Novel human hemicentin 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. 60/232,793, which was filed on Sep. 15, 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 membrane proteins. 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 over express 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 that 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] In addition to providing the structural and mechanical scaffolding for cells and tissues, proteins can also serve as recognition markers, mediate signal transduction, and can mediate or facilitate the passage of materials across the lipid bilayer. As such, proteins, and particularly protein ligands and membrane receptor proteins, are good drug targets and soluble formulations thereof can directly serve as therapeutic agents.

3. SUMMARY OF THE INVENTION

[0004] The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human hemicentin 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 variety of mammalian proteins such as hemicentins, titin, basement membrane proteins, semaphorins, fibulin, and cell adhesion proteins.

[0005] The novel human nucleic acid sequences described herein encode alternative proteins/open reading frames (ORFs) of 5,518 and 4,126 amino acids in length (SEQ ID NOS: 2 and 4).

[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:1-4 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:1-4 are "knocked-out" provide a unique source in which to elicit antibodies to homologous and orthologous proteins that would have been previously viewed by the immune system as "self+ and therefore would have failed to elicit significant antibody responses. To these ends, gene trapped knockout ES cells have been generated in murine homologs of the described NHPs.

[0007] Additionally, the unique NHP sequences described in SEQ ID NOS:1-4 are useful for the identification of protein coding sequence and mapping a unique gene to a particular chromosome. These sequences identify actual, biologically relevant, exon splice junctions as opposed to those that might have been predicted bioinformatically from genomic sequence alone.

[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 described NHP ORFs that encode 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, spinal cord, thymus, pituitary, lymph node, trachea, kidney, liver, prostate, testis, stomach, small intestine, skeletal muscle, adrenal gland, heart, uterus, mammary gland, adipose, skin, esophagus, bladder, cervix, rectum, pericardium, ovary, and gene trapped human cells.

[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., New York, at p. 2.10.3) and encodes a functionally equivalent expression product. 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. No. 5,837,458). The invention also includes degenerate nucleic acid variants of the disclosed NHP polynucleotide sequences.

[0013] 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).

[0014] 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.

[0015] 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: 1-4 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: 1-4, 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.

[0016] Addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-4 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:1-4.

[0017] 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.

[0018] 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:1-4 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.

[0019] Probes consisting of sequences first disclosed in SEQ ID NOS:1-4 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.

[0020] As an example of utility, the sequences first disclosed in SEQ ID NOS:1-4 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:1-4 in silico and by comparing previously collected genetic databases and the disclosed sequences using computer software known to those in the art.

[0021] Thus the sequences first disclosed in SEQ ID NOS:1-4 can be used to identify mutations associated with a particular disease and also as a diagnostic or prognostic assay.

[0022] 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: 1-4. 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.

[0023] 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 (for 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.

[0024] Inhibitory antisense or double stranded oligonucleotides can additionally comprise at least one modified base moiety that 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-N6-isopenten- yladenine, 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.

[0025] 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.

[0026] In yet another embodiment, the antisense oligonucleotide will comprise at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

[0027] 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'-0-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.

[0028] 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.

[0029] 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 Springs Harbor Press, N.Y.; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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, osteoporosis, 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.

[0035] 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.) 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.

[0036] 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.

[0037] 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.).

[0038] 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.

[0039] 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.

[0040] Various aspects of the invention are described in greater detail in the subsections below.

5.1 The NHP Sequences

[0041] 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 genomic sequence, ESTs, gene trapped sequence data, and cDNAs from mammary gland, thyroid, adipose, lymph node, testis, skeletal muscle, kidney, esophagus, heart, placenta, and bone marrow mRNAs (Edge Biosystems, Gaithersburg, Md.).

[0042] A number of polymorphism were identified during the sequencing of the NHPs that can result in a ser or pro being present at the amino acid (aa) position represented by, for example, position 133 of SEQ ID NO:2, and ile or asn at aa position 375, a lys or arg at aa position 691, a pro or leu at aa position 838, a ser or pro at aa position 1,082, a thr or ala at aa position 1,263, an asp or ala at aa position 1,556, a val or ala at aa position 2,245, a ile or thr at aa position 2,418, and a ser or thr at aa position 4,046. The present invention contemplates sequences comprising any of the above polymorphisms, as well as any and all combinations and permutations of the above.

[0043] The described NHPs are likely encoded on human chromosome 1 (see GENBANK accession no. AF156100).

[0044] An additional application of the described novel human polynucleotide sequences is their use 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.

[0045] 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.

[0046] 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.

[0047] The present invention provides for transgenic animals that carry the NHP transgene in all their cells, as well as animals that 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.

[0048] 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).

[0049] 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.

[0050] 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 that 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.

5.2 NHPS and NHP Polypeptides

[0051] NHPs, NHP polypeptides, NHP 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, for 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 disease. 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, arthritis, or as antiviral agents.

[0052] The Sequence Listing discloses the amino acid sequences encoded by the described NHP sequences. The NHPs display initiator methionines in DNA sequence contexts consistent with translation initiation sites, and a hydrophobic region at the N-terminus that may serve as a signal sequence, which indicates that the described NHPs is probably membrane-associated or secreted, or possibly cytoplasmic.

[0053] 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-l 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.

[0054] 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.). Such functionally equivalent NHP proteins include, but are not limited to, additions or substitutions of amino acid residues within the amino acid sequence encoded by the NHP nucleotide sequences described above, but that result in a silent change, thus producing a functionally equivalent expression product. 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.

