly Val Ile Thr Ala Ala Asp 1090 1095 1100 Ile Leu Asp Arg Glu Thr Met Gly Ser Tyr Trp Leu Thr Val Tyr Ala 1105 1110 1115 1120 Thr Asp Arg Gly Val Val Pro Leu Tyr Ser Thr Ile Glu Val Tyr Ile 1125 1130 1135 Glu Val Glu Asp Val Asn Asp Asn Ala Pro Leu Thr Ser Glu Pro Ile 1140 1145 1150 Tyr Tyr Pro Val Val Met Glu Asn Ser Pro Lys Asp Val Ser Val Ile 1155 1160 1165 Gln Ile Gln Ala Glu Asp Pro Asp Ser Ser Ser Asn Glu Lys Leu Thr 1170 1175 1180 Tyr Arg Ile Thr Ser Gly Asn Pro Gln Asn Phe Phe Ala Ile Asn Ile 1185 1190 1195 1200 Lys Thr Gly Leu Ile Thr Thr Thr Ser Arg Lys Leu Asp Arg Glu Gln 1205 1210 1215 Gln Ala Glu His Phe Leu Glu Val Thr Val Thr Asp Gly Gly Pro Ser 1220 1225 1230 Pro Lys Gln Ser Thr Ile Trp Val Val Val Gln Val Leu Asp Glu Asn 1235 1240 1245 Asp Asn Lys Pro Gln Phe Pro Glu Lys Val Tyr Gln Ile Lys Leu Pro 1250 1255 1260 Glu Arg Asp Arg Lys Lys Arg Gly Glu Pro Ile Tyr Arg Ala Phe Ala 1265 1270 1275 1280 Phe Asp Arg Asp Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Val 1285 1290 1295 Asp Gly Asn Asp Asp Gly Lys Phe Phe Ile Asp Pro Lys Thr Gly Met 1300 1305 1310 Val Ser Ser Arg Lys Gln Phe Thr Ala Gly Ser Tyr Asp Ile Leu Thr 1315 1320 1325 Ile Lys Ala Val Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr Ala Arg 1330 1335 1340 Leu His Ile Glu Trp Ile Lys Lys Pro Pro Pro Ser Pro Ile Pro Leu 1345 1350 1355 1360 Thr Phe Asp Glu Pro Phe Tyr Asn Phe Thr Val Met Glu Ser Asp Arg 1365 1370 1375 Val Thr Glu Ile Val Gly Val Val Ser Val Gln Pro Ala Asn Thr Pro 1380 1385 1390 Leu Trp Phe Asp Ile Val Gly Gly Asn Phe Asp Ser Ala Phe Asp Ala 1395 1400 1405 Glu Lys Gly Val Gly Thr Ile Val Ile Ala Lys Pro Leu Asp Ala Glu 1410 1415 1420 Gln Arg Ser Ile Tyr Asn Met Ser Val Glu Val Thr Asp Gly Thr Asn 1425 1430 1435 1440 Val Ala Val Thr Gln Val Phe Ile Lys Val Leu Asp Asn Asn Asp Asn 1445 1450 1455 Gly Pro Glu Phe Ser Gln Pro Asn Tyr Asp Val Thr Ile Ser Glu Asp 1460 1465 1470 Val Leu Pro Asp Thr Glu Ile Leu Gln Ile Glu Ala Thr Asp Arg Asp 1475 1480 1485 Glu Lys His Lys Leu Ser Tyr Thr Val His Ser Ser Ile Asp Ser Ile 1490 1495 1500 Ser Met Arg Lys Phe Arg Ile Asp Pro Ser Thr Gly Val Leu Tyr Thr 1505 1510 1515 1520 Ala Glu Arg Leu Asp His Glu Ala Gln Asp Lys His Ile Leu Asn Ile 1525 1530 1535 Met Val Arg Asp Gln Glu Phe Pro Tyr Arg Arg Asn Leu Ala Arg Val 1540 1545 1550 Ile Val Asn Val Glu Asp Ala Asn Asp His Ser Pro Tyr Phe Thr Asn 1555 1560 1565 Pro Leu Tyr Glu Ala Ser Val Phe Glu Ser Ala Ala Leu Gly Ser Ala 1570 1575 1580 Val Leu Gln Val Thr Ala Leu Asp Lys Asp Lys Gly Glu Asn Ala Glu 1585 1590 1595 1600 Leu Ile Tyr Thr Ile Glu Ala Gly Asn Thr Gly Asn Met Phe Lys Ile 1605 1610 1615 Glu Pro Val Leu Gly Ile Ile Thr Ile Cys Lys Glu Pro Asp Met Thr 1620 1625 1630 Thr Met Gly Gln Phe Val Leu Ser Ile Lys Val Thr Asp Gln Gly Ser 1635 1640 1645 Pro Pro Met Ser Ala Thr Ala Ile Val Arg Ile Ser Val Thr Met Ser 1650 1655 1660 Asp Asn Ser His Pro Lys Phe Ile His Lys Asp Tyr Gln Ala Glu Val 1665 1670 1675 1680 Asn Glu Asn Val Asp Ile Gly Thr Ser Val Ile Leu Ile Ser Ala Ile 1685 1690 1695 Ser Gln Ser Thr Leu Ile Tyr Glu Val Lys Asp Gly Asp Ile Asn Gly 1700 1705 1710 Ile Phe Thr Ile Asn Pro Tyr Ser Gly Val Ile Thr Thr Gln Lys Ala 1715 1720 1725 Leu Asp Tyr Glu Arg Thr Ser Ser Tyr Gln Leu Ile Ile Gln Ala Thr 1730 1735 1740 Asn Met Ala Gly Met Ala Ser Asn Ala Thr Val Asn Ile Gln Ile Val 1745 1750 1755 1760 Asp Glu Asn Asp Asn Ala Pro Val Phe Leu Phe Ser Gln Tyr Ser Gly 1765 1770 1775 Ser Leu Ser Glu Ala Ala Pro Ile Asn Ser Ile Val Arg Ser Leu Asp 1780 1785 1790 Asn Ser Pro Leu Val Ile Arg Ala Thr Asp Ala Asp Ser Asn Arg Asn 1795 1800 1805 Ala Leu Leu Val Tyr Gln Ile Val Glu Ser Thr Ala Lys Lys Phe Phe 1810 1815 1820 Thr Val Asp Ser Ser Thr Gly Ala Ile Arg Thr Ile Ala Asn Leu Asp 1825 1830 1835 1840 His Glu Thr Ile Ala His Phe His Phe His Val His Val Arg Asp Ser 1845 1850 1855 Gly Ser Pro Gln Leu Thr Ala Glu Ser Pro Val Glu Val Asn Ile Glu 1860 1865 1870 Val Thr Asp Val Asn Asp Asn Pro Pro Val Phe Thr Gln Ala Val Phe 1875 1880 1885 Glu Thr Ile Leu Leu Leu Pro Thr Tyr Val Gly Val Glu Val Leu Lys 1890 1895 1900 Val Ser Ala Thr Asp Pro Asp Ser Glu Val Pro Pro Glu Leu Thr Tyr 1905 1910 1915 1920 Ser Leu Met Glu Gly Ser Leu Asp His Phe Leu Ile Asp Ser Asn Ser 1925 1930 1935 Gly Val Leu Thr Ile Lys Asn Asn Asn Leu Ser Lys Asp His Tyr Met 1940 1945 1950 Leu Ile Val Lys Val Ser Asp Gly Lys Phe Tyr Ser Thr Ser Met Val 1955 1960 1965 Thr Ile Met Val Lys Glu Ala Met Asp Ser Gly Leu His Phe Thr Gln 1970 1975 1980 Ser Phe Tyr Ser Thr Ser Ile Ser Glu Asn Asn Thr Asn Ile Thr Lys 1985 1990 1995 2000 Val Ala Ile Val Asn Ala Val Gly Asn Arg Leu Asn Glu Pro Leu Lys 2005 2010 2015 Tyr Ser Ile Leu Asn Pro Gly Asn Lys Phe Lys Ile Lys Ser Thr Ser 2020 2025 2030 Gly Val Ile Gln Thr Thr Gly Val Pro Phe Asp Arg Glu Glu Gln Glu 2035 2040 2045 Leu Tyr Glu Leu Val Val Glu Ala Ser Arg Glu Leu Asp His Leu Arg 2050 2055 2060 Val Ala Arg Val Val Val Arg Val Asn Ile Glu Asp Ile Asn Asp Asn 2065 2070 2075 2080 Ser Pro Val Phe Val Gly Leu Pro Tyr Tyr Ala Ala Val Gln Val Asp 2085 2090 2095 Ala Glu Pro Gly Thr Leu Ile Tyr Gln Val Thr Ala Ile Asp Lys Asp 2100 2105 2110 Lys Gly Pro Asn Gly Glu Val Thr Tyr Val Leu Gln Asp Asp Tyr Gly 2115 2120 2125 His Phe Glu Ile Asn Pro Asn Ser Gly Asn Val Ile Leu Lys Glu Ala 2130 2135 2140 Phe Asn Ser Asp Leu Ser Asn Ile Glu Tyr Gly Val Thr Ile Leu Ala 2145 2150 2155 2160 Lys Asp Gly Gly Lys Pro Ser Leu Ser Thr Ser Val Glu Leu Pro Ile 2165 2170 2175 Thr Ile Val Asn Lys Ala Met Pro Val Phe Asp Lys Pro Phe Tyr Thr 2180 2185 2190 Ala Ser Val Asn Glu Asp Ile Arg Met Asn Thr Pro Ile Leu Ser Ile 2195 2200 2205 Asn Ala Thr Ser Pro Glu Gly Gln Gly Ile Ile Tyr Ile Ile Ile Asp 2210 2215 2220 Gly Asp Pro Phe Lys Gln Phe Asn Ile Asp Phe Asp Thr Gly Val Leu 2225 2230 2235 2240 Lys Val Val Ser Pro Leu Asp Tyr Glu Val Thr Ser Ala Tyr Lys Leu 2245 2250 2255 Thr Ile Arg Ala Ser Asp Ala Leu Thr Gly Ala Arg Ala Glu Val Thr 2260 2265 2270 Val Asp Leu Leu Val Asn Asp Val Asn Asp Asn Pro Pro Ile Phe Asp 2275 2280 2285 Gln Pro Thr Tyr Asn Thr Thr Leu Ser Glu Ala Ser Leu Ile Gly Thr 2290 2295 2300 Pro Val Leu Gln Val Val Ser Ile Asp Ala Asp Ser Glu Asn Asn Lys 2305 2310 2315 2320 Met Val His Tyr Gln Ile Val Gln Asp Thr Tyr Asn Ser Thr Asp Tyr 2325 2330 2335 Phe His Ile Asp Ser Ser Ser Gly Leu Ile Leu Thr Ala Arg Met Leu 2340 2345 2350 Asp His Glu Leu Val Gln His Cys Thr Leu Lys Val Arg Ser Ile Asp 2355 2360 2365 Ser Gly Phe Pro Ser Leu Ser Ser Glu Val Leu Val His Ile Tyr Ile 2370 2375 2380 Ser Asp Val Asn Asp Asn Pro Pro Val Phe Asn Gln Leu Ile Tyr Glu 2385 2390 2395 2400 Ser Tyr Val Ser Glu Leu Ala Pro Arg Gly His Phe Val Thr Cys Val 2405 2410 2415 Gln Ala Ser Asp Ala Asp Ser Ser Asp Phe Asp Arg Leu Glu Tyr Ser 2420 2425 2430 Ile Leu Ser Gly Asn Asp Arg Thr Ser Phe Leu Met Asp Ser Lys Ser 2435 2440 2445 Gly Val Ile Thr Leu Ser Asn His Arg Lys Gln Arg Met Glu Pro Leu 2450 2455 2460 Tyr Ser Leu Asn Val Ser Val Ser Asp Gly Leu Phe Thr Ser Thr Ala 2465 2470 2475 2480 Gln Val His Ile Arg Val Leu Gly Ala Asn Leu Tyr Ser Pro Ala Phe 2485 2490 2495 Ser Gln Ser Thr Tyr Val Ala Glu Val Arg Glu Asn Val Ala Ala Gly 2500 2505 2510 Thr Lys Val Ile His Val Arg Ala Thr Asp Gly Asp Pro Gly Thr Tyr 2515 2520 2525 Gly Gln Ile Ser Tyr Ala Ile Ile Asn Asp Phe Ala Lys Asp Arg Phe 2530 2535 2540 Leu Ile Asp Ser Asn Gly Gln Val Ile Thr Thr Glu Arg Leu Asp Arg 2545 2550 2555 2560 Glu Asn Pro Leu Glu Gly Asp Val Ser Ile Phe Val Arg Ala Leu Asp 2565 2570 2575 Gly Gly Gly Arg Thr Thr Phe Cys Thr Val Arg Val Ile Val Val Asp 2580 2585 2590 Glu Asn Asp Asn Ala Pro Gln Phe Met Thr Val Glu Tyr Arg Ala Ser 2595 2600 2605 Val Arg Ala Asp Val Gly Arg Gly His Leu Val Thr Gln Val Gln Ala 2610 2615 2620 Ile Asp Pro Asp Asp Gly Ala Asn Ser Arg Ile Thr Tyr Ser Leu Tyr 2625 2630 2635 2640 Ser Glu Ala Ser Val Ser Val Ala Asp Leu Leu Glu Ile Asp Pro Asp 2645 2650 2655 Asn Gly Trp Met Val Thr Lys Gly Asn Phe Asn Gln Leu Lys Asn Thr 2660 2665 2670 Val Leu Ser Phe Phe Val Lys Ala Val Asp Gly Gly Ile Pro Val Lys 2675 2680 2685 His Ser Leu Ile Pro Val Tyr Ile His Val Leu Pro Pro Glu Thr Phe 2690 2695 2700 Leu Pro Ser Phe Thr Gln Ser Gln Tyr Ser Phe Thr Ile Ala Glu Asp 2705 2710 2715 2720 Thr Ala Ile Gly Ser Thr Val Asp Thr Leu Arg Ile Leu Pro Ser Gln 2725 2730 2735 Asn Val Trp Phe Ser Thr Val Asn Gly Glu Arg Pro Glu Asn Asn Lys 2740 2745 2750 Gly Gly Val Phe Val Ile Glu Gln Glu Thr Gly Thr Ile Lys Leu Asp 2755 2760 2765 Lys Arg Leu Asp Arg Glu Thr Ser Pro Ala Phe His Phe Lys Val Ala 2770 2775 2780 Ala Thr Ile Pro Leu Asp Lys Val Asp Ile Val Phe Thr Val Asp Val 2785 2790 2795 2800 Asp Ile Lys Val Leu Asp Leu Asn Asp Asn Lys Pro Val Phe Glu Thr 2805 2810 2815 Ser Ser Tyr Asp Thr Ile Ile Met Glu Gly Met Pro Val Gly Thr Lys 2820 2825 2830 Leu Thr Gln Val Arg Ala Ile Asp Met Asp Trp Gly Ala Asn Gly Gln 2835 2840 2845 Val Thr Tyr Ser Leu His Ser Asp Ser Gln Pro Glu Lys Val Met Glu 2850 2855 2860 Ala Phe Asn Ile Asp Ser Asn Thr Gly Trp Ile Ser Thr Leu Lys Asp 2865 2870 2875 2880 Leu Asp His Glu Thr Asp Pro Thr Phe Thr Phe Ser Val Val Ala Ser 2885 2890 2895 Asp Leu Gly Glu Ala Phe Ser Leu Ser Ser Thr Ala Leu Val Ser Val 2900 2905 2910 Arg Val Thr Asp Ile Asn Asp Asn Ala Pro Val Phe Ala Gln Glu Val 2915 2920 2925 Tyr Arg Gly Asn Val Lys Glu Ser Asp Pro Pro Gly Glu Val Val Ala 2930 2935 2940 Val Leu Ser Thr Trp Asp Arg Asp Thr Ser Asp Val Asn Arg Gln Val 2945 2950 2955 2960 Ser Tyr His Ile Thr Gly Gly Asn Pro Arg Gly Arg Phe Ala Leu Gly 2965 2970 2975 Leu Val Gln Ser Glu Trp Lys Val Tyr Val Lys Arg Pro Leu Asp Arg 2980 2985 2990 Glu Glu Gln Asp Ile Tyr Phe Leu Asn Ile Thr Ala Thr Asp Gly Leu 2995 3000 3005 Phe Val Thr Gln Ala Met Val Glu Val Ser Val Ser Asp Val Asn Asp 3010 3015 3020 Asn Ser Pro Val Cys Asp Gln Val Ala Tyr Thr Ala Leu Leu Pro Glu 3025 3030 3035 3040 Asp Ile Pro Ser Asn Lys Ile Ile Leu Lys Val Ser Ala Lys Asp Ala 3045 3050 3055 Asp Ile Gly Ser Asn Gly Tyr Ile Arg Tyr Ser Leu Tyr Gly Ser Gly 3060 3065 3070 Asn Ser Glu Phe Phe Leu Asp Pro Glu Ser Gly Glu Leu Lys Thr Leu 3075 3080 3085 Ala Leu Leu Asp Arg Glu Arg Ile Pro Val Tyr Ser Leu Met Ala Lys 3090 3095 3100 Ala Thr Asp Gly Gly Gly Arg Phe Cys Gln Ser Asn Ile His Leu Ile 3105 3110 3115 3120 Leu Glu Asp Val Asn Asp Asn Pro Pro Val Phe Ser Ser Asp His Tyr 3125 3130 3135 Asn Thr Cys Val Tyr Glu Asn Thr Ala Thr Lys Ala Leu Leu Thr Arg 3140 3145 3150 Val Gln Ala Val Asp Pro Asp Ile Gly Ile Asn Arg Lys Val Val Tyr 3155 3160 3165 Ser Leu Ala Asp Ser Ala Gly Gly Val Phe Ser Ile Asp Ser Ser Ser 3170 3175 3180 Gly Ile Ile Ile Leu Glu Gln Pro Leu Asp Arg Glu Gln Gln Ser Ser 3185 3190 3195 3200 Tyr Asn Ile Ser Val Arg Ala Thr Asp Gln Ser Pro Gly Gln Ser Leu 3205 3210 3215 Ser Ser Leu Thr Thr Val Thr Ile Thr Val Leu Asp Ile Asn Asp Asn 3220 3225 3230 Pro Pro Val Phe Glu Arg Arg Asp Tyr Leu Val Thr Val Pro Glu Asp 3235 3240 3245 Thr Ser Pro Gly Thr Gln Val Leu Ala Val Phe Ala Thr Ser Lys Asp 3250 3255 3260 Ile Gly Thr Asn Ala Glu Ile Thr Tyr Leu Ile Arg Ser Gly Asn Glu 3265 3270 3275 3280 Gln Gly Lys Phe Lys Ile Asn Pro Lys Thr Gly Gly Ile Ser Val Ser 3285 3290 3295 Glu Val Leu Asp Tyr Glu Leu Cys Lys Arg Phe Tyr Leu Val Val Glu 3300 3305 3310 Ala Lys Asp Gly Gly Thr Pro Ala Leu Ser Ala Val Ala Thr Val Asn 3315 3320 3325 Ile Asn Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Ser Gln Asp 3330 3335 3340 Val Tyr Ser Ala Val Ile Ser Glu Asp Ala Leu Val Gly Asp Ser Val 3345 3350 3355 3360 Ile Leu Leu Ile Ala Glu Asp Val Asp Ser Gln Pro Asn Gly Gln Ile 3365 3370 3375 His Phe Ser Ile Val Asn Gly Asp Arg Asp Asn Glu Phe Thr Val Asp 3380 3385 3390 Pro Val Leu Gly Leu Val Lys Val Lys Lys Lys Leu Asp Arg Glu Arg 3395 3400 3405 Val Ser Gly Tyr Ser Leu Leu Val Gln Ala Val Asp Ser Gly Ile Pro 3410