[0055] 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 drug screening assays.

[0056] 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 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 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).

[0057] 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.

[0058] 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).

[0059] 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).

[0060] 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 that 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.

[0061] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines that stably express the NHP sequences described above can be engineered. Rather than using expression vectors that contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells 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 that 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.

[0062] 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 & 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, 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 & 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., 19,84, Gene 30:147).

[0063] 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.

[0064] 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

[0065] 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.

[0066] 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.

[0067] 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.

[0068] Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique that 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.

[0069] In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984, Proc. Natl. Acad. Sci., 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 constant region. 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.

[0070] 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.

[0071] Antibody fragments that 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.

[0072] 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 that 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.

[0073] 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).

[0074] 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

4 1 16557 DNA homo sapiens 1 atgatttcct gggaagttgt ccatacagta ttcctgtttg ctcttcttta ttcttcccta 60 gctcaagatg cgagccccca gtcagagatc agagctgagg aaattcccga gggggcctcc 120 acgttggctt ttgtgtttga tgtgactggt tctatgtatg atgatttagt tcaggtgatt 180 gaaggggctt ccaaaatttt ggagacgtct ttgaaaagac ctaaaagacc tcttttcaac 240 tttgcgttgg tgcctttcca tgatccagaa attggcccag tgacaattac cacagatccc 300 aagaaatttc aatatgaact cagagaactg tatgttcagg gtggtggtga ttgcccagaa 360 atgagtattg gagctataaa aattgccttg gaaattyctc ttcctggttc tttcatctat 420 gttttcactg atgctcggtc caaagattac cggctcaccc atgaggtgct gcaacttatc 480 caacagaaac agtcacaagt cgtatttgtt ctgactggag attgtgatga caggacccat 540 attggatata aagtctatga agaaattgcc tctacaagtt ctggtcaagt gttccatctg 600 gacaaaaaac aagttaatga ggtattaaaa tgggtagaag aagcagtaca ggcctccaaa 660 gttcaccttt tatccacaga tcatttggaa caggctgtaa atacttggag aattcctttt 720 gatcccagcc tgaaagaggt cactgtgtct ttgagtgggc cttctccaat gattgaaatt 780 cgcaatcctt tagggaagct gataaaaaag ggatttggcc tgcatgagct attaaatatc 840 cataactctg ccaaagtagt gaatgtgaaa gagccagagg ctggaatgtg gacagtgaag 900 acctcaagca gtggaaggca ctctgttcgc attactggcc tcagtactat tgatttccga 960 gctggctttt ctcgaaagcc caccctggac ttcaaaaaaa cagtcagcag accagtgcaa 1020 ggaataccta cctatgtact gctcaatact tctggaattt ccactccagc tagaatagat 1080 cttcttgaac ttttgagtat ctcaggaagt tctcttaaga ctawtcctgt taaatattac 1140 ccacatcgaa aaccttatgg catatggaat atttctgact ttgtaccacc aaatgaagct 1200 ttctttctca aagtaacagg ctatgataaa gatgattacc tcttccagag agtatcaagt 1260 gtttcctttt ctagtattgt cccagatgct cccaaagtta cgatgcctga gaaaacccca 1320 ggatactatc tgcagccggg ccaaattccc tgctctgttg acagtctttt gccctttacc 1380 ttgagctttg tcagaaatgg agttacactt ggagtagacc agtatttgaa agaatctgcc 1440 agtgtgaact tagatattgc aaaggtcact ttgtctgacg aaggtttcta tgaatgcatt 1500 