3415 3420 Ala Met Ser Ser Thr Ala Thr Val Asn Ile Asp Ile Ser Asp Val Asn 3425 3430 3435 3440 Asp Asn Ser Pro Val Phe Thr Pro Ala Asn Tyr Thr Ala Val Ile Gln 3445 3450 3455 Glu Asn Lys Pro Val Gly Thr Ser Ile Leu Gln Leu Val Val Thr Asp 3460 3465 3470 Arg Asp Ser Phe His Asn Gly Pro Pro Phe Ser Phe Ser Ile Leu Ser 3475 3480 3485 Gly Asn Glu Glu Glu Glu Phe Val Leu Asp Pro His Gly Ile Leu Arg 3490 3495 3500 Ser Ala Val Val Phe Gln His Thr Glu Ser Leu Glu Tyr Val Leu Cys 3505 3510 3515 3520 Val Gln Ala Lys Asp Ser Gly Lys Pro Gln Gln Val Ser His Thr Tyr 3525 3530 3535 Ile Arg Val Arg Val Ile Glu Glu Ser Thr His Lys Pro Thr Ala Ile 3540 3545 3550 Pro Leu Glu Ile Phe Ile Val Thr Met Glu Asp Asp Phe Pro Gly Gly 3555 3560 3565 Val Ile Gly Lys Ile His Ala Thr Asp Gln Asp Met Tyr Asp Val Leu 3570 3575 3580 Thr Phe Ala Leu Lys Ser Glu Gln Lys Ser Leu Phe Lys Val Asn Ser 3585 3590 3595 3600 His Asp Gly Lys Ile Ile Ala Leu Gly Gly Leu Asp Ser Gly Lys Tyr 3605 3610 3615 Val Leu Asn Val Ser Val Ser Asp Gly Arg Phe Gln Val Pro Ile Asp 3620 3625 3630 Val Val Val His Val Glu Gln Leu Val His Glu Met Leu Gln Asn Thr 3635 3640 3645 Val Thr Ile Arg Phe Glu Asn Val Ser Pro Glu Asp Phe Val Gly Leu 3650 3655 3660 His Met His Gly Phe Arg Arg Thr Leu Arg Asn Ala Val Leu Thr Gln 3665 3670 3675 3680 Lys Gln Asp Ser Leu Arg Ile Ile Ser Ile Gln Pro Val Ala Gly Thr 3685 3690 3695 Asn Gln Leu Asp Met Leu Phe Ala Val Glu Met His Ser Ser Glu Phe 3700 3705 3710 Tyr Lys Pro Ala Tyr Leu Ile Gln Lys Leu Ser Asn Ala Arg Arg His 3715 3720 3725 Leu Glu Asn Ile Met Arg Ile Ser Ala Ile Leu Glu Lys Asn Cys Ser 3730 3735 3740 Gly Leu Asp Cys Gln Glu Gln His Cys Glu Gln Gly Leu Ser Leu Asp 3745 3750 3755 3760 Ser His Ala Leu Met Thr Tyr Ser Thr Ala Arg Ile Ser Phe Val Cys 3765 3770 3775 Pro Arg Phe Tyr Arg Asn Val Arg Cys Thr Cys Asn Gly Gly Leu Cys 3780 3785 3790 Pro Gly Ser Asn Asp Pro Cys Val Glu Lys Pro Cys Pro Gly Asp Met 3795 3800 3805 Gln Cys Val Gly Tyr Glu Ala Ser Arg Arg Pro Phe Leu Cys Gln Cys 3810 3815 3820 Pro Pro Gly Lys Leu Gly Glu Cys Ser Gly His Thr Ser Leu Ser Phe 3825 3830 3835 3840 Ala Gly Asn Ser Tyr Ile Lys Tyr Arg Leu Ser Glu 3845 3850 5 13758 DNA homo sapiens 5 atgggacact gtgtgggcac acggcctcct gcttgttgcc tcatcctcct gcttttcaag 60 cttttggcca ctgtctccca ggggctgcca gggactggac ccctgggctt ccacttcaca 120 cattccattt ataatgctac cgtgtatgag aactcagcag caaggaccta cgtcaacagc 180 cagagtagaa tgggcatcac cttaatagat ctatcctggg atatcaaata cagaatagtg 240 tccggagacg aggaaggctt tttcaaagca gaggaagtca tcattgcaga tttctgtttt 300 ctcagaataa gaactaaagg tggcaattct gccatattaa atagggaaat ccaggataat 360 tatttattga tagtaaaagg ttctgtcaga ggagaggatt tggaagcatg gaccaaagtg 420 aatatacagg ttttagatat gaatgatctg agacctttgt tttcacccac aacatactct 480 gttaccatag cagaaagcac acctctaagg actagtgttg cccaggtgac tgcaacagac 540 gcagatattg gttccaatgg agaattctac tactacttta aaaataaagt tgatctcttt 600 tcagttcacc ccacgagtgg tgtcatctcc ttaagtggtc gattaaatta tgatgaaaag 660 aataggtatg atctggaaat tttggctgtg gaccggggaa tgaaactgta tgggaacaat 720 ggagtgagca gtactgcaaa gctttatgtt cacattgagc gcataaatga acatgcccca 780 acaatccatg tagtcactca tgttcctttc tcgttggaaa aagagccaac atatgcagtg 840 gtgacagttg atgacttaga tgatggagcg aatggagaga tcgaatctgt ttccattgtg 900 gctggggatc ctttagatca gttcttcctg gctaaggaag gaaagtggtt gaatgagtac 960 aagattaagg agaggaagca gattgactgg gagagctttc cctatggcta caatctcact 1020 cttcaagcaa aagacaaggg atctcctcaa aaatgttcag cattaaaggc agtctacatt 1080 ggcaacccca caagagacac tgtccccatt agatttgaaa aagaagtgta cgatgtgagc 1140 ataagtgaat tttcccctcc tggtgtcgtg gttgctatag taaaattaag tcctgaaccg 1200 atagatgtgg aatacaaatt atctcctggt gaggatgcag tgtactttaa aattaatcct 1260 cggtcgggtc tgattgttac agcacggcca ctgaatactg ttaagaagga ggtttataaa 1320 ctggaggtga caaacaagga aggagattta aaagcacagg tcaccatcag catagaagat 1380 gcaaatgacc acaccccaga atttcagcaa ccactgtatg atgcttatgt gaatgaaagt 1440 gtcccagtgg gaaccagcgt tctaacagtt tcagcttctg ataaggataa aggagaaaat 1500 gggtacatca cctatagtat cgctagcctg aatttgttac catttgtcat taatcagttt 1560 acaggtgtta ttagcacaac tgaagaactg gattttgaat cctccccaga aatttacaga 1620 ttcattgtta gagcctctga ctggggttca ccataccgcc atgaaagtga ggtcaatgtg 1680 actattcgaa taggaaatgt caacgacaac agccctctct ttgaaaaagt ggcttgccag 1740 ggagttattt catatgactt tccagttggt ggtcacatca cagcagtctc agcgatcgat 1800 atcgatgaac ttgaacttgt aaagtacaaa atcatttctg gaaatgaact tggcttcttt 1860 tatttaaacc cagattctgg tgttttacag cttaaaaaat cactgacaaa ttctggcatt 1920 aaaaatggca attttgccct cagaattaca gcaactgatg gagagaatct tgcagacccc 1980 atgtctatta acatttcagt cctacatggg aaagtgtctt caaagagctt cagttgcaga 2040 gaaactcgtg tggctcaaaa gctggcagag aaactactca ttaaggcaaa agcaaatggg 2100 aaactgaatc tggaagatgg atttcttgac ttttattcaa ttaatagaca gggaccatat 2160 tttgacaagt cttttccttc tgatgtggct gtaaaggagg atctgccagt tggtgctaac 2220 attctgaaga ttaaagccta tgatgccgac tctggcttca atggaaaagt gctatttaca 2280 atatcagatg gaaatacgga tagttgcttt aatattgata tggagactgg gcagcttaaa 2340 gtccttatgc ccatggatcg agaacacaca gacctctatc tccttaatat caccatctat 2400 gacttaggta atccacagaa atcgtcatgg agactgctga ccatcaatgt ggaggatgct 2460 aatgacaata gcccagtttt tattcaagac agttactcag ttaacattct tgaaagttca 2520 ggcattggta ctgaaatcat tcaagtggaa gccagagaca aagacttagg ttctaatggt 2580 gaagtgactt actcagtctt gacagataca cagcagtttg ccatcaatag ctcaactgga 2640 atcgtttatg tagccgacca gttggaccgg gaatccaaag ccaattattc tttgaaaata 2700 gaagccaggg acaaggcaga gagtggtcag cagctgtttt cagttgtcac tcttaaagtt 2760 tttttagatg atgtcaatga ctgctcccca gctttcattc ccagtagcta tagtgtgaag 2820 gttcttgaag atctccctgt tggcactgtc attgcttggc ttgagaccca tgatccagat 2880 cttggactgg ggggtcaagt gcgctattct ttggtcaatg actataatgg gagatttgaa 2940 atagataaag caagtggtgc catccgcttg agcaaagagc ttgattatga gaaacagcag 3000 ttctataacc ttactgtgcg ggccaaagac aaagggcggc ctgtctctct gtcatctgtt 3060 tcctttgttg aggtggaagt ggtggatgtc aatgaaaacc tccacactcc ctatttccca 3120 gactttgctg ttgttggatc tgtaaaggaa aactcacgca ttggaacaag cgtgctgcag 3180 gtgactgctc gagatgaaga ctccggaagg gatggagaga tccagtactc catcagggat 3240 ggcagtggtc ttggaaggtt cagtatagac gacgagagtg gggtcatcac tgccgcagac 3300 attcttgatc gggagacaat ggggtcatac tggctaacag tgtatgccac agacaggggc 3360 gttgttccac tctactccac cattgaggtc tacattgaag ttgaagatgt gaatgacaat 3420 gccccgctga cctcagaacc tatatattat cctgttgtca tggaaaactc tccaaaggac 3480 gtatctgtca ttcagatcca ggctgaagat cctgactcca gttccaatga aaaactgaca 3540 tacaggatta caagtggaaa tcctcagaat ttttttgcca tcaatatcaa aacaggtctg 3600 attacaacaa cttcaaggaa attggatcga gaacagcagg cagaacattt tctggaggtg 3660 actgtgacag atggtggtcc ctctccaaaa cagtcaacca tttgggtggt ggttcaggtt 3720 ctagatgaaa atgacaacaa gccccagttc ccagagaagg tctaccagat caagctgcca 3780 gaacgtgacc gaaagaagag aggagaaccg atttacaggg cttttgcatt tgatagagat 3840 gagggcccca acgcagaaat ctcctacagt attgtggatg ggaatgatga cggaaagttc 3900 tttattgacc ctaaaactgg gatggtttct tctagaaagc agtttacagc aggcagttat 3960 gacatcctaa cgataaaggc agtggacaat gggcgcccac agaaatcctc cacggcccgc 4020 ctccacattg aatggattaa gaaaccaccc ccttcaccta taccattgac cttcgatgag 4080 ccgttttata acttcacagt catggaaagt gatagagtga ctgaaattgt aggggtggtg 4140 tctgtgcagc cagctaacac ccctctgtgg tttgacatag ttggggggaa ttttgacagc 4200 gcttttgatg cagagaaggg tgttgggaca attgtcatcg caaaaccttt ggatgcagag 4260 cagaggtcca tctataatat gagtgtggaa gtcaccgatg ggacaaatgt tgctgttact 4320 caggtattta tcaaagtgct ggataataat gataatggcc cagaattctc tcagccgaat 4380 tacgatgtga caatttccga ggatgtgctt ccagacacgg agatcctgca gattgaagcc 4440 acagatagag atgagaagca caagctgagc tacactgttc atagcagcat cgactccatc 4500 agcatgagaa aattccggat tgaccctagc actggcgtgc tctatactgc cgagaggctg 4560 gaccatgagg cccaggacaa gcacattctc aacataatgg tcagagatca ggagtttcct 4620 tatcgaagaa acttggcccg agtcattgtg aatgtggagg atgctaatga tcacagtcct 4680 tattttacca acccactgta tgaagcgtct gtgtttgaat ctgctgctct gggatcagct 4740 gttctgcaag tgacggctct ggacaaagac aaaggagaaa atgcagaact catatatacc 4800 atagaagcag ggaacactgg gaacatgttt aagatcgaac cggtcctagg catcatcacc 4860 atttgcaaag aaccagacat gacgacgatg ggtcagtttg tcctatccat caaagtcaca 4920 gatcagggat ccccgccaat gtctgctact gcaattgtgc gcatttccgt caccatgtct 4980 gacaattctc accccaagtt cattcacaaa gactaccaag cagaagtaaa tgaaaatgtt 5040 gacattggaa catcagtcat tctaatctct gccatcagtc aatctaccct catttatgaa 5100 gtcaaagatg gagacattaa tgggatcttt accataaatc catattctgg agtcatcacc 5160 actcagaagg ccctggatta tgagcgcaca tcctcttatc aactcatcat tcaggccacc 5220 aatatggcag gaatggcttc caatgctaca gtcaatattc agattgttga tgaaaatgat 5280 aatgccccag tttttctctt ttctcaatac tcaggcagcc taagtgaggc tgccccaatt 5340 aatagcattg tcaggagctt ggataacagc ccactggtga ttcgagccac agatgctgac 5400 agcaaccgga atgctctgct tgtgtatcag attgtggagt caacagcaaa aaagtttttc 5460 acggtggact ccagtacagg tgcaatcaga acaattgcca acctggacca tgaaaccatt 5520 gcccatttcc attttcatgt gcatgtgaga gacagtggta gcccccaact gactgcagag 5580 agtcccgttg aagtcaacat tgaggtgaca gatgtgaatg ataacccacc tgtttttact 5640 caggctgtgt ttgagactat cttacttcta cctacctatg ttggagtgga ggttctgaaa 5700 gttagtgcca cagatcctga ctctgaggta ccccctgaac tgacatacag cctaatggaa 5760 ggcagtttgg atcatttttt aattgactca aacagtggag tacttaccat aaaaaacaac 5820 aacctctcca aggatcacta catgctgata gttaaggtgt ctgatggaaa gttctacagt 5880 acctccatgg tcaccatcat ggttaaagaa gccatggaca gcggcctcca ctttacacaa 5940 agcttctatt ccacctcaat ctcagagaac aacactaaca taaccaaagt tgctattgtc 6000 aatgcagttg gaaatcgcct taatgagccc ttaaaataca gcatcttaaa cccaggaaat 6060 aagttcaaga taaaatctac ctcaggggtc attcagacga ctggagtccc ctttgaccgt 6120 gaagaacaag agttatatga gctggtggta gaagccagcc gtgagctgga ccatctgcgt 6180 gtggccagag tggtggtcag ggttaacatt gaagacataa atgacaattc tccagtcttt 6240 gtgggcctcc catactatgc tgctgttcaa gtggatgcgg aacccgggac tctgatttat 6300 caggtgacag ccattgacaa agataaaggt ccaaatggag aagtgaccta tgtcctgcag 6360 gatgactatg gccactttga aattaaccct aattcaggga atgttatttt aaaggaagca 6420 ttcaactctg acttgtccaa cattgagtat ggagtcacca tcctagccaa ggatggcgga 6480 aaaccttctt tgtctacatc tgtggagctt cccatcacta ttgtcaacaa agcaatgcct 6540 gtgtttgata agccctttta tacagcatct gtcaatgaag acatcagaat gaacacaccc 6600 atcctaagca tcaatgccac cagtccagaa ggccaaggca tcatatatat cattatcgat 6660 ggggaccctt ttaaacagtt taacattgac tttgacactg gggtcctgaa agttgttagc 6720 cctttggatt atgaagttac atctgcttac aagctgacaa taagagccag cgacgccctt 6780 actggtgcta gggctgaagt cactgttgac ttgctagtta atgatgtaaa tgacaacccc 6840 cctattttcg atcagcctac atacaataca acactatcag aagcatctct tattgggaca 6900 cctgttttac aagttgtctc tattgatgca gactcagaaa acaataaaat ggtacattat 6960 cagattgtcc aggataccta caatagcaca gattattttc acatagatag ctcaagtggc 7020 ttaatcctga cagcacgaat gctggaccat gagttagtac aacactgcac tttgaaagtc 7080 agatcaatag atagtggctt cccatcactg agcagtgagg ttctcgttca tatctacatc 7140 tctgatgtaa atgacaaccc tccagttttt aatcagctca tttatgagtc atatgtgagt 7200 gaattagccc cccggggcca ttttgtaacc tgtgtacaag cctctgatgc agacagctct 7260 gattttgacc ggttggaata tagcatttta tctgggaatg accggacgag ctttctgatg 7320 gacagcaaga gtggagttat cacattgtcc aaccatcgga agcagcggat ggagcctctg 7380 tacagtctca atgtgtctgt ctctgatggg ttgttcacca gcactgcaca ggtgcatatt 7440 agggtacttg gggctaactt gtacagccct gccttttcac aaagcacata cgtagctgag 7500 gtgagagaga acgtggctgc aggaacaaag gtaattcatg ttcgagccac agatggtgat 7560 ccagggactt atgggcagat cagctatgcc atcatcaatg actttgccaa ggatcgattc 7620 ctcatagaca gcaatgggca ggtcatcacc acagaaaggc tagaccggga aaaccctcta 7680 gaaggggatg ttagtatttt tgtgagggcc cttgatggtg gagggagaac aactttctgc 7740 actgtgagag tgattgttgt ggatgaaaat gacaatgctc cccagttcat gacagtggaa 7800 tatagagcca gtgtcagggc agatgttgga aggggccact tggtcactca agttcaagcc 7860 atagatcccg atgatggagc aaattcaagg attacttatt ccctctatag cgaggcctct 7920 gtttcagtgg ccgacctcct ggaaatcgat cctgacaatg gctggatggt cacaaagggt 7980 aattttaacc agctgaaaaa tacagtgctt tcgttctttg tcaaagcagt agatgggggc 8040 atcccagtaa agcactccct cattcctgtc tatatccacg tcttgccccc tgaaacgttc 8100 ttgccatcat tcacccagtc tcagtattcc tttaccattg cagaagatac agccattggg 8160 agtacagtgg acaccctgag gattttgccc agtcagaatg tctggttcag cacagttaat 8220 ggggaacggc cagaaaataa caaagggggc gtattcgtca tagaacagga aacaggcact 8280 attaagcttg acaaacgcct tgaccgtgaa accagcccag ctttccactt taaagtagca 8340 gccactatac ccctggacaa agtagacatt gtgtttactg tggatgtaga tatcaaggta 8400 ttggatttga atgacaacaa gccagtcttt gaaacttcaa gctatgacac cattataatg 8460 gaagggatgc ctgttggcac caaactcaca caagtgagag ctattgatat ggactgggga 8520 gccaatggac aagtcactta ctccctccac tcggattccc agcccgaaaa ggtaatggaa 8580 gcattcaata ttgacagcaa cacgggctgg atcagtacct tgaaggacct agatcacgag 8640 acagacccca cattcacctt ctctgtggtg gcctctgacc ttggagaggc attctctctt 8700 tcctccacgg ccttggtctc tgtcagagtg acagatataa atgacaatgc accagtcttc 8760 gcgcaggaag tgtaccgagg gaatgtgaag gagagcgacc caccgggcga ggtggtagcc 8820 gtcctcagca cctgggacag agacacatcc gacgttaatc gccaagtgag ctaccatatt 8880 acaggaggaa accctcgagg aaggtttgct ctgggcctgg tgcaaagtga gtggaaggtc 8940 tatgtgaaga ggcctctaga cagagaagaa caggacattt actttctcaa tatcactgcc 9000 actgatgggc tttttgtcac acaggccatg gtggaagtga gcgtcagtga tgtgaatgac 9060 aatagcccag tgtgtgatca ggttgcatat acagcattac ttcctgaaga cattccatca 9120 aataaaatca tcctgaaagt cagtgcaaag gatgctgata ttggatccaa tggatatata 9180 cgatactcac tctatggatc tggaaacagt gaattttttc tagatccaga aagtggcgag 9240 ttaaaaacct tggctctgtt ggaccgggag aggatccccg tgtacagcct gatggccaag 9300 gccactgacg ggggtggcag gttctgccag tccaacatcc acctaatcct ggaggatgtg 9360 aatgataacc cccctgtgtt ttcttctgac cactacaaca cctgtgtcta tgagaacaca 9420 gccaccaagg ctctgttgac cagagttcaa gccgtggacc ccgacattgg catcaatagg 9480 aaggtcgtgt actccctggc agactcagct ggtggggtct tctccattga cagctcatct 9540 ggcatcatca tcctggagca gccactggac cgtgagcagc agtcttcgta caacatcagc 9600 gtgcgggcca ctgaccagag tcctggacag tccctgtcct ctctcactac tgtcaccatc 9660 accgttctgg acattaatga caacccccct gtgtttgaga ggagggacta cctggtgacg 9720 gtgcctgagg acacctcccc tggcacccaa gtccttgctg tttttgccac cagcaaagat 9780 attggcacaa atgctgagat cacttatctc atccggtctg ggaacgaaca agggaaattt 9840 aagatcaacc ccaagacagg gggtatttct gtctctgaag tcctggacta tgaattatgc 9900 aaaaggtttt acctggtagt ggaagccaaa gatgggggca ccccagctct cagcgctgtg 9960 gccactgtca acatcaacct cacagatgtt aatgacaacc ctcccaagtt cagccaagac 10020 gtctacagtg cggttatcag tgaagacgcc ttggtgggag actctgtcat tttgctaata 10080 gcagaagatg tagacagcca gcccaacgga cagattcatt tttccattgt gaatggagat 10140 cgggacaatg aatttactgt agatcctgtc ttgggacttg tgaaagttaa gaagaaattg 10200 gaccgggaac gggtgtctgg atactctctg cttgtccagg ccgtagacag tggcattcct 10260 gcaatgtcat caactgcaac tgtcaacatt gatatttctg atgtgaatga caacagcccg 10320 gtgtttacac ctgccaacta tactgctgtg attcaggaaa ataagccagt gggcaccagc 10380 atcttgcagc tggtggtgac agacagagac tcctttcaca atgggcctcc cttttcattc 10440 tctattttgt cgggaaatga agaggaggag tttgtgttgg accctcatgg gatcttgcgg 10500 tcggctgtgg tcttccagca cacagagtct ctggaatacg tgttgtgtgt ccaggcaaag 10560 gattcaggca aaccccagca agtttctcac acttacatcc gcgtgcgagt cattgaggaa 10620 agcacccaca agcccacagc cattcccctg gaaattttca ttgtcaccat ggaggatgac 10680 tttcctggtg gggtcattgg gaagattcat gccacagatc aagacatgta tgatgtgctc 10740 acatttgccc tgaaatcgga gcagaaaagc ttatttaaag tgaacagtca cgatgggaaa 10800 atcatcgccc tgggaggcct ggacagcggc aagtatgtcc tgaatgtgtc tgtgagtgat 10860 ggtcgcttcc aggtacccat tgatgtggtc gtgcatgtgg agcagttggt gcatgagatg 10920 ctgcagaaca ctgtcaccat ccgctttgaa aatgtgtccc ctgaggactt cgtggggctg 10980 cacatgcatg ggttccggcg caccctgcgg aatgcagtcc tcacccagaa gcaggacagc 11040 ctgcgcatca tcagcatcca gcccgtggca ggcaccaacc aactggacat gctgtttgcg 11100 gtggagatgc acagcagcga gttctacaag ccagcctacc tgatccagaa gctgtccaat 11160 gctagaagac acctggagaa tatcatgcgc atctcagcca tcttggagaa gaactgctca 11220 gggctggact gtcaggaaca gcattgtgag caaggcttgt cactcgattc ccacgcgctc 11280 atgacctaca gcacggctcg catcagcttt gtgtgtccgc gtttctacag gaacgtgcgt 11340 tgcacctgca atggaggact gtgtccgggg tccaacgatc cttgtgtgga gaagccgtgt 11400 ccaggggaca tgcagtgtgt cggttatgaa gccagcagga gaccgttcct ctgccagtgt 11460 ccaccaggga agctcggaga gtgctcaggg cacacttctc tcagctttgc tggaaacagt 11520 tacatcaaat atcggctttc tgaaaatagc aaagaagagg atttcaaact agctctgcgt 11580 cttcgaacac tgcaaagcaa tgggattata atgtacacca gagcaaatcc ctgcataatt 11640 ctgaagattg tggatggcaa gctgtggttc cagctggact gcggcagcgg ccctggaatc 11700 ttgggcatct cgggccgtgc tgtcaacgac gggagctggc actcggtctt cctggagctc 11760 aaccgcaatt tcacgagcct gtccctggat gacagctacg tggagcggcg ccgggcgccc 11820 ctctacttcc agacgctgag cactgagagt agcatctact tcggcgccct ggtgcaagcg 11880 gataacatcc gcagcctgac tgacacgcgg gtcacgcagg tgctcagcgg cttccagggc 11940 tgcctggact cggtgatact gaataacaat gagctgccgc tgcagaacaa gcgcagcagc 12000 ttcgcggagg tggtgggcct gacggagctg aagctgggct gcgtgctcta tcccgacgcc 12060 tgcaagcgca gcccgtgcca gcacgggggc agctgcactg gcctgccatc ggggggctat 12120 cagtgtacct gtctctcaca gtttacgggg agaaactgtg aatctgagat tacagcctgc 12180 ttcccaaacc cctgccggaa tggaggatcc tgcgatccaa taggaaacac tttcatctgc 12240 aattgtaaag ctgggctcac tggagtcacg tgtgaggagg acatcaatga gtgcgaacga 12300 gaggagtgtg agaacggagg

ctcctgcgtg aacgtgttcg gctccttcct ctgcaactgc 12360 acgccgggct acgtgggcca gtactgcggg ctgcgccccg tggtggtacc caatatccag 12420 gctggccact cctacgtggg gaaggaggag ctcatcggca tcgccgtggt cctcttcgtc 12480 atcttcatcc tggtggttct cttcatagtc ttccgcaaga aggtcttccg caagaactac 12540 tcccgcaaca acatcacgct agtgcaggac ccggccaccg ccgccctgct taacaagagc 12600 aatggcatcc cgttccggaa cctgcgcggc agtggggacg gccgcaacgt ctaccaggag 12660 gtggggcccc cgcaggtccc cgtgcgcccc atggcctaca caccctgctt ccagagtgac 12720 tccaggagca acctggataa gatcgtggac gggctgggag gcgagcacca ggaaatgacc 12780 acgtttcacc ctgagtcgcc ccgcatcctg acagcccggc ggggcgtggt cgtgtgcagt 12840 gtggccccca acctccccgc cgtgtcaccc tgccgctccg actgcgactc catccggaag 12900 aatggctggg acgcgggaac tgagaacaaa ggggttgatg acccgggaga agtgacctgc 12960 tttgcaggta gtaataaagg cagcaactct gaagttcagt ccctcagctc cttccagtca 13020 gattctggtg acgacaatgc ctccatagtg actgtcattc agcttgtcaa caatgtagtt 13080 gacactatag agaatgaagt gtctgtcatg gaccaaggac agaactacaa ccgagcctat 13140 cactgggaca cctctgattg gatgccaggg gcccgcctgt cggacataga ggaagtgccc 13200 aactatgaga accaggatgg agggtctgca caccagggga gcacacggga gctggagagc 13260 gattactacc tgggtggtta tgacattgac agtgaatacc caccccctca tgaagaggag 13320 ttcttgagtc aggaccagct gcctcctcct ctcccggagg acttcccaga ccaatatgag 13380 gccctgccac cctcccagcc tgtctccctg gccagcacac tgagcccaga ctgcaggaga 13440 aggccccagt ttcatcctag ccagtatctc cctcctcacc cattccccaa cgaaacggat 13500 ttggtgggcc cgcctgccag ctgtgaattt agtacttttg ctgtgagcat gaaccagggc 13560 acagagccca caggcccagc agacagcgtg tctctgtcct tgcacaattc cagaggcacc 13620 tcatcctcgg atgtgtctgc caactgcggc tttgacgatt ccgaagtagc catgagtgac 13680 tacgagagcg tgggagagct cagcctcgcc agccttcaca ttccctttgt ggagactcag 13740 catcagactc aagtgtag 13758 6 4585 PRT homo sapiens 6 Met Gly His Cys Val Gly Thr Arg Pro Pro Ala Cys Cys Leu Ile Leu 1 5 10 15 Leu Leu Phe Lys Leu Leu Ala Thr Val Ser Gln Gly Leu Pro Gly Thr 20 25 30 Gly Pro Leu Gly Phe His Phe Thr His Ser Ile Tyr Asn Ala Thr Val 35 40 45 Tyr Glu Asn Ser Ala Ala Arg Thr Tyr Val Asn Ser Gln Ser Arg Met 50 55 60 Gly Ile Thr Leu Ile Asp Leu Ser Trp Asp Ile Lys Tyr Arg Ile Val 65 70 75 80 Ser Gly Asp Glu Glu Gly Phe Phe Lys Ala Glu Glu Val Ile Ile Ala 85 90 95 Asp Phe Cys Phe Leu Arg Ile Arg Thr Lys Gly Gly Asn Ser Ala Ile 100 105 110 Leu Asn Arg Glu Ile Gln Asp Asn Tyr Leu Leu Ile Val Lys Gly Ser 115 120 125 Val Arg Gly Glu Asp Leu Glu Ala Trp Thr Lys Val Asn Ile Gln Val 130 135 140 Leu Asp Met Asn Asp Leu Arg Pro Leu Phe Ser Pro Thr Thr Tyr Ser 145 150 155 160 Val Thr Ile Ala Glu Ser Thr Pro Leu Arg Thr Ser Val Ala Gln Val 165 170 175 Thr Ala Thr Asp Ala Asp Ile Gly Ser Asn Gly Glu Phe Tyr Tyr Tyr 180 185 190 Phe Lys Asn Lys Val Asp Leu Phe Ser Val His Pro Thr Ser Gly Val 195 200 205 Ile Ser Leu Ser Gly Arg Leu Asn Tyr Asp Glu Lys Asn Arg Tyr Asp 210 215 220 Leu Glu Ile Leu Ala Val Asp Arg Gly Met Lys Leu Tyr Gly Asn Asn 225 230 235 240 Gly Val Ser Ser Thr Ala Lys Leu Tyr Val His Ile Glu Arg Ile Asn 245 250 255 Glu His Ala Pro Thr Ile His Val Val Thr His Val Pro Phe Ser Leu 260 265 270 Glu Lys Glu Pro Thr Tyr Ala Val Val Thr Val Asp Asp Leu Asp Asp 275 280 285 Gly Ala Asn Gly Glu Ile Glu Ser Val Ser Ile Val Ala Gly Asp Pro 290 295 300 Leu Asp Gln Phe Phe Leu Ala Lys Glu Gly Lys Trp Leu Asn Glu Tyr 305 310 315 320 Lys Ile Lys Glu Arg Lys Gln Ile Asp Trp Glu Ser Phe Pro Tyr Gly 325 330 335 Tyr Asn Leu Thr Leu Gln Ala Lys Asp Lys Gly Ser Pro Gln Lys Cys 340 345 350 Ser Ala Leu Lys Ala Val Tyr Ile Gly Asn Pro Thr Arg Asp Thr Val 355 360 365 Pro Ile Arg Phe Glu Lys Glu Val Tyr Asp Val Ser Ile Ser Glu Phe 370 375 380 Ser Pro Pro Gly Val Val Val Ala Ile Val Lys Leu Ser Pro Glu Pro 385 390 395 400 Ile Asp Val Glu Tyr Lys Leu Ser Pro Gly Glu Asp Ala Val Tyr Phe 405 410 415 Lys Ile Asn Pro Arg Ser Gly Leu Ile Val Thr Ala Arg Pro Leu Asn 420 425 430 Thr Val Lys Lys Glu Val Tyr Lys Leu Glu Val Thr Asn Lys Glu Gly 435 440 445 Asp Leu Lys Ala Gln Val Thr Ile Ser Ile Glu Asp Ala Asn Asp His 450 455 460 Thr Pro Glu Phe Gln Gln Pro Leu Tyr Asp Ala Tyr Val Asn Glu Ser 465 470 475 480 Val Pro Val Gly Thr Ser Val Leu Thr Val Ser Ala Ser Asp Lys Asp 485 490 495 Lys Gly Glu Asn Gly Tyr Ile Thr Tyr Ser Ile Ala Ser Leu Asn Leu 500 505 510 Leu Pro Phe Val Ile Asn Gln Phe Thr Gly Val Ile Ser Thr Thr Glu 515 520 525 Glu Leu Asp Phe Glu Ser Ser Pro Glu Ile Tyr Arg Phe Ile Val Arg 530 535 540 Ala Ser Asp Trp Gly Ser Pro Tyr Arg His Glu Ser Glu Val Asn Val 545 550 555 560 Thr Ile Arg Ile Gly Asn Val Asn Asp Asn Ser Pro Leu Phe Glu Lys 565 570 575 Val Ala Cys Gln Gly Val Ile Ser Tyr Asp Phe Pro Val Gly Gly His 580 585 590 Ile Thr Ala Val Ser Ala Ile Asp Ile Asp Glu Leu Glu Leu Val Lys 595 600 605 Tyr Lys Ile Ile Ser Gly Asn Glu Leu Gly Phe Phe Tyr Leu Asn Pro 610 615 620 Asp Ser Gly Val Leu Gln Leu Lys Lys Ser Leu Thr Asn Ser Gly Ile 625 630 635 640 Lys Asn Gly Asn Phe Ala Leu Arg Ile Thr Ala Thr Asp Gly Glu Asn 645 650 655 Leu Ala Asp Pro Met Ser Ile Asn Ile Ser Val Leu His Gly Lys Val 660 665 670 Ser Ser Lys Ser Phe Ser Cys Arg Glu Thr Arg Val Ala Gln Lys Leu 675 680 685 Ala Glu Lys Leu Leu Ile Lys Ala Lys Ala Asn Gly Lys Leu Asn Leu 690 695 700 Glu Asp Gly Phe Leu Asp Phe Tyr Ser Ile Asn Arg Gln Gly Pro Tyr 705 710 715 720 Phe Asp Lys Ser Phe Pro Ser Asp Val Ala Val Lys Glu Asp Leu Pro 725 730 735 Val Gly Ala Asn Ile Leu Lys Ile Lys Ala Tyr Asp Ala Asp Ser Gly 740 745 750 Phe Asn Gly Lys Val Leu Phe Thr Ile Ser Asp Gly Asn Thr Asp Ser 755 760 765 Cys Phe Asn Ile Asp Met Glu Thr Gly Gln Leu Lys Val Leu Met Pro 770 775 780 Met Asp Arg Glu His Thr Asp Leu Tyr Leu Leu Asn Ile Thr Ile Tyr 785 790 795 800 Asp Leu Gly Asn Pro Gln Lys Ser Ser Trp Arg Leu Leu Thr Ile Asn 805 810 815 Val Glu Asp Ala Asn Asp Asn Ser Pro Val Phe Ile Gln Asp Ser Tyr 820 825 830 Ser Val Asn Ile Leu Glu Ser Ser Gly Ile Gly Thr Glu Ile Ile Gln 835 840 845 Val Glu Ala Arg Asp Lys Asp Leu Gly Ser Asn Gly Glu Val Thr Tyr 850 855 860 Ser Val Leu Thr Asp Thr Gln Gln Phe Ala Ile Asn Ser Ser Thr Gly 865 870 875 880 Ile Val Tyr Val Ala Asp Gln Leu Asp Arg Glu Ser Lys Ala Asn Tyr 885 890 895 Ser Leu Lys Ile Glu Ala Arg Asp Lys Ala Glu Ser Gly Gln Gln Leu 900 905 910 Phe Ser Val Val Thr Leu Lys Val Phe Leu Asp Asp Val Asn Asp Cys 915 920 925 Ser Pro Ala Phe Ile Pro Ser Ser Tyr Ser Val Lys Val Leu Glu Asp 930 935 940 Leu Pro Val Gly Thr Val Ile Ala Trp Leu Glu Thr His Asp Pro Asp 945 950 955 960 Leu Gly Leu Gly Gly Gln Val Arg Tyr Ser Leu