gctgtcagca gtgcaggtac tggacgggca cagacatttt ttgacgtatc agagccccct 1560 ccggtcatcc aagtgcctaa caatgttaca gtcactcctg gagagagagc agttttaaca 1620 tgtctcatca tcagtgcggt ggattacaat ctaacctggc agaggaatga cagagatgtc 1680 agactggcag agccagcgag aattaggacc ttggctaatc tgtcattgga gctaaagagt 1740 gtgaaattca acgatgctgg agagtatcat tgtatggttt ctagtgaagg tggatcatca 1800 gccgcttcag ttttcctcac agtgcaagaa ccacccaaag tcactgtgat gcccaagaat 1860 cagtctttca caggagggtc tgaggtctcc atcatgtgtt ctgcaacagg ttatcccaaa 1920 ccaaagattg cctggaccgt taacgatatg tttatcgtgg gttcacacag gtataggatg 1980 acctcagatg gtaccttatt tatcaaaaat gcagctccca aagatgcagg gatctatggt 2040 tgcctagcaa gtaattcagc tggaacagat aracagaatt ctactctcag atacattgaa 2100 gcccctaagt tgatggtagt tcagagtgag ctcttggttg cccttgggga tataaccgtt 2160 atggaatgca aaacctctgg tattcctcca cctcaagtta aatggttcaa aggagatctt 2220 gagttgaggc cctcaacatt cctcattatt gaccctctct tgggactttt gaagattcaa 2280 gaaacacaag atctggatgc tggcgattat acctgtgtag ccatcaatga ggctggaaga 2340 gcaactggca agataactct ggatgttggc tcacctccag ttttcataca agaacctgct 2400 gatgtgtcta tggaaattgg ctcaaatgtg acattacctt gttatgttca gggttatcca 2460 gaaccaacaa tcaaatggcg aagattagac aacatgccaa ttttctcaag acytttttca 2520 gttagttcca tcagccaact aagaacagga gctctcttta ttttaaactt atgggcaagt 2580 gataaaggaa cctatatttg tgaagctgaa aaccagtttg gaaagatcca gtcagagaca 2640 acagtaacag tgaccggact tgttgctcca cttattggaa tcagcccttc agtggccaat 2700 gttattgaag gacagcagct tactttgccc tgtactctgt tagctggaaa tcccattcca 2760 gaacgtcggt ggattaagaa ttcagctatg ttgctccaaa atccttacat cactgtgcgc 2820 agtgatggga gcctccatat tgaaagagtt cagcttcagg atggtggtga atatacttgt 2880 gtggccagta acgttgctgg gaccaataac aaaactacct ctgtggttgt gcatgttctg 2940 ccaaccattc agcatgggca gcagatactc agtacaattg aaggcattcc agtaacttta 3000 ccatgcaaag caagtggaaa tcccaaaccg tctgtcatct ggtccaagaa aggagagctg 3060 atttcaacca gcagtgctaa gttttcagca ggagctgatg gtagtctgta tgtggtatca 3120 cctggaggag aggagagtgg ggagtatgtc tgcactgcca ccaatacagc cggctacgcc 3180 aaaaggaaag tgcagctaac agtctatgta aggcccagag tgtttggaga tcaacgagga 3240 ctgycccagg ataagcctgt tgagatctcc gtccttgcag gggaagaggt aacacttcca 3300 tgtgaagtga agagcttacc tccacccata attacttggg ccaaagaaac ccagctcatc 3360 tcaccgttct ctccaagaca cacattcctc ccttctggtt caatgaagat cactgaaacc 3420 cgcacttcag atagtgggat gtatctttgt gttgccacaa atattgctgg gaatgtgact 3480 caggctgtca aattaaatgt ccatgttcct ccaaagatac agcgtggacc taaacatctc 3540 aaagtccaag ttggtcaaag agtggatatt ccatgtaatg ctcaagggac tcctcttcct 3600 gtaatcacct ggtccaaagg tggaagcact atgctggttg atggagagca ccatgttagc 3660 aatccagacg gaactttaag catcgaccaa gccacgccct cagatgctgg catatataca 3720 tgtgttgcta ctaacatagc aggcactgat gaaacagaga taacgctaca tgtccaagaa 3780 ccacccrcag tggaagatct agaacctcca tataacacta ctttccaaga aagagtggcc 3840 aatcaacgca ttgaatttcc atgtcctgca aaaggtaccc ctaaaccaac catcaaatgg 3900 ttacacaatg gtagagagtt gacaggcaga gagcctggca tttctatctt ggaagatggc 3960 acattgctgg ttattgcttc tgttacaccc tatgacaatg gggagtacat ctgtgtggca 4020 gtcaatgaag ctggaaccac agaaagaaaa tataacctca aagtccatgt tcctccagta 4080 attaaagata aagaacaagt tacaaatgtg tcggtgttgt taaatcagct gaccaatctc 4140 ttctgtgaag tggaaggcac tccatctccc atcattatgt ggtataaaga taatgtccag 4200 gtgactgaaa gcagcactat tcagactgtg aacaatggga agatactgaa gctcttcaga 4260 gccactccag aggatgcagg aagatattcc tgcaaagcaa ttaatattgc aggcacttct 4320 cagaagtact ttaacattga tgtgctagtt ccacccacca taataggtac caacttccca 4380 aatgaagtct cagttgtcct caaccgtgac gtcgcccttg aatgccaggt caaaggcact 4440 ccctttcctg atattcattg gttcaaagat ggcaagcctt tatttttggg cgatcctaat 4500 gttgaacttc tagacagagg acaagtctta catttaaaga atgcacggag aaatgacaag 4560 gggcgctacc aatgtactgt gtctaatgca gctggcaaac aagccaagga tataaaactg 4620 actatctata ttccacctag tattaaagga ggaaatgtca ccacrgmcat atcagtattg 4680 atcaacagcc ttattaaact ggaatgtgaa acacggggac ttccaatgcc tgccattact 4740 tggtataagg acgggcagcc aatcatgtcc agctcacaag cactttatat tgataaagga 4800 caatatcttc atattcctcg agcacaggtc tctgattcag caacatatac gtgtcaygta 4860 gccaatgttg ctggaactgc tgaaaaatca ttccatgtgg atgtctatgt tcctccaatg 4920 attgaaggca acttggccac gcctttgaat aagcaagtag ttattgctca ttctctgaca 4980 ctggagtgca aagctgctgg aaacccttct cccattctca cctggttgaa agatggtgta 5040 cctgtgaaag ctaatgacaa tatccgcata gaagctggtg ggaagaaact cgaaatcatg 5100 agtgcccaag aaattgatcg aggacagtac atatgcgtgg ctaccagtgt ggcaggagaa 5160 aaggaaatca aatatgaagt tgatgtcttg gtgccaccag ctatagaagg aggagatgaa 5220 acatcttact tcattgtgat ggttaataac ttactggagc tagattgtca tgtgacaggc 5280 tctcccccac caactatcat gtggctgaag gatggccagt taattgatga aagggatgga 5340 ttcaagattt tattaaatgg acgcaaactg gttattgctc aggctcaagt gtcaaacaca 5400 ggcctttatc ggtgcatggc agcaaatact gctggagacc acaagaagga atttgaagtg 5460 actgttcatg ttcctccaac aatcaagtcc tcaggccttt ctgagagagt tgtggtaaaa 5520 tacaagcctg tcgccttgca gtgcatagcc aatgggattc caaatccttc cattacatgg 5580 ttaaaagatg accagcctgt gaacactgcc caaggaaacc ttaaaataca gtcttctggt 5640 cgagttctac aaattgccaa aaccctgttg gaagatgctg gcagatacac atgtgtggct 5700 accaacgcag ctggagaaac acaacagcac attcaactgc atgttcatga accacctagt 5760 ctggaagatg ctggaaaaat gctgaatgag actgtgttgg tgagcaaccc tgtacagctg 5820 gagtgtaagg cagctggaaa tcctgtgcct gttattacat ggtacaaaga taatcgtcta 5880 ctctcaggtt ccaccagcat gactttcttg aacagaggac agatcattga tattgaaagt 5940 gcccagatct cagatgctgg catatataaa tgcgtggcca tcaactcagc tggagctaca 6000 gagttatttt acagtctgca agttcatgtg gccccatcaa tttctggcag caataacatg 6060 gtggcagtgg tggttaataa cccggtgagg ttagaatgtg aagccagagg tattcctgcc 6120 ccaagtctga cctggttgaa agatgggagt cctgtttcta gtttttctaa tggattacag 6180 gttctctctg gtggtcgaat cctagcattg accagtgcac aaatcagcga cacaggaagg 6240 tacacctgcg tggcagtgaa tgctgctgga gaaaagcaaa gggacattga cctccgagta 6300 tatgttccgc caaatattat gggagaagaa cagaatgtct ctgtcctcat tagccaagct 6360 gtggaattac tatgtcaaag tgatgctatt cccccaccta ctcttacttg gttaaaagac 6420 ggccacccct tgctgaagaa accaggcctc agtatatctg aaaatagaag tgtgttaaag 6480 attgaagatg ctcaggttca agacactggt cgttacactt gtgaagcaac aaatgttgct 6540 ggaaaaactg aaaaaaacta caatgtcaac atttgggtcc ccccaaatat tggtggttct 6600 gatgaactta ctcaacttac agtcattgaa gggaatctca ttagtctgtt gtgtgaatca 6660 agtggtattc cacccccaaa tctcatctgg aagaagaaag gctctccagt gctgactgat 6720 tccatggggc gagytagaat tttatctggg ggcaggcaat tacaaatttc aattgctgaa 6780 aagtctgatg cagcactcta ttcatgtgtg gcgtcgaatg ttgctgggac tgcaaagaaa 6840 gaatacaatc tgcaagttta cattagacca accataacca acagtggcag ccaccctact 6900 gaaattattg tgacccgagg gaagagtatc tccttggagt gtgaggtgca gggtattcca 6960 ccaccaacag tgacctggat gaaagatggc caccccttga tcaaggcaaa gggagtagaa 7020 atactggatg aaggtcacat ccttcagctg aagaacattc atgtatctga cacaggccgt 7080 tatgtgtgtg ttgctgtgaa tgtagcagga atgactgaca aaaaatatga cttaagtgtc 7140 catgctcctc caagcatcat aggaaaccac aggtcacctg aaaatattag tgtggtagaa 7200 aagaactcag tatctttgac ttgtgaagct tctggaattc ccctgccttc cayaacctgg 7260 ttcaaagatg ggtggcctgt cagccttagc aattctgtga ggattctttc aggaggcagg 7320 atgctacggc tgatgcagac cacaatggaa gatgctggcc aatatacttg cgttgtaagg 7380 aatgcagctg gtgaagaaag aaaaatcttt gggctttcag tattagtacc acctcatatt 7440 gtgggtgaaa atacattgga agatgtgaag gtaaaagaga aacagagtgt tacgctgact 7500 tgtgaagtga cagggaatcc agtgccagaa attacatggc acaaagatgg gcagcccctc 7560 caagaagatg aagcccatca cattatatct ggtggccgtt ttcttcaaat taccaatgtc 7620 caggtgccac acactggaag atatacatgt ttggcttcca gtccagctgg ccacaagagc 7680 aggagcttca gtcttaatgt atttgtatct cctacaattg ctggtgtagg tagtgatggc 7740 aaccctgaag atgtcactgt catccttaac agccctacat ctttggtctg tgaagcttat 7800 tcatatcctc cagctaccat cacctggttt aaggatggca ctcctttaga atctaaccga 7860 aatattcgta ttcttccagg aggcagaact ctgcagatcc tcaatgcaca ggaggacaat 7920 gctggaagat actcttgtgt agccacgaat gaggctggag aaatgataaa gcactatgaa 7980 gtgaaggtgt acattccacc cataatcaat aaaggggacc tttgggggcc aggtctttcc 8040 cctaaagaag tgaagatcaa agtaaacaac actctgacct tggaatgtga agcgtatgca 8100 attccttctg cctccctcag ctggtacaag gatggacagc cccttaaatc cgatgatcat 8160 gttaatattg ctgcgaatgg acacacactt caaataaagg aggctcaaat atcagacacc 8220 ggacgatata cttgtgtagc atctaacatt gcaggtgaag atgagttgga ttttgatgtg 8280 aatattcaag ttcctccaag ttttcagaaa