Val Asn Asp Tyr Asn 965 970 975 Gly Arg Phe Glu Ile Asp Lys Ala Ser Gly Ala Ile Arg Leu Ser Lys 980 985 990 Glu Leu Asp Tyr Glu Lys Gln Gln Phe Tyr Asn Leu Thr Val Arg Ala 995 1000 1005 Lys Asp Lys Gly Arg Pro Val Ser Leu Ser Ser Val Ser Phe Val Glu 1010 1015 1020 Val Glu Val Val Asp Val Asn Glu Asn Leu His Thr Pro Tyr Phe Pro 1025 1030 1035 1040 Asp Phe Ala Val Val Gly Ser Val Lys Glu Asn Ser Arg Ile Gly Thr 1045 1050 1055 Ser Val Leu Gln Val Thr Ala Arg Asp Glu Asp Ser Gly Arg Asp Gly 1060 1065 1070 Glu Ile Gln Tyr Ser Ile Arg Asp Gly Ser Gly Leu Gly Arg Phe Ser 1075 1080 1085 Ile Asp Asp Glu Ser Gly Val Ile Thr Ala Ala Asp Ile Leu Asp Arg 1090 1095 1100 Glu Thr Met Gly Ser Tyr Trp Leu Thr Val Tyr Ala Thr Asp Arg Gly 1105 1110 1115 1120 Val Val Pro Leu Tyr Ser Thr Ile Glu Val Tyr Ile Glu Val Glu Asp 1125 1130 1135 Val Asn Asp Asn Ala Pro Leu Thr Ser Glu Pro Ile Tyr Tyr Pro Val 1140 1145 1150 Val Met Glu Asn Ser Pro Lys Asp Val Ser Val Ile Gln Ile Gln Ala 1155 1160 1165 Glu Asp Pro Asp Ser Ser Ser Asn Glu Lys Leu Thr Tyr Arg Ile Thr 1170 1175 1180 Ser Gly Asn Pro Gln Asn Phe Phe Ala Ile Asn Ile Lys Thr Gly Leu 1185 1190 1195 1200 Ile Thr Thr Thr Ser Arg Lys Leu Asp Arg Glu Gln Gln Ala Glu His 1205 1210 1215 Phe Leu Glu Val Thr Val Thr Asp Gly Gly Pro Ser Pro Lys Gln Ser 1220 1225 1230 Thr Ile Trp Val Val Val Gln Val Leu Asp Glu Asn Asp Asn Lys Pro 1235 1240 1245 Gln Phe Pro Glu Lys Val Tyr Gln Ile Lys Leu Pro Glu Arg Asp Arg 1250 1255 1260 Lys Lys Arg Gly Glu Pro Ile Tyr Arg Ala Phe Ala Phe Asp Arg Asp 1265 1270 1275 1280 Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Val Asp Gly Asn Asp 1285 1290 1295 Asp Gly Lys Phe Phe Ile Asp Pro Lys Thr Gly Met Val Ser Ser Arg 1300 1305 1310 Lys Gln Phe Thr Ala Gly Ser Tyr Asp Ile Leu Thr Ile Lys Ala Val 1315 1320 1325 Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr Ala Arg Leu His Ile Glu 1330 1335 1340 Trp Ile Lys Lys Pro Pro Pro Ser Pro Ile Pro Leu Thr Phe Asp Glu 1345 1350 1355 1360 Pro Phe Tyr Asn Phe Thr Val Met Glu Ser Asp Arg Val Thr Glu Ile 1365 1370 1375 Val Gly Val Val Ser Val Gln Pro Ala Asn Thr Pro Leu Trp Phe Asp 1380 1385 1390 Ile Val Gly Gly Asn Phe Asp Ser Ala Phe Asp Ala Glu Lys Gly Val 1395 1400 1405 Gly Thr Ile Val Ile Ala Lys Pro Leu Asp Ala Glu Gln Arg Ser Ile 1410 1415 1420 Tyr Asn Met Ser Val Glu Val Thr Asp Gly Thr Asn Val Ala Val Thr 1425 1430 1435 1440 Gln Val Phe Ile Lys Val Leu Asp Asn Asn Asp Asn Gly Pro Glu Phe 1445 1450 1455 Ser Gln Pro Asn Tyr Asp Val Thr Ile Ser Glu Asp Val Leu Pro Asp 1460 1465 1470 Thr Glu Ile Leu Gln Ile Glu Ala Thr Asp Arg Asp Glu Lys His Lys 1475 1480 1485 Leu Ser Tyr Thr Val His Ser Ser Ile Asp Ser Ile Ser Met Arg Lys 1490 1495 1500 Phe Arg Ile Asp Pro Ser Thr Gly Val Leu Tyr Thr Ala Glu Arg Leu 1505 1510 1515 1520 Asp His Glu Ala Gln Asp Lys His Ile Leu Asn Ile Met Val Arg Asp 1525 1530 1535 Gln Glu Phe Pro Tyr Arg Arg Asn Leu Ala Arg Val Ile Val Asn Val 1540 1545 1550 Glu Asp Ala Asn Asp His Ser Pro Tyr Phe Thr Asn Pro Leu Tyr Glu 1555 1560 1565 Ala Ser Val Phe Glu Ser Ala Ala Leu Gly Ser Ala Val Leu Gln Val 1570 1575 1580 Thr Ala Leu Asp Lys Asp Lys Gly Glu Asn Ala Glu Leu Ile Tyr Thr 1585 1590 1595 1600 Ile Glu Ala Gly Asn Thr Gly Asn Met Phe Lys Ile Glu Pro Val Leu 1605 1610 1615 Gly Ile Ile Thr Ile Cys Lys Glu Pro Asp Met Thr Thr Met Gly Gln 1620 1625 1630 Phe Val Leu Ser Ile Lys Val Thr Asp Gln Gly Ser Pro Pro Met Ser 1635 1640 1645 Ala Thr Ala Ile Val Arg Ile Ser Val Thr Met Ser Asp Asn Ser His 1650 1655 1660 Pro Lys Phe Ile His Lys Asp Tyr Gln Ala Glu Val Asn Glu Asn Val 1665 1670 1675 1680 Asp Ile Gly Thr Ser Val Ile Leu Ile Ser Ala Ile Ser Gln Ser Thr 1685 1690 1695 Leu Ile Tyr Glu Val Lys Asp Gly Asp Ile Asn Gly Ile Phe Thr Ile 1700 1705 1710 Asn Pro Tyr Ser Gly Val Ile Thr Thr Gln Lys Ala Leu Asp Tyr Glu 1715 1720 1725 Arg Thr Ser Ser Tyr Gln Leu Ile Ile Gln Ala Thr Asn Met Ala Gly 1730 1735 1740 Met Ala Ser Asn Ala Thr Val Asn Ile Gln Ile Val Asp Glu Asn Asp 1745 1750 1755 1760 Asn Ala Pro Val Phe Leu Phe Ser Gln Tyr Ser Gly Ser Leu Ser Glu 1765 1770 1775 Ala Ala Pro Ile Asn Ser Ile Val Arg Ser Leu Asp Asn Ser Pro Leu 1780 1785 1790 Val Ile Arg Ala Thr Asp Ala Asp Ser Asn Arg Asn Ala Leu Leu Val 1795 1800 1805 Tyr Gln Ile Val Glu Ser Thr Ala Lys Lys Phe Phe Thr Val Asp Ser 1810 1815 1820 Ser Thr Gly Ala Ile Arg Thr Ile Ala Asn Leu Asp His Glu Thr Ile 1825 1830 1835 1840 Ala His Phe His Phe His Val His Val Arg Asp Ser Gly Ser Pro Gln 1845 1850 1855 Leu Thr Ala Glu Ser Pro Val Glu Val Asn Ile Glu Val Thr Asp Val 1860 1865 1870 Asn Asp Asn Pro Pro Val Phe Thr Gln Ala Val Phe Glu Thr Ile Leu 1875 1880 1885 Leu Leu Pro Thr Tyr Val Gly Val Glu Val Leu Lys Val Ser Ala Thr 1890 1895 1900 Asp Pro Asp Ser Glu Val Pro Pro Glu Leu Thr Tyr Ser Leu Met Glu 1905 1910 1915 1920 Gly Ser Leu Asp His Phe Leu Ile Asp Ser Asn Ser Gly Val Leu Thr 1925 1930 1935 Ile Lys Asn Asn Asn Leu Ser Lys Asp His Tyr Met Leu Ile Val Lys 1940 1945 1950 Val Ser Asp Gly Lys Phe Tyr Ser Thr Ser Met Val Thr Ile Met Val 1955 1960 1965 Lys Glu Ala Met Asp Ser Gly Leu His Phe Thr Gln Ser Phe Tyr Ser 1970 1975 1980 Thr Ser Ile Ser Glu Asn Asn Thr Asn Ile Thr Lys Val Ala Ile Val 1985 1990 1995 2000 Asn Ala Val Gly Asn Arg Leu Asn Glu Pro Leu Lys Tyr Ser Ile Leu 2005 2010 2015 Asn Pro Gly Asn Lys Phe Lys Ile Lys Ser Thr Ser Gly Val Ile Gln 2020 2025 2030 Thr Thr Gly Val Pro Phe Asp Arg Glu Glu Gln Glu Leu Tyr Glu Leu 2035 2040 2045 Val Val Glu Ala Ser Arg Glu Leu Asp His Leu Arg Val Ala Arg Val 2050 2055 2060 Val Val Arg Val Asn Ile Glu Asp Ile Asn Asp Asn Ser Pro Val Phe 2065 2070 2075 2080 Val Gly Leu Pro Tyr Tyr Ala Ala Val Gln Val Asp Ala Glu Pro Gly 2085 2090 2095 Thr Leu Ile Tyr Gln Val Thr Ala Ile Asp Lys Asp Lys Gly Pro Asn 2100 2105 2110 Gly Glu Val Thr Tyr Val Leu Gln Asp Asp Tyr Gly His Phe Glu Ile 2115 2120 2125 Asn Pro Asn Ser Gly Asn Val Ile Leu Lys Glu Ala Phe Asn Ser Asp 2130 2135 2140 Leu Ser Asn Ile Glu Tyr Gly Val Thr Ile Leu Ala Lys Asp Gly Gly 2145 2150 2155 2160 Lys Pro Ser Leu Ser Thr Ser Val Glu Leu Pro Ile Thr Ile Val Asn 2165 2170 2175 Lys Ala Met Pro Val Phe Asp Lys Pro Phe Tyr Thr Ala Ser Val Asn

2180 2185 2190 Glu Asp Ile Arg Met Asn Thr Pro Ile Leu Ser Ile Asn Ala Thr Ser 2195 2200 2205 Pro Glu Gly Gln Gly Ile Ile Tyr Ile Ile Ile Asp Gly Asp Pro Phe 2210 2215 2220 Lys Gln Phe Asn Ile Asp Phe Asp Thr Gly Val Leu Lys Val Val Ser 2225 2230 2235 2240 Pro Leu Asp Tyr Glu Val Thr Ser Ala Tyr Lys Leu Thr Ile Arg Ala 2245 2250 2255 Ser Asp Ala Leu Thr Gly Ala Arg Ala Glu Val Thr Val Asp Leu Leu 2260 2265 2270 Val Asn Asp Val Asn Asp Asn Pro Pro Ile Phe Asp Gln Pro Thr Tyr 2275 2280 2285 Asn Thr Thr Leu Ser Glu Ala Ser Leu Ile Gly Thr Pro Val Leu Gln 2290 2295 2300 Val Val Ser Ile Asp Ala Asp Ser Glu Asn Asn Lys Met Val His Tyr 2305 2310 2315 2320 Gln Ile Val Gln Asp Thr Tyr Asn Ser Thr Asp Tyr Phe His Ile Asp 2325 2330 2335 Ser Ser Ser Gly Leu Ile Leu Thr Ala Arg Met Leu Asp His Glu Leu 2340 2345 2350 Val Gln His Cys Thr Leu Lys Val Arg Ser Ile Asp Ser Gly Phe Pro 2355 2360 2365 Ser Leu Ser Ser Glu Val Leu Val His Ile Tyr Ile Ser Asp Val Asn 2370 2375 2380 Asp Asn Pro Pro Val Phe Asn Gln Leu Ile Tyr Glu Ser Tyr Val Ser 2385 2390 2395 2400 Glu Leu Ala Pro Arg Gly His Phe Val Thr Cys Val Gln Ala Ser Asp 2405 2410 2415 Ala Asp Ser Ser Asp Phe Asp Arg Leu Glu Tyr Ser Ile Leu Ser Gly 2420 2425 2430 Asn Asp Arg Thr Ser Phe Leu Met Asp Ser Lys Ser Gly Val Ile Thr 2435 2440 2445 Leu Ser Asn His Arg Lys Gln Arg Met Glu Pro Leu Tyr Ser Leu Asn 2450 2455 2460 Val Ser Val Ser Asp Gly Leu Phe Thr Ser Thr Ala Gln Val His Ile 2465 2470 2475 2480 Arg Val Leu Gly Ala Asn Leu Tyr Ser Pro Ala Phe Ser Gln Ser Thr 2485 2490 2495 Tyr Val Ala Glu Val Arg Glu Asn Val Ala Ala Gly Thr Lys Val Ile 2500 2505 2510 His Val Arg Ala Thr Asp Gly Asp Pro Gly Thr Tyr Gly Gln Ile Ser 2515 2520 2525 Tyr Ala Ile Ile Asn Asp Phe Ala Lys Asp Arg Phe Leu Ile Asp Ser 2530 2535 2540 Asn Gly Gln Val Ile Thr Thr Glu Arg Leu Asp Arg Glu Asn Pro Leu 2545 2550 2555 2560 Glu Gly Asp Val Ser Ile Phe Val Arg Ala Leu Asp Gly Gly Gly Arg 2565 2570 2575 Thr Thr Phe Cys Thr Val Arg Val Ile Val Val Asp Glu Asn Asp Asn 2580 2585 2590 Ala Pro Gln Phe Met Thr Val Glu Tyr Arg Ala Ser Val Arg Ala Asp 2595 2600 2605 Val Gly Arg Gly His Leu Val Thr Gln Val Gln Ala Ile Asp Pro Asp 2610 2615 2620 Asp Gly Ala Asn Ser Arg Ile Thr Tyr Ser Leu Tyr Ser Glu Ala Ser 2625 2630 2635 2640 Val Ser Val Ala Asp Leu Leu Glu Ile Asp Pro Asp Asn Gly Trp Met 2645 2650 2655 Val Thr Lys Gly Asn Phe Asn Gln Leu Lys Asn Thr Val Leu Ser Phe 2660 2665 2670 Phe Val Lys Ala Val Asp Gly Gly Ile Pro Val Lys His Ser Leu Ile 2675 2680 2685 Pro Val Tyr Ile His Val Leu Pro Pro Glu Thr Phe Leu Pro Ser Phe 2690 2695 2700 Thr Gln Ser Gln Tyr Ser Phe Thr Ile Ala Glu Asp Thr Ala Ile Gly 2705 2710 2715 2720 Ser Thr Val Asp Thr Leu Arg Ile Leu Pro Ser Gln Asn Val Trp Phe 2725 2730 2735 Ser Thr Val Asn Gly Glu Arg Pro Glu Asn Asn Lys Gly Gly Val Phe 2740 2745 2750 Val Ile Glu Gln Glu Thr Gly Thr Ile Lys Leu Asp Lys Arg Leu Asp 2755 2760 2765 Arg Glu Thr Ser Pro Ala Phe His Phe Lys Val Ala Ala Thr Ile Pro 2770 2775 2780 Leu Asp Lys Val Asp Ile Val Phe Thr Val Asp Val Asp Ile Lys Val 2785 2790 2795 2800 Leu Asp Leu Asn Asp Asn Lys Pro Val Phe Glu Thr Ser Ser Tyr Asp 2805 2810 2815 Thr Ile Ile Met Glu Gly Met Pro Val Gly Thr Lys Leu Thr Gln Val 2820 2825 2830 Arg Ala Ile Asp Met Asp Trp Gly Ala Asn Gly Gln Val Thr Tyr Ser 2835 2840 2845 Leu His Ser Asp Ser Gln Pro Glu Lys Val Met Glu Ala Phe Asn Ile 2850 2855 2860 Asp Ser Asn Thr Gly Trp Ile Ser Thr Leu Lys Asp Leu Asp His Glu 2865 2870 2875 2880 Thr Asp Pro Thr Phe Thr Phe Ser Val Val Ala Ser Asp Leu Gly Glu 2885 2890 2895 Ala Phe Ser Leu Ser Ser Thr Ala Leu Val Ser Val Arg Val Thr Asp 2900 2905 2910 Ile Asn Asp Asn Ala Pro Val Phe Ala Gln Glu Val Tyr Arg Gly Asn 2915 2920 2925 Val Lys Glu Ser Asp Pro Pro Gly Glu Val Val Ala Val Leu Ser Thr 2930 2935 2940 Trp Asp Arg Asp Thr Ser Asp Val Asn Arg Gln Val Ser Tyr His Ile 2945 2950 2955 2960 Thr Gly Gly Asn Pro Arg Gly Arg Phe Ala Leu Gly Leu Val Gln Ser 2965 2970 2975 Glu Trp Lys Val Tyr Val Lys Arg Pro Leu Asp Arg Glu Glu Gln Asp 2980 2985 2990 Ile Tyr Phe Leu Asn Ile Thr Ala Thr Asp Gly Leu Phe Val Thr Gln 2995 3000 3005 Ala Met Val Glu Val Ser Val Ser Asp Val Asn Asp Asn Ser Pro Val 3010 3015 3020 Cys Asp Gln Val Ala Tyr Thr Ala Leu Leu Pro Glu Asp Ile Pro Ser 3025 3030 3035 3040 Asn Lys Ile Ile Leu Lys Val Ser Ala Lys Asp Ala Asp Ile Gly Ser 3045 3050 3055 Asn Gly Tyr Ile Arg Tyr Ser Leu Tyr Gly Ser Gly Asn Ser Glu Phe 3060 3065 3070 Phe Leu Asp Pro Glu Ser Gly Glu Leu Lys Thr Leu Ala Leu Leu Asp 3075 3080 3085 Arg Glu Arg Ile Pro Val Tyr Ser Leu Met Ala Lys Ala Thr Asp Gly 3090 3095 3100 Gly Gly Arg Phe Cys Gln Ser Asn Ile His Leu Ile Leu Glu Asp Val 3105 3110 3115 3120 Asn Asp Asn Pro Pro Val Phe Ser Ser Asp His Tyr Asn Thr Cys Val 3125 3130 3135 Tyr Glu Asn Thr Ala Thr Lys Ala Leu Leu Thr Arg Val Gln Ala Val 3140 3145 3150 Asp Pro Asp Ile Gly Ile Asn Arg Lys Val Val Tyr Ser Leu Ala Asp 3155 3160 3165 Ser Ala Gly Gly Val Phe Ser Ile Asp Ser Ser Ser Gly Ile Ile Ile 3170 3175 3180 Leu Glu Gln Pro Leu Asp Arg Glu Gln Gln Ser Ser Tyr Asn Ile Ser 3185 3190 3195 3200 Val Arg Ala Thr Asp Gln Ser Pro Gly Gln Ser Leu Ser Ser Leu Thr 3205 3210 3215 Thr Val Thr Ile Thr Val Leu Asp Ile Asn Asp Asn Pro Pro Val Phe 3220 3225 3230 Glu Arg Arg Asp Tyr Leu Val Thr Val Pro Glu Asp Thr Ser Pro Gly 3235 3240 3245 Thr Gln Val Leu Ala Val Phe Ala Thr Ser Lys Asp Ile Gly Thr Asn 3250 3255 3260 Ala Glu Ile Thr Tyr Leu Ile Arg Ser Gly Asn Glu Gln Gly Lys Phe 3265 3270 3275 3280 Lys Ile Asn Pro Lys Thr Gly Gly Ile Ser Val Ser Glu Val Leu Asp 3285 3290 3295 Tyr Glu Leu Cys Lys Arg Phe Tyr Leu Val Val Glu Ala Lys Asp Gly 3300 3305 3310 Gly Thr Pro Ala Leu Ser Ala Val Ala Thr Val Asn Ile Asn Leu Thr 3315 3320 3325 Asp Val Asn Asp Asn Pro Pro Lys Phe Ser Gln Asp Val Tyr Ser Ala 3330 3335 3340 Val Ile Ser Glu Asp Ala Leu Val Gly Asp Ser Val Ile Leu Leu Ile 3345 3350 3355 3360 Ala Glu Asp Val Asp Ser Gln Pro Asn Gly Gln Ile His Phe Ser Ile 3365 3370 3375 Val Asn Gly Asp Arg Asp Asn Glu Phe Thr Val Asp Pro Val Leu Gly 3380 3385 3390 Leu Val Lys Val Lys Lys Lys Leu Asp Arg Glu Arg Val Ser Gly Tyr 3395 3400 3405 Ser Leu Leu Val Gln Ala Val Asp Ser Gly Ile Pro Ala Met Ser Ser 3410 3415 3420 Thr Ala Thr Val Asn Ile Asp Ile Ser Asp Val Asn Asp Asn Ser Pro 3425 3430 3435 3440 Val Phe Thr Pro Ala Asn Tyr Thr Ala Val Ile Gln Glu Asn Lys Pro 3445 3450 3455 Val Gly Thr Ser Ile Leu Gln Leu Val Val Thr Asp Arg Asp Ser Phe 3460 3465 3470 His Asn Gly Pro Pro Phe Ser Phe Ser Ile Leu Ser Gly Asn Glu Glu 3475 3480 3485 Glu Glu Phe Val Leu Asp Pro His Gly Ile Leu Arg Ser Ala Val Val 3490 3495 3500 Phe Gln His Thr Glu Ser Leu Glu Tyr Val Leu Cys Val Gln Ala Lys 3505 3510 3515 3520 Asp Ser Gly Lys Pro Gln Gln Val Ser His Thr Tyr Ile Arg Val Arg 3525 3530 3535 Val Ile Glu Glu Ser Thr His Lys Pro Thr Ala Ile Pro Leu Glu Ile 3540 3545 3550 Phe Ile Val Thr Met Glu Asp Asp Phe Pro Gly Gly Val Ile Gly Lys 3555 3560 3565 Ile His Ala Thr Asp Gln Asp Met Tyr Asp Val Leu Thr Phe Ala Leu 3570 3575 3580 Lys Ser Glu Gln Lys Ser Leu Phe Lys Val Asn Ser His Asp Gly Lys 3585 3590 3595 3600 Ile Ile Ala Leu Gly Gly Leu Asp Ser Gly Lys Tyr Val Leu Asn Val 3605 3610 3615 Ser Val Ser Asp Gly Arg Phe Gln Val Pro Ile Asp Val Val Val His 3620 3625 3630 Val Glu Gln Leu Val His Glu Met Leu Gln Asn Thr Val Thr Ile Arg 3635 3640 3645 Phe Glu Asn Val Ser Pro Glu Asp Phe Val Gly Leu His Met His Gly 3650 3655 3660 Phe Arg Arg Thr Leu Arg Asn Ala Val Leu Thr Gln Lys Gln Asp Ser 3665 3670 3675 3680 Leu Arg Ile Ile Ser Ile Gln Pro Val Ala Gly Thr Asn Gln Leu Asp 3685 3690 3695 Met Leu Phe Ala Val Glu Met His Ser Ser Glu Phe Tyr Lys Pro Ala 3700 3705 3710 Tyr Leu Ile Gln Lys Leu Ser Asn Ala Arg Arg His Leu Glu Asn Ile 3715 3720 3725 Met Arg Ile Ser Ala Ile Leu Glu Lys Asn Cys Ser Gly Leu Asp Cys 3730 3735 3740 Gln Glu Gln His Cys Glu Gln Gly Leu Ser Leu Asp Ser His Ala Leu 3745 3750 3755 3760 Met Thr Tyr Ser Thr Ala Arg Ile Ser Phe Val Cys Pro Arg Phe Tyr 3765 3770 3775 Arg Asn Val Arg Cys Thr Cys Asn Gly Gly Leu Cys Pro Gly Ser Asn 3780 3785 3790 Asp Pro Cys Val Glu Lys Pro Cys Pro Gly Asp Met Gln Cys Val Gly 3795 3800 3805 Tyr Glu Ala Ser Arg Arg Pro Phe Leu Cys Gln Cys Pro Pro Gly Lys 3810 3815 3820 Leu Gly Glu Cys Ser Gly His Thr Ser Leu Ser Phe Ala Gly Asn Ser 3825 3830 3835 3840 Tyr Ile Lys Tyr Arg Leu Ser Glu Asn Ser Lys Glu Glu Asp Phe Lys 3845 3850 3855 Leu Ala Leu Arg Leu Arg Thr Leu Gln Ser Asn Gly Ile Ile Met Tyr 3860 3865 3870 Thr Arg Ala Asn Pro Cys Ile Ile Leu Lys Ile Val Asp Gly Lys Leu 3875 3880 3885 Trp Phe Gln Leu Asp Cys Gly Ser Gly Pro Gly Ile Leu Gly Ile Ser 3890 3895 3900 Gly Arg Ala Val Asn Asp Gly Ser Trp His Ser Val Phe Leu Glu Leu 3905 3910 3915 3920 Asn Arg Asn Phe Thr Ser Leu Ser Leu Asp Asp Ser Tyr Val Glu Arg 3925 3930 3935 Arg Arg Ala Pro Leu Tyr Phe Gln Thr Leu Ser Thr Glu Ser Ser Ile 3940 3945 3950 Tyr Phe Gly Ala Leu Val Gln Ala Asp Asn Ile Arg Ser Leu Thr Asp 3955 3960 3965 Thr Arg Val Thr Gln Val Leu Ser Gly Phe Gln Gly Cys Leu Asp Ser 3970 3975 3980 Val Ile Leu Asn Asn Asn Glu Leu Pro Leu Gln Asn Lys Arg Ser Ser 3985 3990 3995 4000 Phe Ala Glu Val Val Gly Leu Thr Glu Leu Lys Leu Gly Cys Val Leu 4005 4010 4015 Tyr Pro Asp Ala Cys Lys Arg Ser Pro Cys Gln His Gly Gly Ser Cys 4020 4025 4030 Thr Gly Leu Pro Ser Gly Gly Tyr Gln Cys Thr Cys Leu Ser Gln Phe 4035 4040 4045 Thr Gly Arg Asn Cys Glu Ser Glu Ile Thr Ala Cys Phe Pro Asn Pro 4050 4055 4060 Cys Arg Asn Gly Gly Ser Cys Asp Pro Ile Gly Asn Thr Phe Ile Cys 4065 4070 4075 4080 Asn Cys Lys Ala Gly Leu Thr Gly Val Thr Cys Glu Glu Asp Ile Asn 4085 4090 4095 Glu Cys Glu Arg Glu Glu Cys Glu Asn Gly Gly Ser Cys Val Asn Val 4100 4105 4110 Phe Gly Ser Phe Leu Cys Asn Cys Thr Pro Gly Tyr Val Gly Gln Tyr 4115 4120 4125 Cys Gly Leu Arg Pro Val Val Val Pro Asn Ile Gln Ala Gly His Ser 4130 4135 4140 Tyr Val Gly Lys Glu Glu Leu Ile Gly Ile Ala Val Val Leu Phe Val 4145 4150 4155 4160 Ile Phe Ile Leu Val Val Leu Phe Ile Val Phe Arg Lys Lys Val Phe 4165 4170 4175 Arg Lys Asn Tyr Ser Arg Asn Asn Ile Thr Leu Val Gln Asp Pro Ala 4180 4185 4190 Thr Ala Ala Leu Leu Asn Lys Ser Asn Gly Ile Pro Phe Arg Asn Leu 4195 4200 4205 Arg Gly Ser Gly Asp Gly Arg Asn Val Tyr Gln Glu Val Gly Pro Pro 4210 4215 4220 Gln Val Pro Val Arg Pro Met Ala Tyr Thr Pro Cys Phe Gln Ser Asp 4225 4230 4235 4240 Ser Arg Ser Asn Leu Asp Lys Ile Val Asp Gly Leu Gly Gly Glu His 4245 4250 4255 Gln Glu Met Thr Thr Phe His Pro Glu Ser Pro Arg Ile Leu Thr Ala 4260 4265 4270 Arg Arg Gly Val Val Val Cys Ser Val Ala Pro Asn Leu Pro Ala Val 4275 4280 4285 Ser Pro Cys Arg Ser Asp Cys Asp Ser Ile Arg Lys Asn Gly Trp Asp 4290 4295 4300 Ala Gly Thr Glu Asn Lys Gly Val Asp Asp Pro Gly Glu Val Thr Cys 4305 4310 4315 4320 Phe Ala Gly Ser Asn Lys Gly Ser Asn Ser Glu Val Gln Ser Leu Ser 4325 4330 4335 Ser Phe Gln Ser Asp Ser Gly Asp Asp Asn Ala Ser Ile Val Thr Val 4340 4345 4350 Ile Gln Leu Val Asn Asn Val Val Asp Thr Ile Glu Asn Glu Val Ser 4355 4360 4365 Val Met Asp Gln Gly Gln Asn Tyr Asn Arg Ala Tyr His Trp Asp Thr 4370 4375 4380 Ser Asp Trp Met Pro Gly Ala Arg Leu Ser Asp Ile Glu Glu Val Pro 4385 4390 4395 4400 Asn Tyr Glu Asn Gln Asp Gly Gly Ser Ala His Gln Gly Ser Thr Arg 4405 4410 4415 Glu Leu Glu Ser Asp Tyr Tyr Leu Gly Gly Tyr Asp Ile Asp Ser Glu 4420 4425 4430 Tyr Pro Pro Pro His Glu Glu Glu Phe Leu Ser Gln Asp Gln Leu Pro 4435 4440 4445 Pro Pro Leu Pro Glu Asp Phe Pro Asp Gln Tyr Glu Ala Leu Pro Pro 4450 4455 4460 Ser Gln Pro Val Ser Leu Ala Ser Thr Leu Ser Pro Asp Cys Arg Arg 4465 4470 4475 4480 Arg Pro Gln Phe His Pro Ser Gln Tyr Leu Pro Pro His Pro Phe Pro 4485 4490 4495 Asn Glu Thr Asp Leu Val Gly Pro Pro Ala Ser Cys Glu Phe Ser Thr 4500 4505 4510 Phe Ala Val Ser Met Asn Gln Gly Thr Glu Pro Thr Gly Pro Ala Asp 4515 4520 4525 Ser Val Ser Leu Ser Leu His Asn Ser Arg Gly Thr Ser Ser Ser Asp 4530 4535 4540 Val Ser Ala Asn Cys Gly Phe Asp Asp Ser Glu Val Ala Met Ser Asp 4545 4550 4555 4560 Tyr Glu Ser Val Gly Glu Leu Ser Leu Ala Ser Leu His Ile Pro Phe 4565 4570 4575 Val Glu Thr Gln His Gln Thr Gln Val 4580 4585 7 13767 DNA homo sapiens 7 atggatataa ttatgggaca ctgtgtgggc acacggcctc

ctgcttgttg cctcatcctc 60 ctgcttttca agcttttggc cactgtctcc caggggctgc cagggactgg acccctgggc 120 ttccacttca cacattccat ttataatgct accgtgtatg agaactcagc agcaaggacc 180 tacgtcaaca gccagagtag aatgggcatc accttaatag atctatcctg ggatatcaaa 240 tacagaatag tgtccggaga cgaggaaggc tttttcaaag cagaggaagt catcattgca 300 gatttctgtt ttctcagaat aagaactaaa ggtggcaatt ctgccatatt aaatagggaa 360 atccaggata attatttatt gatagtaaaa ggttctgtca gaggagagga tttggaagca 420 tggaccaaag tgaatataca ggttttagat atgaatgatc tgagaccttt gttttcaccc 480 acaacatact ctgttaccat agcagaaagc acacctctaa ggactagtgt tgcccaggtg 540 actgcaacag acgcagatat tggttccaat ggagaattct actactactt taaaaataaa 600 gttgatctct tttcagttca ccccacgagt ggtgtcatct ccttaagtgg tcgattaaat 660 tatgatgaaa agaataggta tgatctggaa attttggctg tggaccgggg aatgaaactg 720 tatgggaaca atggagtgag cagtactgca aagctttatg ttcacattga gcgcataaat 780 gaacatgccc caacaatcca tgtagtcact catgttcctt tctcgttgga aaaagagcca 840 acatatgcag tggtgacagt tgatgactta gatgatggag cgaatggaga gatcgaatct 900 gtttccattg tggctgggga tcctttagat cagttcttcc tggctaagga aggaaagtgg 960 ttgaatgagt acaagattaa ggagaggaag cagattgact gggagagctt tccctatggc 1020 tacaatctca ctcttcaagc aaaagacaag ggatctcctc aaaaatgttc agcattaaag 1080 gcagtctaca ttggcaaccc cacaagagac actgtcccca ttagatttga aaaagaagtg 1140 tacgatgtga gcataagtga attttcccct cctggtgtcg tggttgctat agtaaaatta 1200 agtcctgaac cgatagatgt ggaatacaaa ttatctcctg gtgaggatgc agtgtacttt 1260 aaaattaatc ctcggtcggg tctgattgtt acagcacggc cactgaatac tgttaagaag 1320 gaggtttata aactggaggt gacaaacaag gaaggagatt taaaagcaca ggtcaccatc 1380 agcatagaag atgcaaatga ccacacccca gaatttcagc aaccactgta tgatgcttat 1440 gtgaatgaaa gtgtcccagt gggaaccagc gttctaacag tttcagcttc tgataaggat 1500 aaaggagaaa atgggtacat cacctatagt atcgctagcc tgaatttgtt accatttgtc 1560 attaatcagt ttacaggtgt tattagcaca actgaagaac tggattttga atcctcccca 1620 gaaatttaca gattcattgt tagagcctct gactggggtt caccataccg ccatgaaagt 1680 gaggtcaatg tgactattcg aataggaaat gtcaacgaca acagccctct ctttgaaaaa 1740 gtggcttgcc agggagttat ttcatatgac tttccagttg gtggtcacat cacagcagtc 1800 tcagcgatcg atatcgatga acttgaactt gtaaagtaca aaatcatttc tggaaatgaa 1860 cttggcttct tttatttaaa cccagattct ggtgttttac agcttaaaaa atcactgaca 1920 aattctggca ttaaaaatgg caattttgcc ctcagaatta cagcaactga tggagagaat 1980 cttgcagacc ccatgtctat taacatttca gtcctacatg ggaaagtgtc ttcaaagagc 2040 ttcagttgca gagaaactcg tgtggctcaa aagctggcag agaaactact cattaaggca 2100 aaagcaaatg ggaaactgaa tctggaagat ggatttcttg acttttattc aattaataga 2160 cagggaccat attttgacaa gtcttttcct tctgatgtgg ctgtaaagga ggatctgcca 2220 gttggtgcta acattctgaa gattaaagcc tatgatgccg actctggctt caatggaaaa 2280 gtgctattta caatatcaga tggaaatacg gatagttgct ttaatattga tatggagact 2340 gggcagctta aagtccttat gcccatggat cgagaacaca cagacctcta tctccttaat 2400 atcaccatct atgacttagg taatccacag aaatcgtcat ggagactgct gaccatcaat 2460 gtggaggatg ctaatgacaa tagcccagtt tttattcaag acagttactc agttaacatt 2520 cttgaaagtt caggcattgg tactgaaatc attcaagtgg aagccagaga caaagactta 2580 ggttctaatg gtgaagtgac ttactcagtc ttgacagata cacagcagtt tgccatcaat 2640 agctcaactg gaatcgttta tgtagccgac cagttggacc gggaatccaa agccaattat 2700 tctttgaaaa tagaagccag ggacaaggca gagagtggtc agcagctgtt ttcagttgtc 2760 actcttaaag tttttttaga tgatgtcaat gactgctccc cagctttcat tcccagtagc 2820 tatagtgtga aggttcttga agatctccct gttggcactg tcattgcttg gcttgagacc 2880 catgatccag atcttggact ggggggtcaa gtgcgctatt ctttggtcaa tgactataat 2940 gggagatttg aaatagataa agcaagtggt gccatccgct tgagcaaaga gcttgattat 3000 gagaaacagc agttctataa ccttactgtg cgggccaaag acaaagggcg gcctgtctct 3060 ctgtcatctg tttcctttgt tgaggtggaa gtggtggatg tcaatgaaaa cctccacact 3120 ccctatttcc cagactttgc tgttgttgga tctgtaaagg aaaactcacg cattggaaca 3180 agcgtgctgc aggtgactgc tcgagatgaa gactccggaa gggatggaga gatccagtac 3240 tccatcaggg atggcagtgg tcttggaagg ttcagtatag acgacgagag tggggtcatc 3300 actgccgcag acattcttga tcgggagaca atggggtcat actggctaac agtgtatgcc 3360 acagacaggg gcgttgttcc actctactcc accattgagg tctacattga agttgaagat 3420 gtgaatgaca atgccccgct gacctcagaa cctatatatt atcctgttgt catggaaaac 3480 tctccaaagg acgtatctgt cattcagatc caggctgaag atcctgactc cagttccaat 3540 gaaaaactga catacaggat tacaagtgga aatcctcaga atttttttgc catcaatatc 3600 aaaacaggtc tgattacaac aacttcaagg aaattggatc gagaacagca ggcagaacat 3660 tttctggagg tgactgtgac agatggtggt ccctctccaa aacagtcaac catttgggtg 3720 gtggttcagg ttctagatga aaatgacaac aagccccagt tcccagagaa ggtctaccag 3780 atcaagctgc cagaacgtga ccgaaagaag agaggagaac cgatttacag ggcttttgca 3840 tttgatagag atgagggccc caacgcagaa atctcctaca gtattgtgga tgggaatgat 3900 gacggaaagt tctttattga ccctaaaact gggatggttt cttctagaaa gcagtttaca 3960 gcaggcagtt atgacatcct aacgataaag gcagtggaca atgggcgccc acagaaatcc 4020 tccacggccc gcctccacat tgaatggatt aagaaaccac ccccttcacc tataccattg 4080 accttcgatg agccgtttta taacttcaca gtcatggaaa gtgatagagt gactgaaatt 4140 gtaggggtgg tgtctgtgca gccagctaac acccctctgt ggtttgacat agttgggggg 4200 aattttgaca gcgcttttga tgcagagaag ggtgttggga caattgtcat cgcaaaacct 4260 ttggatgcag agcagaggtc catctataat atgagtgtgg aagtcaccga tgggacaaat 4320 