ctctgggaaa taggaaacat gctagatact 8340 ggcaggaatg gtgaagccaa agatgtgatc atcaacaatc ccatttctct ttactgtgag 8400 acaaatgctg ctccccctcc tacactgaca tggtacaaag atggccaccc tctgacctca 8460 agtgataaag tattgatttt gccaggaggg cgagtgttgc agattcctcg ggctaaagta 8520 gaagatgctg ggagatacac atgtgtggct gtgaatgagg ctggagaaga ttcccttcaa 8580 tatgatgtcc gtgtactcgt gccgccaatt atcaagggag caaatagtga tctccctgaa 8640 gaggtcaccg tgctggtgaa caagagtgca ctgatagagt gtttatccag tggcagccca 8700 gcaccaagga attcctggca gaaagatgga cagcccttgc tagaagatga ccatcataaa 8760 tttctatcta atggacgaat tctgcagatt ctgaatactc aaataacaga tatcggcagg 8820 tatgtgtgtg ttgctgagaa cacagctggg agtgccaaaa aatattttaa cctcaatgtt 8880 catgttcctc caagtgtcat tggtcctaaa tctgaaaatc ttaccgtcgt ggtgaacaat 8940 ttcatctctt tgacctgtga ggtctctggt tttccacctc ctgacctcag ctggctcaag 9000 aatgaacagc ccatcaaact gaacacaaat actctcattg tgcctggtgg tcgaactcta 9060 cagattattc gggccaaggt atcagatggt ggtgaataca cttgtatagc tatcaatcaa 9120 gctggcgaaa gcaagaaaaa gttttccctg actgtttatg tgcccccaag cattaaagac 9180 catgacagtg aatctctttc tgtagttaat gtaagagagg gaacttctgt gtctttggag 9240 tgtgagtcga acgctgtgcc acctccagtc atcacttggt ataagaatgg gcggatgata 9300 acagagtcta ctcatgtgga gattttagct gatggacaaa tgctacacat taagaaagct 9360 gaggtatctg acacaggcca gtatgtatgt agagctataa atgtagcagg acgggatgat 9420 aaaaatttcc acctcaatgt atatgtgcca cccagtattg aaggacctga aagagaagtg 9480 attgtggaga cgatcagcaa tcctgtgaca ttaacatgtg atgccactgg gatcccacct 9540 cccacgatag catggttaaa gaaccacaag cgcatagaaa attctgactc actggaagtt 9600 cgtattttgt ctggaggtag caaactccag attgcccggt ctcagcattc agatagtgga 9660 aactatacat gtattgcttc aaatatggag ggaaaagccc agaaatatta ctttctttca 9720 attcaagttc ctccaagtgt tgctggtgct gaaattccaa gtgatgtcag tgtccttcta 9780 ggagaaaatg ttgagctggt ctgcaatgca aatggcattc ctactccact tattcaatgg 9840 cttaaagatg gaaagcccat agctagtggt gaaacagaaa gaatccgagt gagtgcaaat 9900 ggcagcacat taaacattta tggagctctt acatctgaca cggggaaata cacatgtgtt 9960 gctactaatc ccgctggaga agaagaccga atttttaact tgaatgtcta tgttacacct 10020 acaattaggg gtaataaaga tgaagcagag aaactaatga ctttagtgga tacttcaata 10080 aatattgaat gcagagccac agggacgcct ccaccacaga taaactggct gaagaatgga 10140 cttcctctgc ctctctcctc ccatatccgg ttactggcag caggacaagt tatcaggatt 10200 gtgagagctc aggtgtctga tgtcgctgtg tatacttgtg tggcctccaa cagagctggg 10260 gtggataata agcattacaa tcttcaagtg tttgcaccac caaatatgga caattcaatg 10320 gggacagagg aaatcacagt tctcaaaggt agttccacct ctatggcatg cattactgat 10380 ggaaccccag ctcccagtat ggcctggctt agagatggcc agcctctggg gcttgatgcc 10440 catctgacag tcagcaccca tggaatggtc ctgcagctcc tcaaagcaga gactgaagat 10500 tcgggaaagt acacctgcat tgcctcaaat gaagctggag aagtcagcaa gcactttatc 10560 ctcaaggtcc tagaaccacc tcacattaat ggatctgaag aacatgaaga gatatcagta 10620 attgttaata acccacttga acttacctgc attgcttctg gaatcccagc ccctaaaatg 10680 acctggatga aagatggccg gccccttcca cagacggatc aagtgcaaac tctaggagga 10740 ggagaggttc ttcgaatttc tactgctcag gtggaggata caggaagata tacatgtctg 10800 gcatccagtc ctgcaggaga tgatgataag gaatatctag tgagagtgca tgtacctcct 10860 aatattgctg gaactgatga gccccgggat atcactgtgt tacggaacag acaagtgaca 10920 ttggaatgca agtcagatgc agtgccccca cctgtaatta cttggctcag aaatggagaa 10980 cggttacagg caacacctcg agtgcgaatc ctatctggag ggagatactt gcaaatcaac 11040 aatgctgacc taggtgatac agccaattat acctgtgttg ccagcaacat tgcaggaaag 11100 actacaagag aatttattct cactgtaaat gttcctccaa acataaaggg gggcccccag 11160 agccttgtaa ttcttttaaa taagtcaact gtattggaat gcatcgctga aggtgtgcca 11220 actccaagga taacatggag aaaggatgga gctgttctag ctgggaatca tgcaagatat 11280 tccatcttgg aaaatggatt ccttcatatt caatcagcac atgtcactga cactggacgg 11340 tatttgtgta tggccaccaa tgctgctgga acagatcgca ggcgaataga tttacaggtc 11400 catgttcctc catctattgc tccgggtcct accaacatga ctgtaatagt aaatgttcaa 11460 actactctgg cttgtgaggc tactgggata ccaaaaccat caatcaattg gagaaaaaat 11520 gggcatcttc ttaatgtgga tcaaaatcag aactcataca ggctcctttc ttcaggttca 11580 ctagtaatta tttccccttc tgtggatgac actgcaacct atgaatgtac tgtgacaaac 11640 ggtgctggag atgataaaag aactgtggat ctcactgtcc aagttccacc ttccatagct 11700 gatgagccta cagatttcct agtaaccaaa catgccccag cagtaattac ctgcactgct 11760 tcgggagttc catttccctc aattcactgg accaaaaatg gtataagact gcttcccagg 11820 ggagatggct atagaattct gtcctcagga gcaattgaaa tacttgccac ccaattaaac 11880 catgctggaa gatacacttg tgtcgctagg aatgcggctg gctctgcaca tcgacacgts 11940 acccttcatg ttcatgagcc tccagtcatt cagccccaac caagtgaact acacgtcatt 12000 ctgaacaatc ctattttatt accatgtgaa gcaacaggga cacccagtcc tttcattact 12060 tggcaaaaag aaggcatcaa tgttaacact tcaggcagaa accatgcagt tcttcctagt 12120 ggcggcttac agatcwccag agctgtccga gaggatgctg gcacttacat gtgtgtggcc 12180 cagaacccgg ctggtacagc cttgggcaaa atcaagttaa atgtccaagt tcctccagtc 12240 attagccctc atctaaagga atatgttatt gctgtggaca agcccatcac gttatcctgt 12300 gaagcagatg gcctccctcc gcctgacatt acatggcata aagatgggcg tgcaattgtg 12360 gaatctatcc gccagcgcgt cctcagctct ggctctctgc aaatagcatt tgtccagcct 12420 ggtgatgctg gccattacac gtgcatggca gccaatgtag caggatcaag cagcacaagc 12480 accaagctca ccgtccatgt accacccagg atcagaagta cagaaggaca ctacacggtc 12540 aatgagaatt cacaagccat tcttccatgc gtagctgatg gaatccccac accagcaatt 12600 aactggaaaa aagacaatgt tcttttagct aacttgttag gaaaatacac tgctgaacca 12660 tatggagaac tcattttaga aaatgttgtg ctggaggatt ctggcttcta tacctgtgtt 12720 gctaacaatg ctgcaggtga agatacacac actgtcagcc tgactgtgca tgttctcccc 12780 acttttactg aacttcctgg agacgtgtca ttaaataaag gagaacagct acgattaagc 12840 tgtaaagcta ctggtattcc attgcccaaa ttaacatgga ccttcaataa caatattatt 12900 ccagcccact ttgacagtgt gaatggacac agtgaacttg ttattgaaag agtgtcaaaa 12960 gaggattcag gtacttatgt gtgcaccgca gagaacagcg ttggctttgt gaaggcaatt 13020 ggatttgttt atgtgaaaga acctccagtc ttcaaaggtg attatccttc taactggatt 13080 gaaccacttg gtgggaatgc aatcctgaat tgtgaggtga aaggagaccc caccccaacc 13140 atccagtgga acagaaaggg agtggatatt gaaattagcc acagaatccg gcaactgggc 13200 aatggctccc tggccatcta tggcactgtt aatgaagatg ccggtgacta tacatgtgta 13260 gctaccaatg aagctggggt ggtggagcgc agcatgagtc tgactctgca aagtcctcct 13320 attatcactc ttgagccagt ggaaactgtt attaatgctg gtggcaaaat catattgaat 13380 tgtcaggcaa ctggagagcc tcaaccaacc attacatggt cccgtcaagg gcactctatt 13440 tcctgggatg accgggttaa cgtgttgtcc aacaactcat tatatattgc tgatgctcag 13500 aaagaagata cctctgaatt tgaatgtgtt gctcgaaact taatgggttc tgtccttgtc 13560 agagtgccag tcatagtcca ggttcatggt ggattttccc agtggtctgc atggagagcc 13620 tgcagtgtca cctgtggaaa aggcatccaa aagaggagtc gtctgtgcaa ccagcccctt 13680 ccagccaatg gtgggaagcc ctgccaaggt tcagatttgg aaatgcgaaa ctgtcaaaat 13740 aagccttgtc cagtggatgg tagctggtcg gaatggagtc tttgggaaga atgcacaagg 13800 agctgtggac gcggcaacca aaccaggacc aggacttgca ataatccatc agttcagcat 13860 ggtgggcggc catgtgaagg gaatgctgtg gaaataatta tgtgcaacat taggccttgc 13920 ccagttcatg gagcatggag cgcttggcag ccttggggaa catgcagcga aagttgtggg 13980 aaaggtactc agacaagagc aagactttgt aataacccac caccagcgtt tggtgggtcc 14040 tactgtgatg gagcagaaac acagatgcaa gtttgcaatg aaagaaattg tccaattcat 14100 ggcaagtggg cgacttgggc cagttggagt gcctgttctg tgtcatgtgg aggaggtgcc 14160 agacagagaa caaggggctg ctccgaccct gtgccccagt atggaggaag gaaatgcgaa 14220 gggagtgatg tccagagtga tttttgcaac agtgaccctt gcccaaccca tggtaactgg 14280 agtccttgga gtggctgggg aacatgcagc cggacgtgta acggagggca gatgcggcgg 14340 taccgcacat gtgataaccc tcctccctcc aatgggggaa gagcttgtgg gggaccagac 14400 tcccagatcc agaggtgcaa cactgacatg tgtcctgtgg atggaagttg gggaagctgg 14460 catagttgga gccagtgctc tgcctcctgt ggaggaggtg aaaagactcg gaagcggctg 14520 tgcgaccatc ctgtgccagt taaaggtggc cgtccctgtc ccggagacac tactcaggtg 14580 accaggtgca atgtacaagc atgtccaggt gggccccagc gagccagagg aagtgttatt 14640 ggaaatatta atgatgttga atttggaatt gctttcctta atgccacaat aactgatagc 14700 cctaactctg atactagaat aatacgtgcc aaaattacca atgtacctcg tagtcttggt 14760 tcagcaatga gaaagatagt ttctattcta aatcccattt attggacaac agcaaaggaa 14820 ataggagaag cagtcaatgg ctttaccctc accaatgcag tcttcaaaag agaaactcaa 14880 gtggaatttg caactggaga aatcttgcag atgagtcata ttgcccgggg cttggattcc 14940 gatggttctt tgctgctaga tatcgttgtg agtggctatg tcctacagct tcagtcacct 15000 gctgaagtca ctgtaaagga ttacacagag gactacattc