gttgctgtta ctcaggtatt tatcaaagtg ctggataata atgataatgg cccagaattc 4380 tctcagccga attacgatgt gacaatttcc gaggatgtgc ttccagacac ggagatcctg 4440 cagattgaag ccacagatag agatgagaag cacaagctga gctacactgt tcatagcagc 4500 atcgactcca tcagcatgag aaaattccgg attgacccta gcactggcgt gctctatact 4560 gccgagaggc tggaccatga ggcccaggac aagcacattc tcaacataat ggtcagagat 4620 caggagtttc cttatcgaag aaacttggcc cgagtcattg tgaatgtgga ggatgctaat 4680 gatcacagtc cttattttac caacccactg tatgaagcgt ctgtgtttga atctgctgct 4740 ctgggatcag ctgttctgca agtgacggct ctggacaaag acaaaggaga aaatgcagaa 4800 ctcatatata ccatagaagc agggaacact gggaacatgt ttaagatcga accggtccta 4860 ggcatcatca ccatttgcaa agaaccagac atgacgacga tgggtcagtt tgtcctatcc 4920 atcaaagtca cagatcaggg atccccgcca atgtctgcta ctgcaattgt gcgcatttcc 4980 gtcaccatgt ctgacaattc tcaccccaag ttcattcaca aagactacca agcagaagta 5040 aatgaaaatg ttgacattgg aacatcagtc attctaatct ctgccatcag tcaatctacc 5100 ctcatttatg aagtcaaaga tggagacatt aatgggatct ttaccataaa tccatattct 5160 ggagtcatca ccactcagaa ggccctggat tatgagcgca catcctctta tcaactcatc 5220 attcaggcca ccaatatggc aggaatggct tccaatgcta cagtcaatat tcagattgtt 5280 gatgaaaatg ataatgcccc agtttttctc ttttctcaat actcaggcag cctaagtgag 5340 gctgccccaa ttaatagcat tgtcaggagc ttggataaca gcccactggt gattcgagcc 5400 acagatgctg acagcaaccg gaatgctctg cttgtgtatc agattgtgga gtcaacagca 5460 aaaaagtttt tcacggtgga ctccagtaca ggtgcaatca gaacaattgc caacctggac 5520 catgaaacca ttgcccattt ccattttcat gtgcatgtga gagacagtgg tagcccccaa 5580 ctgactgcag agagtcccgt tgaagtcaac attgaggtga cagatgtgaa tgataaccca 5640 cctgttttta ctcaggctgt gtttgagact atcttacttc tacctaccta tgttggagtg 5700 gaggttctga aagttagtgc cacagatcct gactctgagg taccccctga actgacatac 5760 agcctaatgg aaggcagttt ggatcatttt ttaattgact caaacagtgg agtacttacc 5820 ataaaaaaca acaacctctc caaggatcac tacatgctga tagttaaggt gtctgatgga 5880 aagttctaca gtacctccat ggtcaccatc atggttaaag aagccatgga cagcggcctc 5940 cactttacac aaagcttcta ttccacctca atctcagaga acaacactaa cataaccaaa 6000 gttgctattg tcaatgcagt tggaaatcgc cttaatgagc ccttaaaata cagcatctta 6060 aacccaggaa ataagttcaa gataaaatct acctcagggg tcattcagac gactggagtc 6120 ccctttgacc gtgaagaaca agagttatat gagctggtgg tagaagccag ccgtgagctg 6180 gaccatctgc gtgtggccag agtggtggtc agggttaaca ttgaagacat aaatgacaat 6240 tctccagtct ttgtgggcct cccatactat gctgctgttc aagtggatgc ggaacccggg 6300 actctgattt atcaggtgac agccattgac aaagataaag gtccaaatgg agaagtgacc 6360 tatgtcctgc aggatgacta tggccacttt gaaattaacc ctaattcagg gaatgttatt 6420 ttaaaggaag cattcaactc tgacttgtcc aacattgagt atggagtcac catcctagcc 6480 aaggatggcg gaaaaccttc tttgtctaca tctgtggagc ttcccatcac tattgtcaac 6540 aaagcaatgc ctgtgtttga taagcccttt tatacagcat ctgtcaatga agacatcaga 6600 atgaacacac ccatcctaag catcaatgcc accagtccag aaggccaagg catcatatat 6660 atcattatcg atggggaccc ttttaaacag tttaacattg actttgacac tggggtcctg 6720 aaagttgtta gccctttgga ttatgaagtt acatctgctt acaagctgac aataagagcc 6780 agcgacgccc ttactggtgc tagggctgaa gtcactgttg acttgctagt taatgatgta 6840 aatgacaacc cccctatttt cgatcagcct acatacaata caacactatc agaagcatct 6900 cttattggga cacctgtttt acaagttgtc tctattgatg cagactcaga aaacaataaa 6960 atggtacatt atcagattgt ccaggatacc tacaatagca cagattattt tcacatagat 7020 agctcaagtg gcttaatcct gacagcacga atgctggacc atgagttagt acaacactgc 7080 actttgaaag tcagatcaat agatagtggc ttcccatcac tgagcagtga ggttctcgtt 7140 catatctaca tctctgatgt aaatgacaac cctccagttt ttaatcagct catttatgag 7200 tcatatgtga gtgaattagc cccccggggc cattttgtaa cctgtgtaca agcctctgat 7260 gcagacagct ctgattttga ccggttggaa tatagcattt tatctgggaa tgaccggacg 7320 agctttctga tggacagcaa gagtggagtt atcacattgt ccaaccatcg gaagcagcgg 7380 atggagcctc tgtacagtct caatgtgtct gtctctgatg ggttgttcac cagcactgca 7440 caggtgcata ttagggtact tggggctaac ttgtacagcc ctgccttttc acaaagcaca 7500 tacgtagctg aggtgagaga gaacgtggct gcaggaacaa aggtaattca tgttcgagcc 7560 acagatggtg atccagggac ttatgggcag atcagctatg ccatcatcaa tgactttgcc 7620 aaggatcgat tcctcataga cagcaatggg caggtcatca ccacagaaag gctagaccgg 7680 gaaaaccctc tagaagggga tgttagtatt tttgtgaggg cccttgatgg tggagggaga 7740 acaactttct gcactgtgag agtgattgtt gtggatgaaa atgacaatgc tccccagttc 7800 atgacagtgg aatatagagc cagtgtcagg gcagatgttg gaaggggcca cttggtcact 7860 caagttcaag ccatagatcc cgatgatgga gcaaattcaa ggattactta ttccctctat 7920 agcgaggcct ctgtttcagt ggccgacctc ctggaaatcg atcctgacaa tggctggatg 7980 gtcacaaagg gtaattttaa ccagctgaaa aatacagtgc tttcgttctt tgtcaaagca 8040 gtagatgggg gcatcccagt aaagcactcc ctcattcctg tctatatcca cgtcttgccc 8100 cctgaaacgt tcttgccatc attcacccag tctcagtatt cctttaccat tgcagaagat 8160 acagccattg ggagtacagt ggacaccctg aggattttgc ccagtcagaa tgtctggttc 8220 agcacagtta atggggaacg gccagaaaat aacaaagggg gcgtattcgt catagaacag 8280 gaaacaggca ctattaagct tgacaaacgc cttgaccgtg aaaccagccc agctttccac 8340 tttaaagtag cagccactat acccctggac aaagtagaca ttgtgtttac tgtggatgta 8400 gatatcaagg tattggattt gaatgacaac aagccagtct ttgaaacttc aagctatgac 8460 accattataa tggaagggat gcctgttggc accaaactca cacaagtgag agctattgat 8520 atggactggg gagccaatgg acaagtcact tactccctcc actcggattc ccagcccgaa 8580 aaggtaatgg aagcattcaa tattgacagc aacacgggct ggatcagtac cttgaaggac 8640 ctagatcacg agacagaccc cacattcacc ttctctgtgg tggcctctga ccttggagag 8700 gcattctctc tttcctccac ggccttggtc tctgtcagag tgacagatat aaatgacaat 8760 gcaccagtct tcgcgcagga agtgtaccga gggaatgtga aggagagcga cccaccgggc 8820 gaggtggtag ccgtcctcag cacctgggac agagacacat ccgacgttaa tcgccaagtg 8880 agctaccata ttacaggagg aaaccctcga ggaaggtttg ctctgggcct ggtgcaaagt 8940 gagtggaagg tctatgtgaa gaggcctcta gacagagaag aacaggacat ttactttctc 9000 aatatcactg ccactgatgg gctttttgtc acacaggcca tggtggaagt gagcgtcagt 9060 gatgtgaatg acaatagccc agtgtgtgat caggttgcat atacagcatt acttcctgaa 9120 gacattccat caaataaaat catcctgaaa gtcagtgcaa aggatgctga tattggatcc 9180 aatggatata tacgatactc actctatgga tctggaaaca gtgaattttt tctagatcca 9240 gaaagtggcg agttaaaaac cttggctctg ttggaccggg agaggatccc cgtgtacagc 9300 ctgatggcca aggccactga cgggggtggc aggttctgcc agtccaacat ccacctaatc 9360 ctggaggatg tgaatgataa cccccctgtg ttttcttctg accactacaa cacctgtgtc 9420 tatgagaaca cagccaccaa ggctctgttg accagagttc aagccgtgga ccccgacatt 9480 ggcatcaata ggaaggtcgt gtactccctg gcagactcag ctggtggggt cttctccatt 9540 gacagctcat ctggcatcat catcctggag cagccactgg accgtgagca gcagtcttcg 9600 tacaacatca gcgtgcgggc cactgaccag agtcctggac agtccctgtc ctctctcact 9660 actgtcacca tcaccgttct ggacattaat gacaaccccc ctgtgtttga gaggagggac 9720 tacctggtga cggtgcctga ggacacctcc cctggcaccc aagtccttgc tgtttttgcc 9780 accagcaaag atattggcac aaatgctgag atcacttatc tcatccggtc tgggaacgaa 9840 caagggaaat ttaagatcaa ccccaagaca gggggtattt ctgtctctga agtcctggac 9900 tatgaattat gcaaaaggtt ttacctggta gtggaagcca aagatggggg caccccagct 9960 ctcagcgctg tggccactgt caacatcaac ctcacagatg ttaatgacaa ccctcccaag 10020 ttcagccaag acgtctacag tgcggttatc agtgaagacg ccttggtggg agactctgtc 10080 attttgctaa tagcagaaga tgtagacagc cagcccaacg gacagattca tttttccatt 10140 gtgaatggag atcgggacaa tgaatttact gtagatcctg tcttgggact tgtgaaagtt 10200 aagaagaaat tggaccggga acgggtgtct ggatactctc tgcttgtcca ggccgtagac 10260 agtggcattc ctgcaatgtc atcaactgca actgtcaaca ttgatatttc tgatgtgaat 10320 gacaacagcc cggtgtttac acctgccaac tatactgctg tgattcagga aaataagcca 10380 gtgggcacca gcatcttgca gctggtggtg acagacagag actcctttca caatgggcct 10440 cccttttcat tctctatttt gtcgggaaat gaagaggagg agtttgtgtt ggaccctcat 10500 gggatcttgc ggtcggctgt ggtcttccag cacacagagt ctctggaata cgtgttgtgt 10560 gtccaggcaa aggattcagg caaaccccag caagtttctc acacttacat ccgcgtgcga 10620 gtcattgagg aaagcaccca caagcccaca gccattcccc tggaaatttt cattgtcacc 10680 atggaggatg actttcctgg tggggtcatt gggaagattc atgccacaga tcaagacatg 10740 tatgatgtgc tcacatttgc cctgaaatcg gagcagaaaa gcttatttaa agtgaacagt 10800 cacgatggga aaatcatcgc cctgggaggc ctggacagcg gcaagtatgt cctgaatgtg 10860 tctgtgagtg atggtcgctt ccaggtaccc attgatgtgg tcgtgcatgt ggagcagttg 10920 gtgcatgaga tgctgcagaa cactgtcacc atccgctttg aaaatgtgtc ccctgaggac 10980 ttcgtggggc tgcacatgca tgggttccgg cgcaccctgc ggaatgcagt cctcacccag 11040 aagcaggaca gcctgcgcat catcagcatc cagcccgtgg caggcaccaa ccaactggac 11100 atgctgtttg cggtggagat gcacagcagc gagttctaca agccagccta cctgatccag 11160 aagctgtcca atgctagaag acacctggag aatatcatgc gcatctcagc catcttggag 11220 aagaactgct cagggctgga ctgtcaggaa cagcattgtg agcaaggctt gtcactcgat 11280 tcccacgcgc tcatgaccta cagcacggct cgcatcagct ttgtgtgtcc gcgtttctac 11340 aggaacgtgc gttgcacctg caatggagga ctgtgtccgg ggtccaacga tccttgtgtg 11400 gagaagccgt gtccagggga catgcagtgt gtcggttatg aagccagcag gagaccgttc 11460 ctctgccagt gtccaccagg gaagctcgga gagtgctcag ggcacacttc tctcagcttt 11520 gctggaaaca gttacatcaa atatcggctt tctgaaaata gcaaagaaga ggatttcaaa 11580 ctagctctgc gtcttcgaac actgcaaagc aatgggatta taatgtacac cagagcaaat 11640 ccctgcataa ttctgaagat tgtggatggc aagctgtggt tccagctgga ctgcggcagc 11700 ggccctggaa tcttgggcat ctcgggccgt gctgtcaacg acgggagctg gcactcggtc 11760 ttcctggagc tcaaccgcaa tttcacgagc ctgtccctgg atgacagcta cgtggagcgg 11820 cgccgggcgc ccctctactt ccagacgctg agcactgaga gtagcatcta cttcggcgcc 11880 ctggtgcaag cggataacat ccgcagcctg actgacacgc gggtcacgca ggtgctcagc 11940 ggcttccagg gctgcctgga ctcggtgata ctgaataaca atgagctgcc gctgcagaac 12000 aagcgcagca gcttcgcgga ggtggtgggc ctgacggagc tgaagctggg ctgcgtgctc 12060 tatcccgacg cctgcaagcg cagcccgtgc cagcacgggg gcagctgcac tggcctgcca 12120 tcggggggct atcagtgtac ctgtctctca cagtttacgg ggagaaactg tgaatctgag 12180 attacagcct gcttcccaaa cccctgccgg aatggaggat cctgcgatcc aataggaaac 12240 actttcatct gcaattgtaa agctgggctc actggagtca cgtgtgagga ggacatcaat 12300 gagtgcgaac gagaggagtg tgagaacgga ggctcctgcg tgaacgtgtt cggctccttc 12360 ctctgcaact gcacgccggg ctacgtgggc cagtactgcg ggcgccccgt ggtggtaccc 12420 aatatccagg ctggccactc ctacgtgggg aaggaggagc tcatcggcat cgccgtggtc 12480 ctcttcgtca tcttcatcct ggtggttctc ttcatagtct tccgcaagaa ggtcttccgc 12540 aagaactact cccgcaacaa catcacgcta gtgcaggacc cggccaccgc cgccctgctt 12600 aacaagagca atggcatccc gttccggaac ctgcgcggca gtggggacgg ccgcaacgtc 12660 taccaggagg tggggccccc gcaggtcccc gtgcgcccca tggcctacac accctgcttc 12720 cagagtgact ccaggagcaa cctggataag atcgtggacg ggctgggagg cgagcaccag 12780 gaaatgacca cgtttcaccc tgagtcgccc cgcatcctga cagcccggcg gggcgtggtc 12840 gtgtgcagtg tggcccccaa cctccccgcc gtgtcaccct gccgctccga ctgcgactcc 12900 atccggaaga atggctggga cgcgggaact gagaacaaag gggttgatga cccgggagaa 12960 gtgacctgct ttgcaggtag taataaaggc agcaactctg aagttcagtc cctcagctcc 13020 ttccagtcag attctggtga cgacaatgcc tccatagtga ctgtcattca gcttgtcaac 13080 aatgtagttg acactataga gaatgaagtg tctgtcatgg accaaggaca gaactacaac 13140 cgagcctatc actgggacac ctctgattgg atgccagggg cccgcctgtc ggacatagag 13200 gaagtgccca actatgagaa ccaggatgga gggtctgcac accaggggag cacacgggag 13260 ctggagagcg attactacct gggtggttat gacattgaca gtgaataccc accccctcat 13320 gaagaggagt tcttgagtca ggaccagctg cctcctcctc tcccggagga cttcccagac 13380 caatatgagg ccctgccacc ctcccagcct gtctccctgg ccagcacact gagcccagac 13440 tgcaggagaa ggccccagtt tcatcctagc cagtatctcc ctcctcaccc attccccaac 13500 gaaacggatt tggtgggccc gcctgccagc tgtgaattta gtacttttgc tgtgagcatg 13560 aaccagggca cagagcccac aggcccagca gacagcgtgt ctctgtcctt gcacaattcc 13620 agaggcacct catcctcgga tgtgtctgcc aactgcggct ttgacgattc cgaagtagcc 13680 atgagtgact acgagagcgt gggagagctc agcctcgcca gccttcacat tccctttgtg 13740 gagactcagc atcagactca agtgtag 13767 8 4588 PRT homo sapiens 8 Met Asp Ile Ile Met Gly His Cys Val Gly Thr Arg Pro Pro Ala Cys 1 5 10 15 Cys Leu Ile Leu Leu Leu Phe Lys Leu Leu Ala Thr Val Ser Gln Gly 20 25 30 Leu Pro Gly Thr Gly Pro Leu Gly Phe His Phe Thr His Ser Ile Tyr 35 40 45 Asn Ala Thr Val Tyr Glu Asn Ser Ala Ala Arg Thr Tyr Val Asn Ser 50 55 60 Gln Ser Arg Met Gly Ile Thr Leu Ile Asp Leu Ser Trp Asp Ile Lys 65 70 75 80 Tyr Arg Ile Val Ser Gly Asp Glu Glu Gly Phe Phe Lys Ala Glu Glu 85 90 95 Val Ile Ile Ala Asp Phe Cys Phe Leu Arg Ile Arg Thr Lys Gly Gly 100 105 110 Asn Ser Ala Ile Leu Asn Arg Glu Ile Gln Asp Asn Tyr Leu Leu Ile 115 120 125 Val Lys Gly Ser Val Arg Gly Glu Asp Leu Glu Ala Trp Thr Lys Val 130 135 140 Asn Ile Gln Val Leu Asp Met Asn Asp Leu Arg Pro Leu Phe Ser Pro 145 150 155 160 Thr Thr Tyr Ser Val Thr Ile Ala Glu Ser Thr Pro Leu Arg Thr Ser 165 170 175 Val Ala Gln Val Thr Ala Thr Asp Ala Asp Ile Gly Ser Asn Gly Glu 180 185 190 Phe Tyr Tyr Tyr Phe Lys Asn Lys Val Asp Leu Phe Ser Val His Pro 195 200 205