aaacaggtcc tgggcagctg 15060 tacgcctact caacccggct gttcaccatt gatggcatca gcatcccata cacatggaac 15120 cacaccgttt tctatgatca ggcacaggga agaatgcctt tcttggttga aacacttcat 15180 gcatcctctg tggaatctga ctataaccag atagaagaga cactgggttt taaaattcat 15240 gcttcaatat ccaaaggaga tcgcagtaat cagtgcccct ccgggtttac cttagactca 15300 gttggacctt tttgtgctga tgaggatgaa tgtgcagcag ggaatccctg ctcccatagc 15360 tgccacaatg ccatggggac ttactactgc tcctgcccta aaggcctcac catagctgca 15420 gatggaagaa cttgtcaaga tattgatgag tgtgctttgg gtaggcatac ctgccacgct 15480 ggtcaggact gtgacaatac gattggatct tatcgctgtg tggtccgttg tggaagtggc 15540 tttcgaagaa cctctgatgg gctgagttgt caagatatta atgaatgtca agaatccagc 15600 ccctgtcacc agcgctgttt caatgccata ggaagtttcc attgtggatg tgaacctggg 15660 tatcagctca aaggcagaaa atgcatggat gtgaacgagt gtagacaaaa tgtatgcaga 15720 ccagatcagc actgtaagaa cacccgtggt ggctataagt gcattgatct ttgtccaaat 15780 ggaatgacca aggcagaaaa tggaacctgt attgatattg atgaatgtaa agatgggacc 15840 catcagtgca gatataacca gatatgtgag aatacaagag gcagctatcg ttgtgtatgc 15900 ccaagaggtt atcggtctca aggagttgga agaccctgca tggatattga tgaatgtgaa 15960 aatacagatg cctgccagca tgagtgtaag aatacctttg gaagttatca gtgcatctgc 16020 ccacctggct atcaactcac acacaatgga aagacatgcc aagatatcga tgaatgtctg 16080 gagcagaatg tgcactgtgg acccaatcgc atgtgcttca acatgagagg aagctaccag 16140 tgcatcgata caccctgtcc acccaactac caacgggatc ctgtttcagg gttctgcctc 16200 aagaactgtc cacccaatga tttggaatgt gccttgagcc catatgcctt ggaatacaaa 16260 ctcgtctccc tcccatttgg aatagccacc aatcaagatt taatccggct ggttgcatac 16320 acacaggatg gagtgatgca tcccaggaca actttcctca tggtagatga ggaacagact 16380 gttccttttg ccttgaggga tgaaaacctg aaaggagtgg tgtatacaac acgaccacta 16440 cgagaagcag agacctaccg catgagggtc cgagcctcat cctacagtgc caatgggacc 16500 attgaatatc agaccacatt catagtttat atagctgtgt ccgcctatcc atactaa 16557 2 5518 PRT homo sapiens VARIANT (1)...(5518) Xaa = Any Amino Acid 2 Met Ile Ser Trp Glu Val Val His Thr Val Phe Leu Phe Ala Leu Leu 1 5 10 15 Tyr Ser Ser Leu Ala Gln Asp Ala Ser Pro Gln Ser Glu Ile Arg Ala 20 25 30 Glu Glu Ile Pro Glu Gly Ala Ser Thr Leu Ala Phe Val Phe Asp Val 35 40 45 Thr Gly Ser Met Tyr Asp Asp Leu Val Gln Val Ile Glu Gly Ala Ser 50 55 60 Lys Ile Leu Glu Thr Ser Leu Lys Arg Pro Lys Arg Pro Leu Phe Asn 65 70 75 80 Phe Ala Leu Val Pro Phe His Asp Pro Glu Ile Gly Pro Val Thr Ile 85 90 95 Thr Thr Asp Pro Lys Lys Phe Gln Tyr Glu Leu Arg Glu Leu Tyr Val 100 105 110 Gln Gly Gly Gly Asp Cys Pro Glu Met Ser Ile Gly Ala Ile Lys Ile 115 120 125 Ala Leu Glu Ile Xaa Leu Pro Gly Ser Phe Ile Tyr Val Phe Thr Asp 130 135 140 Ala Arg Ser Lys Asp Tyr Arg Leu Thr His Glu Val Leu Gln Leu Ile 145 150 155 160 Gln Gln Lys Gln Ser Gln Val Val Phe Val Leu Thr