Thr Ser Gly Val Ile Ser Leu Ser Gly Arg Leu Asn Tyr Asp Glu Lys 210 215 220 Asn Arg Tyr Asp Leu Glu Ile Leu Ala Val Asp Arg Gly Met Lys Leu 225 230 235 240 Tyr Gly Asn Asn Gly Val Ser Ser Thr Ala Lys Leu Tyr Val His Ile 245 250 255 Glu Arg Ile Asn Glu His Ala Pro Thr Ile His Val Val Thr His Val 260 265 270 Pro Phe Ser Leu Glu Lys Glu Pro Thr Tyr Ala Val Val Thr Val Asp 275 280 285 Asp Leu Asp Asp Gly Ala Asn Gly Glu Ile Glu Ser Val Ser Ile Val 290 295 300 Ala Gly Asp Pro Leu Asp Gln Phe Phe Leu Ala Lys Glu Gly Lys Trp 305 310 315 320 Leu Asn Glu Tyr Lys Ile Lys Glu Arg Lys Gln Ile Asp Trp Glu Ser 325 330 335 Phe Pro Tyr Gly Tyr Asn Leu Thr Leu Gln Ala Lys Asp Lys Gly Ser 340 345 350 Pro Gln Lys Cys Ser Ala Leu Lys Ala Val Tyr Ile Gly Asn Pro Thr 355 360 365 Arg Asp Thr Val Pro Ile Arg Phe Glu Lys Glu Val Tyr Asp Val Ser 370 375 380 Ile Ser Glu Phe Ser Pro Pro Gly Val Val Val Ala Ile Val Lys Leu 385 390 395 400 Ser Pro Glu Pro Ile Asp Val Glu Tyr Lys Leu Ser Pro Gly Glu Asp 405 410 415 Ala Val Tyr Phe Lys Ile Asn Pro Arg Ser Gly Leu Ile Val Thr Ala 420 425 430 Arg Pro Leu Asn Thr Val Lys Lys Glu Val Tyr Lys Leu Glu Val Thr 435 440 445 Asn Lys Glu Gly Asp Leu Lys Ala Gln Val Thr Ile Ser Ile Glu Asp 450 455 460 Ala Asn Asp His Thr Pro Glu Phe Gln Gln Pro Leu Tyr Asp Ala Tyr 465 470 475 480 Val Asn Glu Ser Val Pro Val Gly Thr Ser Val Leu Thr Val Ser Ala 485 490 495 Ser Asp Lys Asp Lys Gly Glu Asn Gly Tyr Ile Thr Tyr Ser Ile Ala 500 505 510 Ser Leu Asn Leu Leu Pro Phe Val Ile Asn Gln Phe Thr Gly Val Ile 515 520 525 Ser Thr Thr Glu Glu Leu Asp Phe Glu Ser Ser Pro Glu Ile Tyr Arg 530 535 540 Phe Ile Val Arg Ala Ser Asp Trp Gly Ser Pro Tyr Arg His Glu Ser 545 550 555 560 Glu Val Asn Val Thr Ile Arg Ile Gly Asn Val Asn Asp Asn Ser Pro 565 570 575 Leu Phe Glu Lys Val Ala Cys Gln Gly Val Ile Ser Tyr Asp Phe Pro 580 585 590 Val Gly Gly His Ile Thr Ala Val Ser Ala Ile Asp Ile Asp Glu Leu 595 600 605 Glu Leu Val Lys Tyr Lys Ile Ile Ser Gly Asn Glu Leu Gly Phe Phe 610 615 620 Tyr Leu Asn Pro Asp Ser Gly Val Leu Gln Leu Lys Lys Ser Leu Thr 625 630 635 640 Asn Ser Gly Ile Lys Asn Gly Asn Phe Ala Leu Arg Ile Thr Ala Thr 645 650 655 Asp Gly Glu Asn Leu Ala Asp Pro Met Ser Ile Asn Ile Ser Val Leu 660 665 670 His Gly Lys Val Ser Ser Lys Ser Phe Ser Cys Arg Glu Thr Arg Val 675 680 685 Ala Gln Lys Leu Ala Glu Lys Leu Leu Ile Lys Ala Lys Ala Asn Gly 690 695 700 Lys Leu Asn Leu Glu Asp Gly Phe Leu Asp Phe Tyr Ser Ile Asn Arg 705 710 715 720 Gln Gly Pro Tyr Phe Asp Lys Ser Phe Pro Ser Asp Val Ala Val Lys 725 730 735 Glu Asp Leu Pro Val Gly Ala Asn Ile Leu Lys Ile Lys Ala Tyr Asp 740 745 750 Ala Asp Ser Gly Phe Asn Gly Lys Val Leu Phe Thr Ile Ser Asp Gly 755 760 765 Asn Thr Asp Ser Cys Phe Asn Ile Asp Met Glu Thr Gly Gln Leu Lys 770 775 780 Val Leu Met Pro Met Asp Arg Glu His Thr Asp Leu Tyr Leu Leu Asn 785 790 795 800 Ile Thr Ile Tyr Asp Leu Gly Asn Pro Gln Lys Ser Ser Trp Arg Leu 805 810 815 Leu Thr Ile Asn Val Glu Asp Ala Asn Asp Asn Ser Pro Val Phe Ile 820 825 830 Gln Asp Ser Tyr Ser Val Asn Ile Leu Glu Ser Ser Gly Ile Gly Thr 835 840 845 Glu Ile Ile Gln Val Glu Ala Arg Asp Lys Asp Leu Gly Ser Asn Gly 850 855 860 Glu Val Thr Tyr Ser Val Leu Thr Asp Thr Gln Gln Phe Ala Ile Asn 865 870 875 880 Ser Ser Thr Gly Ile Val Tyr Val Ala Asp Gln Leu Asp Arg Glu Ser 885 890 895 Lys Ala Asn Tyr Ser Leu Lys Ile Glu Ala Arg Asp Lys Ala Glu Ser 900 905 910 Gly Gln Gln Leu Phe Ser Val Val Thr Leu Lys Val Phe Leu Asp Asp 915 920 925 Val Asn Asp Cys Ser Pro Ala Phe Ile Pro Ser Ser Tyr Ser Val Lys 930 935 940 Val Leu Glu Asp Leu Pro Val Gly Thr Val Ile Ala Trp Leu Glu Thr 945 950 955 960 His Asp Pro Asp Leu Gly Leu Gly Gly Gln Val Arg Tyr Ser Leu Val 965 970 975 Asn Asp Tyr Asn Gly Arg Phe Glu Ile Asp Lys Ala Ser Gly Ala Ile 980 985 990 Arg Leu Ser Lys Glu Leu Asp Tyr Glu Lys Gln Gln Phe Tyr Asn Leu 995 1000 1005 Thr Val Arg Ala Lys Asp Lys Gly Arg Pro Val Ser Leu Ser Ser Val 1010 1015 1020 Ser Phe Val Glu Val Glu Val Val Asp Val Asn Glu Asn Leu His Thr 1025 1030 1035 1040 Pro Tyr Phe Pro Asp Phe Ala Val Val Gly Ser Val Lys Glu Asn Ser 1045 1050 1055 Arg Ile Gly Thr Ser Val Leu Gln Val Thr Ala Arg Asp Glu Asp Ser 1060 1065 1070 Gly Arg Asp Gly Glu Ile Gln Tyr Ser Ile Arg Asp Gly Ser Gly Leu 1075 1080 1085 Gly Arg Phe Ser Ile Asp Asp Glu Ser Gly Val Ile Thr Ala Ala Asp 1090 1095 1100 Ile Leu Asp Arg Glu Thr Met Gly Ser Tyr Trp Leu Thr Val Tyr Ala 1105 1110 1115 1120 Thr Asp Arg Gly Val Val Pro Leu Tyr Ser Thr Ile Glu Val Tyr Ile 1125 1130 1135 Glu Val Glu Asp Val Asn Asp Asn Ala Pro Leu Thr Ser Glu Pro Ile 1140 1145 1150 Tyr Tyr Pro Val Val Met Glu Asn Ser Pro Lys Asp Val Ser Val Ile 1155 1160 1165 Gln Ile Gln Ala Glu Asp Pro Asp Ser Ser Ser Asn Glu Lys Leu Thr 1170 1175 1180 Tyr Arg Ile Thr Ser Gly Asn Pro Gln Asn Phe Phe Ala Ile Asn Ile 1185 1190 1195 1200 Lys Thr Gly Leu Ile Thr Thr Thr Ser Arg Lys Leu Asp Arg Glu Gln 1205 1210 1215 Gln Ala Glu His Phe Leu Glu Val Thr Val Thr Asp Gly Gly Pro Ser 1220 1225 1230 Pro Lys Gln Ser Thr Ile Trp Val Val Val Gln Val Leu Asp Glu Asn 1235 1240 1245 Asp Asn Lys Pro Gln Phe Pro Glu Lys Val Tyr Gln Ile Lys Leu Pro 1250 1255 1260 Glu Arg Asp Arg Lys Lys Arg Gly Glu Pro Ile Tyr Arg Ala Phe Ala 1265 1270 1275 1280 Phe Asp Arg Asp Glu Gly Pro Asn Ala Glu Ile Ser Tyr Ser Ile Val 1285 1290 1295 Asp Gly Asn Asp Asp Gly Lys Phe Phe Ile Asp Pro Lys Thr Gly Met 1300 1305 1310 Val Ser Ser Arg Lys Gln Phe Thr Ala Gly Ser Tyr Asp Ile Leu Thr 1315 1320 1325 Ile Lys Ala Val Asp Asn Gly Arg Pro Gln Lys Ser Ser Thr Ala Arg 1330 1335 1340 Leu His Ile Glu Trp Ile Lys Lys Pro Pro Pro Ser Pro Ile Pro Leu 1345 1350 1355 1360 Thr Phe Asp Glu Pro Phe Tyr Asn Phe Thr Val Met Glu Ser Asp Arg 1365 1370 1375 Val Thr Glu Ile Val Gly Val Val Ser Val Gln Pro Ala Asn Thr Pro 1380 1385 1390 Leu Trp Phe Asp Ile Val Gly Gly Asn Phe Asp Ser Ala Phe Asp Ala 1395 1400 1405 Glu Lys Gly Val Gly Thr Ile Val Ile Ala Lys Pro Leu Asp Ala Glu 1410 1415 1420 Gln Arg Ser Ile Tyr Asn Met Ser Val Glu Val Thr Asp Gly Thr Asn 1425 1430 1435 1440 Val Ala Val Thr Gln Val Phe Ile Lys Val Leu Asp Asn Asn Asp Asn 1445 1450 1455 Gly Pro Glu Phe Ser Gln Pro Asn Tyr Asp Val Thr Ile Ser Glu Asp 1460 1465 1470 Val Leu Pro Asp Thr Glu Ile Leu Gln Ile Glu Ala Thr Asp Arg Asp 1475 1480 1485 Glu Lys His Lys Leu Ser Tyr Thr Val His Ser Ser Ile Asp Ser Ile 1490 1495 1500 Ser Met Arg Lys Phe Arg Ile Asp Pro Ser Thr Gly Val Leu Tyr Thr 1505 1510 1515 1520 Ala Glu Arg Leu Asp His Glu Ala Gln Asp Lys His Ile Leu Asn Ile 1525 1530 1535 Met Val Arg Asp Gln Glu Phe Pro Tyr Arg Arg Asn Leu Ala Arg Val 1540 1545 1550 Ile Val Asn Val Glu Asp Ala Asn Asp His Ser Pro Tyr Phe Thr Asn 1555 1560 1565 Pro Leu Tyr Glu Ala Ser Val Phe Glu Ser Ala Ala Leu Gly Ser Ala 1570 1575 1580 Val Leu Gln Val Thr Ala Leu Asp Lys Asp Lys Gly Glu Asn Ala Glu 1585 1590 1595 1600 Leu Ile Tyr Thr Ile Glu Ala Gly Asn Thr Gly Asn Met Phe Lys Ile 1605 1610 1615 Glu Pro Val Leu Gly Ile Ile Thr Ile Cys Lys Glu Pro Asp Met Thr 1620 1625 1630 Thr Met Gly Gln Phe Val Leu Ser Ile Lys Val Thr Asp Gln Gly Ser 1635 1640 1645 Pro Pro Met Ser Ala Thr Ala Ile Val Arg Ile Ser Val Thr Met Ser 1650 1655 1660 Asp Asn Ser His Pro Lys Phe Ile His Lys Asp Tyr Gln Ala Glu Val 1665 1670 1675 1680 Asn Glu Asn Val Asp Ile Gly Thr Ser Val Ile Leu Ile Ser Ala Ile 1685 1690 1695 Ser Gln Ser Thr Leu Ile Tyr Glu Val Lys Asp Gly Asp Ile Asn Gly 1700 1705 1710 Ile Phe Thr Ile Asn Pro Tyr Ser Gly Val Ile Thr Thr Gln Lys Ala 1715 1720 1725 Leu Asp Tyr Glu Arg Thr Ser Ser Tyr Gln Leu Ile Ile Gln Ala Thr 1730 1735 1740 Asn Met Ala Gly Met Ala Ser Asn Ala Thr Val Asn Ile Gln Ile Val 1745 1750 1755 1760 Asp Glu Asn Asp Asn Ala Pro Val Phe Leu Phe Ser Gln Tyr Ser Gly 1765 1770 1775 Ser Leu Ser Glu Ala Ala Pro Ile Asn Ser Ile Val Arg Ser Leu Asp 1780 1785 1790 Asn Ser Pro Leu Val Ile Arg Ala Thr Asp Ala Asp Ser Asn Arg Asn 1795 1800 1805 Ala Leu Leu Val Tyr Gln Ile Val Glu Ser Thr Ala Lys Lys Phe Phe 1810 1815 1820 Thr Val Asp Ser Ser Thr Gly Ala Ile Arg Thr Ile Ala Asn Leu Asp 1825 1830 1835 1840 His Glu Thr Ile Ala His Phe His Phe His Val His Val Arg Asp Ser 1845 1850 1855 Gly Ser Pro Gln Leu Thr Ala Glu Ser Pro Val Glu Val Asn Ile Glu 1860 1865 1870 Val Thr Asp Val Asn Asp Asn Pro Pro Val Phe Thr Gln Ala Val Phe 1875 1880 1885 Glu Thr Ile Leu Leu Leu Pro Thr Tyr Val Gly Val Glu Val Leu Lys 1890 1895 1900 Val Ser Ala Thr Asp Pro Asp Ser Glu Val Pro Pro Glu Leu Thr Tyr 1905 1910 1915 1920 Ser Leu Met Glu Gly Ser Leu Asp His Phe Leu Ile Asp Ser Asn Ser 1925 1930 1935 Gly Val Leu Thr Ile Lys Asn Asn Asn Leu Ser Lys Asp His Tyr Met 1940 1945 1950 Leu Ile Val Lys Val Ser Asp Gly Lys Phe Tyr Ser Thr Ser Met Val 1955 1960 1965 Thr Ile Met Val Lys Glu Ala Met Asp Ser Gly Leu His Phe Thr Gln 1970 1975 1980 Ser Phe Tyr Ser Thr Ser Ile Ser Glu Asn Asn Thr Asn Ile Thr Lys 1985 1990 1995 2000 Val Ala Ile Val Asn Ala Val Gly Asn Arg Leu Asn Glu Pro Leu Lys 2005 2010 2015 Tyr Ser Ile Leu Asn Pro Gly Asn Lys Phe Lys Ile Lys Ser Thr Ser 2020 2025 2030 Gly Val Ile Gln Thr Thr Gly Val Pro Phe Asp Arg Glu Glu Gln Glu 2035 2040 2045 Leu Tyr Glu Leu Val Val Glu Ala Ser Arg Glu Leu Asp His Leu Arg 2050 2055 2060 Val Ala Arg Val Val Val Arg Val Asn Ile Glu Asp Ile Asn Asp Asn 2065 2070 2075 2080 Ser Pro Val Phe Val Gly Leu Pro Tyr Tyr Ala Ala Val Gln Val Asp 2085 2090 2095 Ala Glu Pro Gly Thr Leu Ile Tyr Gln Val Thr Ala Ile Asp Lys Asp 2100 2105 2110 Lys Gly Pro Asn Gly Glu Val Thr Tyr Val Leu Gln Asp Asp Tyr Gly 2115 2120 2125 His Phe Glu Ile Asn Pro Asn Ser Gly Asn Val Ile Leu Lys Glu Ala 2130 2135 2140 Phe Asn Ser Asp Leu Ser Asn Ile Glu Tyr Gly Val Thr Ile Leu Ala 2145 2150 2155 2160 Lys Asp Gly Gly Lys Pro Ser Leu Ser Thr Ser Val Glu Leu Pro Ile 2165 2170 2175 Thr Ile Val Asn Lys Ala Met Pro Val Phe Asp Lys Pro Phe Tyr Thr 2180 2185 2190 Ala Ser Val Asn Glu Asp Ile Arg Met Asn Thr Pro Ile Leu Ser Ile 2195 2200 2205 Asn Ala Thr Ser Pro Glu Gly Gln Gly Ile Ile Tyr Ile Ile Ile Asp 2210 2215 2220 Gly Asp Pro Phe Lys Gln Phe Asn Ile Asp Phe Asp Thr Gly Val Leu 2225 2230 2235 2240 Lys Val Val Ser Pro Leu Asp Tyr Glu Val Thr Ser Ala Tyr Lys Leu 2245 2250 2255 Thr Ile Arg Ala Ser Asp Ala Leu Thr Gly Ala Arg Ala Glu Val Thr 2260 2265 2270 Val Asp Leu Leu Val Asn Asp Val Asn Asp Asn Pro Pro Ile Phe Asp 2275 2280 2285 Gln Pro Thr Tyr Asn Thr Thr Leu Ser Glu Ala Ser Leu Ile Gly Thr 2290 2295 2300 Pro Val Leu Gln Val Val Ser Ile Asp Ala Asp Ser Glu Asn Asn Lys 2305 2310 2315 2320 Met Val His Tyr Gln Ile Val Gln Asp Thr Tyr Asn Ser Thr Asp Tyr 2325 2330 2335 Phe His Ile Asp Ser Ser Ser Gly Leu Ile Leu Thr Ala Arg Met Leu 2340 2345 2350 Asp His Glu Leu Val Gln His Cys Thr Leu Lys Val Arg Ser Ile Asp 2355 2360 2365 Ser Gly Phe Pro Ser Leu Ser Ser Glu Val Leu Val His Ile Tyr Ile 2370 2375 2380 Ser Asp Val Asn Asp Asn Pro Pro Val Phe Asn Gln Leu Ile Tyr Glu 2385 2390 2395 2400 Ser Tyr Val Ser Glu Leu Ala Pro Arg Gly His Phe Val Thr Cys Val 2405 2410 2415 Gln Ala Ser Asp Ala Asp Ser Ser Asp Phe Asp Arg Leu Glu Tyr Ser 2420 2425 2430 Ile Leu Ser Gly Asn Asp Arg Thr Ser Phe Leu Met Asp Ser Lys Ser 2435 2440 2445 Gly Val Ile Thr Leu Ser Asn His Arg Lys Gln Arg Met Glu Pro Leu 2450 2455 2460 Tyr Ser Leu Asn Val Ser Val Ser Asp Gly Leu Phe Thr Ser Thr Ala 2465 2470 2475 2480 Gln Val His Ile Arg Val Leu Gly Ala Asn Leu Tyr Ser Pro Ala Phe 2485 2490 2495 Ser Gln Ser Thr Tyr Val Ala Glu Val Arg Glu Asn Val Ala Ala Gly 2500 2505 2510 Thr Lys Val Ile His Val Arg Ala Thr Asp Gly Asp Pro Gly Thr Tyr 2515 2520 2525 Gly Gln Ile Ser Tyr Ala Ile Ile Asn Asp Phe Ala Lys Asp Arg Phe 2530 2535 2540 Leu Ile Asp Ser Asn Gly Gln Val Ile Thr Thr Glu Arg Leu Asp Arg 2545 2550 2555 2560 Glu Asn Pro Leu Glu Gly Asp Val Ser Ile Phe Val Arg Ala Leu Asp 2565 2570 2575 Gly Gly Gly Arg Thr Thr Phe Cys Thr Val Arg Val Ile Val Val Asp 2580 2585 2590 Glu Asn Asp Asn Ala Pro Gln Phe Met Thr Val Glu Tyr Arg Ala Ser 2595 2600 2605 Val Arg Ala Asp Val Gly Arg Gly His Leu Val Thr Gln Val Gln Ala 2610 2615 2620 Ile Asp Pro Asp Asp Gly Ala Asn Ser Arg Ile Thr Tyr Ser

Leu Tyr 2625 2630 2635 2640 Ser Glu Ala Ser Val Ser Val Ala Asp Leu Leu Glu Ile Asp Pro Asp 2645 2650 2655 Asn Gly Trp Met Val Thr Lys Gly Asn Phe Asn Gln Leu Lys Asn Thr 2660 2665 2670 Val Leu Ser Phe Phe Val Lys Ala Val Asp Gly Gly Ile Pro Val Lys 2675 2680 2685 His Ser Leu Ile Pro Val Tyr Ile His Val Leu Pro Pro Glu Thr Phe 2690 2695 2700 Leu Pro Ser Phe Thr Gln Ser Gln Tyr Ser Phe Thr Ile Ala Glu Asp 2705 2710 2715 2720 Thr Ala Ile Gly Ser Thr Val Asp Thr Leu Arg Ile Leu Pro Ser Gln 2725 2730 2735 Asn Val Trp Phe Ser Thr Val Asn Gly Glu Arg Pro Glu Asn Asn Lys 2740 2745 2750 Gly Gly Val Phe Val Ile Glu Gln Glu Thr Gly Thr Ile Lys Leu Asp 2755 2760 2765 Lys Arg Leu Asp Arg Glu Thr Ser Pro Ala Phe His Phe Lys Val Ala 2770 2775 2780 Ala Thr Ile Pro Leu Asp Lys Val Asp Ile Val Phe Thr Val Asp Val 2785 2790 2795 2800 Asp Ile Lys Val Leu Asp Leu Asn Asp Asn Lys Pro Val Phe Glu Thr 2805 2810 2815 Ser Ser Tyr Asp Thr Ile Ile Met Glu Gly Met Pro Val Gly Thr Lys 2820 2825 2830 Leu Thr Gln Val Arg Ala Ile Asp Met Asp Trp Gly Ala Asn Gly Gln 2835 2840 2845 Val Thr Tyr Ser Leu His Ser Asp Ser Gln Pro Glu Lys Val Met Glu 2850 2855 2860 Ala Phe Asn Ile Asp Ser Asn Thr Gly Trp Ile Ser Thr Leu Lys Asp 2865 2870 2875 2880 Leu Asp His Glu Thr Asp Pro Thr Phe Thr Phe Ser Val Val Ala Ser 2885 2890 2895 Asp Leu Gly Glu Ala Phe Ser Leu Ser Ser Thr Ala Leu Val Ser Val 2900 2905 2910 Arg Val Thr Asp Ile Asn Asp Asn Ala Pro Val Phe Ala Gln Glu Val 2915 2920 2925 Tyr Arg Gly Asn Val Lys Glu Ser Asp Pro Pro Gly Glu Val Val Ala 2930 2935 2940 Val Leu Ser Thr Trp Asp Arg Asp Thr Ser Asp Val Asn Arg Gln Val 2945 2950 2955 2960 Ser Tyr His Ile Thr Gly Gly Asn Pro Arg Gly Arg Phe Ala Leu Gly 2965 2970 2975 Leu Val Gln Ser Glu Trp Lys Val Tyr Val Lys Arg Pro Leu Asp Arg 2980 2985 2990 Glu Glu Gln Asp Ile Tyr Phe Leu Asn Ile Thr Ala Thr Asp Gly Leu 2995 3000 3005 Phe Val Thr Gln Ala Met Val Glu Val Ser Val Ser Asp Val Asn Asp 3010 3015 3020 Asn Ser Pro Val Cys Asp Gln Val Ala Tyr Thr Ala Leu Leu Pro Glu 3025 3030 3035 3040 Asp Ile Pro Ser Asn Lys Ile Ile Leu Lys Val Ser Ala Lys Asp Ala 3045 3050 3055 Asp Ile Gly Ser Asn Gly Tyr Ile Arg Tyr Ser Leu Tyr Gly Ser Gly 3060 3065 3070 Asn Ser Glu Phe Phe Leu Asp Pro Glu Ser Gly Glu Leu Lys Thr Leu 3075 3080 3085 Ala Leu Leu Asp Arg Glu Arg Ile Pro Val Tyr Ser Leu Met Ala Lys 3090 3095 3100 Ala Thr Asp Gly Gly Gly Arg Phe Cys Gln Ser Asn Ile His Leu Ile 3105 3110 3115 3120 Leu Glu Asp Val Asn Asp Asn Pro Pro Val Phe Ser Ser Asp His Tyr 3125 3130 3135 Asn Thr Cys Val Tyr Glu Asn Thr Ala Thr Lys Ala Leu Leu Thr Arg 3140 3145 3150 Val Gln Ala Val Asp Pro Asp Ile Gly Ile Asn Arg Lys Val Val Tyr 3155 3160 3165 Ser Leu Ala Asp Ser Ala Gly Gly Val Phe Ser Ile Asp Ser Ser Ser 3170 3175 3180 Gly Ile Ile Ile Leu Glu Gln Pro Leu Asp Arg Glu Gln Gln Ser Ser 3185 3190 3195 3200 Tyr Asn Ile Ser Val Arg Ala Thr Asp Gln Ser Pro Gly Gln Ser Leu 3205 3210 3215 Ser Ser Leu Thr Thr Val Thr Ile Thr Val Leu Asp Ile Asn Asp Asn 3220 3225 3230 Pro Pro Val Phe Glu Arg Arg Asp Tyr Leu Val Thr Val Pro Glu Asp 3235 3240 3245 Thr Ser Pro Gly Thr Gln Val Leu Ala Val Phe Ala Thr Ser Lys Asp 3250 3255 3260 Ile Gly Thr Asn Ala Glu Ile Thr Tyr Leu Ile Arg Ser Gly Asn Glu 3265 3270 3275 3280 Gln Gly Lys Phe Lys Ile Asn Pro Lys Thr Gly Gly Ile Ser Val Ser 3285 3290 3295 Glu Val Leu Asp Tyr Glu Leu Cys Lys Arg Phe Tyr Leu Val Val Glu 3300 3305 3310 Ala Lys Asp Gly Gly Thr Pro Ala Leu Ser Ala Val Ala Thr Val Asn 3315 3320 3325 Ile Asn Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Ser Gln Asp 3330 3335 3340 Val Tyr Ser Ala Val Ile Ser Glu Asp Ala Leu Val Gly Asp Ser Val 3345 3350 3355 3360 Ile Leu Leu Ile Ala Glu Asp Val Asp Ser Gln Pro Asn Gly Gln Ile 3365 3370 3375 His Phe Ser Ile Val Asn Gly Asp Arg Asp Asn Glu Phe Thr Val Asp 3380 3385 3390 Pro Val Leu Gly Leu Val Lys Val Lys Lys Lys Leu Asp Arg Glu Arg 3395 3400 3405 Val Ser Gly Tyr Ser Leu Leu Val Gln Ala Val Asp Ser Gly Ile Pro 3410 3415 3420 Ala Met Ser Ser Thr Ala Thr Val Asn Ile Asp Ile Ser Asp Val Asn 3425 3430 3435 3440 Asp Asn Ser Pro Val Phe Thr Pro Ala Asn Tyr Thr Ala Val Ile Gln 3445 3450 3455 Glu Asn Lys Pro Val Gly Thr Ser Ile Leu Gln Leu Val Val Thr Asp 3460 3465 3470 Arg Asp Ser Phe His Asn Gly Pro Pro Phe Ser Phe Ser Ile Leu Ser 3475 3480 3485 Gly Asn Glu Glu Glu Glu Phe Val Leu Asp Pro His Gly Ile Leu Arg 3490 3495 3500 Ser Ala Val Val Phe Gln His Thr Glu Ser Leu Glu Tyr Val Leu Cys 3505 3510 3515 3520 Val Gln Ala Lys Asp Ser Gly Lys Pro Gln Gln Val Ser His Thr Tyr 3525 3530 3535 Ile Arg Val Arg Val Ile Glu Glu Ser Thr His Lys Pro Thr Ala Ile 3540 3545 3550 Pro Leu Glu Ile Phe Ile Val Thr Met Glu Asp Asp Phe Pro Gly Gly 3555 3560 3565 Val Ile Gly Lys Ile His Ala Thr Asp Gln Asp Met Tyr Asp Val Leu 3570 3575 3580 Thr Phe Ala Leu Lys Ser Glu Gln Lys Ser Leu Phe Lys Val Asn Ser 3585 3590 3595 3600 His Asp Gly Lys Ile Ile Ala Leu Gly Gly Leu Asp Ser Gly Lys Tyr 3605 3610 3615 Val Leu Asn Val Ser Val Ser Asp Gly Arg Phe Gln Val Pro Ile Asp 3620 3625 3630 Val Val Val His Val Glu Gln Leu Val His Glu Met Leu Gln Asn Thr 3635 3640 3645 Val Thr Ile Arg Phe Glu Asn Val Ser Pro Glu Asp Phe Val Gly Leu 3650 3655 3660 His Met His Gly Phe Arg Arg Thr Leu Arg Asn Ala Val Leu Thr Gln 3665 3670 3675 3680 Lys Gln Asp Ser Leu Arg Ile Ile Ser Ile Gln Pro Val Ala Gly Thr 3685 3690 3695 Asn Gln Leu Asp Met Leu Phe Ala Val Glu Met His Ser Ser Glu Phe 3700 3705 3710 Tyr Lys Pro Ala Tyr Leu Ile Gln Lys Leu Ser Asn Ala Arg Arg His 3715 3720 3725 Leu Glu Asn Ile Met Arg Ile Ser Ala Ile Leu Glu Lys Asn Cys Ser 3730 3735 3740 Gly Leu Asp Cys Gln Glu Gln His Cys Glu Gln Gly Leu Ser Leu Asp 3745 3750 3755 3760 Ser His Ala Leu Met Thr Tyr Ser Thr Ala Arg Ile Ser Phe Val Cys 3765 3770 3775 Pro Arg Phe Tyr Arg Asn Val Arg Cys Thr Cys Asn Gly Gly Leu Cys 3780 3785 3790 Pro Gly Ser Asn Asp Pro Cys Val Glu Lys Pro Cys Pro Gly Asp Met 3795 3800 3805 Gln Cys Val Gly Tyr Glu Ala Ser Arg Arg Pro Phe Leu Cys Gln Cys 3810 3815 3820 Pro Pro Gly Lys Leu Gly Glu Cys Ser Gly His Thr Ser Leu Ser Phe 3825 3830 3835 3840 Ala Gly Asn Ser Tyr Ile Lys Tyr Arg Leu Ser Glu Asn Ser Lys Glu 3845 3850 3855 Glu Asp Phe Lys Leu Ala Leu Arg Leu Arg Thr Leu Gln Ser Asn Gly 3860 3865 3870 Ile Ile Met Tyr Thr Arg Ala Asn Pro Cys Ile Ile Leu Lys Ile Val 3875 3880 3885 Asp Gly Lys Leu Trp Phe Gln Leu Asp Cys Gly Ser Gly Pro Gly Ile 3890 3895 3900 Leu Gly Ile Ser Gly Arg Ala Val Asn Asp Gly Ser Trp His Ser Val 3905 3910 3915 3920 Phe Leu Glu Leu Asn Arg Asn Phe Thr Ser Leu Ser Leu Asp Asp Ser 3925 3930 3935 Tyr Val Glu Arg Arg Arg Ala Pro Leu Tyr Phe Gln Thr Leu Ser Thr 3940 3945 3950 Glu Ser Ser Ile Tyr Phe Gly Ala Leu Val Gln Ala Asp Asn Ile Arg 3955 3960 3965 Ser Leu Thr Asp Thr Arg Val Thr Gln Val Leu Ser Gly Phe Gln Gly 3970 3975 3980 Cys Leu Asp Ser Val Ile Leu Asn Asn Asn Glu Leu Pro Leu Gln Asn 3985 3990 3995 4000 Lys Arg Ser Ser Phe Ala Glu Val Val Gly Leu Thr Glu Leu Lys Leu 4005 4010 4015 Gly Cys Val Leu Tyr Pro Asp Ala Cys Lys Arg Ser Pro Cys Gln His 4020 4025 4030 Gly Gly Ser Cys Thr Gly Leu Pro Ser Gly Gly Tyr Gln Cys Thr Cys 4035 4040 4045 Leu Ser Gln Phe Thr Gly Arg Asn Cys Glu Ser Glu Ile Thr Ala Cys 4050 4055 4060 Phe Pro Asn Pro Cys Arg Asn Gly Gly Ser Cys Asp Pro Ile Gly Asn 4065 4070 4075 4080 Thr Phe Ile Cys Asn Cys Lys Ala Gly Leu Thr Gly Val Thr Cys Glu 4085 4090 4095 Glu Asp Ile Asn Glu Cys Glu Arg Glu Glu Cys Glu Asn Gly Gly Ser 4100 4105 4110 Cys Val Asn Val Phe Gly Ser Phe Leu Cys Asn Cys Thr Pro Gly Tyr 4115 4120 4125 Val Gly Gln Tyr Cys Gly Arg Pro Val Val Val Pro Asn Ile Gln Ala 4130 4135 4140 Gly His Ser Tyr Val Gly Lys Glu Glu Leu Ile Gly Ile Ala Val Val 4145 4150 4155 4160 Leu Phe Val Ile Phe Ile Leu Val Val Leu Phe Ile Val Phe Arg Lys 4165 4170 4175 Lys Val Phe Arg Lys Asn Tyr Ser Arg Asn Asn Ile Thr Leu Val Gln 4180 4185 4190 Asp Pro Ala Thr Ala Ala Leu Leu Asn Lys Ser Asn Gly Ile Pro Phe 4195 4200 4205 Arg Asn Leu Arg Gly Ser Gly Asp Gly Arg Asn Val Tyr Gln Glu Val 4210 4215 4220 Gly Pro Pro Gln Val Pro Val Arg Pro Met Ala Tyr Thr Pro Cys Phe 4225 4230 4235 4240 Gln Ser Asp Ser Arg Ser Asn Leu Asp Lys Ile Val Asp Gly Leu Gly 4245 4250 4255 Gly Glu His Gln Glu Met Thr Thr Phe His Pro Glu Ser Pro Arg Ile 4260 4265 4270 Leu Thr Ala Arg Arg Gly Val Val Val Cys Ser Val Ala Pro Asn Leu 4275 4280 4285 Pro Ala Val Ser Pro Cys Arg Ser Asp Cys Asp Ser Ile Arg Lys Asn 4290 4295 4300 Gly Trp Asp Ala Gly Thr Glu Asn Lys Gly Val Asp Asp Pro Gly Glu 4305 4310 4315 4320 Val Thr Cys Phe Ala Gly Ser Asn Lys Gly Ser Asn Ser Glu Val Gln 4325 4330 4335 Ser Leu Ser Ser Phe Gln Ser Asp Ser Gly Asp Asp Asn Ala Ser Ile 4340 4345 4350 Val Thr Val Ile Gln Leu Val Asn Asn Val Val Asp Thr Ile Glu Asn 4355 4360 4365 Glu Val Ser Val Met Asp Gln Gly Gln Asn Tyr Asn Arg Ala Tyr His 4370 4375 4380 Trp Asp Thr Ser Asp Trp Met Pro Gly Ala Arg Leu Ser Asp Ile Glu 4385 4390 4395 4400 Glu Val Pro Asn Tyr Glu Asn Gln Asp Gly Gly Ser Ala His Gln Gly 4405 4410 4415 Ser Thr Arg Glu Leu Glu Ser Asp Tyr Tyr Leu Gly Gly Tyr Asp Ile 4420 4425 4430 Asp Ser Glu Tyr Pro Pro Pro His Glu Glu Glu Phe Leu Ser Gln Asp 4435 4440 4445 Gln Leu Pro Pro Pro Leu Pro Glu Asp Phe Pro Asp Gln Tyr Glu Ala 4450 4455 4460 Leu Pro Pro Ser Gln Pro Val Ser Leu Ala Ser Thr Leu Ser Pro Asp 4465 4470 4475 4480 Cys Arg Arg Arg Pro Gln Phe His Pro Ser Gln Tyr Leu Pro Pro His 4485 4490 4495 Pro Phe Pro Asn Glu Thr Asp Leu Val Gly Pro Pro Ala Ser Cys Glu 4500 4505 4510 Phe Ser Thr Phe Ala Val Ser Met Asn Gln Gly Thr Glu Pro Thr Gly 4515 4520 4525 Pro Ala Asp Ser Val Ser Leu Ser Leu His Asn Ser Arg Gly Thr Ser 4530 4535 4540 Ser Ser Asp Val Ser Ala Asn Cys Gly Phe Asp Asp Ser Glu Val Ala 4545 4550 4555 4560 Met Ser Asp Tyr Glu Ser Val Gly Glu Leu Ser Leu Ala Ser Leu His 4565 4570 4575 Ile Pro Phe Val Glu Thr Gln His Gln Thr Gln Val 4580 4585

Claims

What is claimed is:

1. An isolated nucleic acid molecule comprising at least 24 contiguous bases of nucleotide sequence first disclosed in the NHP sequence described in SEQ ID NO: 1.

2. An isolated nucleic acid molecule comprising a nucleotide sequence that: (a) encodes the amino acid sequence shown in SEQ ID NO: 2; and (b) hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO:1 or the complement thereof.

3. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the amino acid sequence shown in SEQ ID NO:2.

4. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the amino acid sequence shown in SEQ ID NO:4.

5. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the amino acid sequence shown in SEQ ID NO:6.

6. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the amino acid sequence shown in SEQ ID NO:8.