Gly Asp Cys Asp 165 170 175 Asp Arg Thr His Ile Gly Tyr Lys Val Tyr Glu Glu Ile Ala Ser Thr 180 185 190 Ser Ser Gly Gln Val Phe His Leu Asp Lys Lys Gln Val Asn Glu Val 195 200 205 Leu Lys Trp Val Glu Glu Ala Val Gln Ala Ser Lys Val His Leu Leu 210 215 220 Ser Thr Asp His Leu Glu Gln Ala Val Asn Thr Trp Arg Ile Pro Phe 225 230 235 240 Asp Pro Ser Leu Lys Glu Val Thr Val Ser Leu Ser Gly Pro Ser Pro 245 250 255 Met Ile Glu Ile Arg Asn Pro Leu Gly Lys Leu Ile Lys Lys Gly Phe 260 265 270 Gly Leu His Glu Leu Leu Asn Ile His Asn Ser Ala Lys Val Val Asn 275 280 285 Val Lys Glu Pro Glu Ala Gly Met Trp Thr Val Lys Thr Ser Ser Ser 290 295 300 Gly Arg His Ser Val Arg Ile Thr Gly Leu Ser Thr Ile Asp Phe Arg 305 310 315 320 Ala Gly Phe Ser Arg Lys Pro Thr Leu Asp Phe Lys Lys Thr Val Ser 325 330 335 Arg Pro Val Gln Gly Ile Pro Thr Tyr Val Leu Leu Asn Thr Ser Gly 340 345 350 Ile Ser Thr Pro Ala Arg Ile Asp Leu Leu Glu Leu Leu Ser Ile Ser 355 360 365 Gly Ser Ser Leu Lys Thr Xaa Pro Val Lys Tyr Tyr Pro His Arg Lys 370 375 380 Pro Tyr Gly Ile Trp Asn Ile Ser Asp Phe Val Pro Pro Asn Glu Ala 385 390 395 400 Phe Phe Leu Lys Val Thr Gly Tyr Asp Lys Asp Asp Tyr Leu Phe Gln 405 410 415 Arg Val Ser Ser Val Ser Phe Ser Ser Ile Val Pro Asp Ala Pro Lys 420 425 430 Val Thr Met Pro Glu Lys Thr Pro Gly Tyr Tyr Leu Gln Pro Gly Gln 435 440 445 Ile Pro Cys Ser Val Asp Ser Leu Leu Pro Phe Thr Leu Ser Phe Val 450 455 460 Arg Asn Gly Val Thr Leu Gly Val Asp Gln Tyr Leu Lys Glu Ser Ala 465 470 475 480 Ser Val Asn Leu Asp Ile Ala Lys Val Thr Leu Ser Asp Glu Gly Phe 485 490 495 Tyr Glu Cys Ile Ala Val Ser Ser Ala Gly Thr Gly Arg Ala Gln Thr 500 505 510 Phe Phe Asp Val Ser Glu Pro Pro Pro Val Ile Gln Val Pro Asn Asn 515 520 525 Val Thr Val Thr Pro Gly Glu Arg Ala Val Leu Thr Cys Leu Ile Ile 530 535 540 Ser Ala Val Asp Tyr Asn Leu Thr Trp Gln Arg Asn Asp Arg Asp Val 545 550 555 560 Arg Leu Ala Glu Pro Ala Arg Ile Arg Thr Leu Ala Asn Leu Ser Leu 565 570 575 Glu Leu Lys Ser Val Lys Phe Asn Asp Ala Gly Glu Tyr His Cys Met 580 585 590 Val Ser Ser Glu Gly Gly Ser Ser Ala Ala Ser Val Phe Leu Thr Val 595 600 605 Gln Glu Pro Pro Lys Val Thr Val Met Pro Lys Asn Gln Ser Phe Thr 610 615 620 Gly Gly Ser Glu Val Ser Ile Met Cys Ser Ala Thr Gly Tyr Pro Lys 625 630 635 640 Pro Lys Ile Ala Trp Thr Val Asn Asp Met Phe Ile Val Gly Ser His 645 650 655 Arg Tyr Arg Met Thr Ser Asp Gly Thr Leu Phe Ile Lys Asn Ala Ala 660 665 670 Pro Lys Asp Ala Gly Ile Tyr Gly Cys Leu Ala Ser Asn Ser Ala Gly 675 680 685 Thr Asp Xaa Gln Asn Ser Thr Leu Arg Tyr Ile Glu Ala Pro Lys Leu 690 695 700 Met Val Val Gln Ser Glu Leu Leu Val Ala Leu Gly Asp Ile Thr Val 705 710 715 720 Met Glu Cys Lys Thr Ser Gly Ile Pro Pro Pro Gln Val Lys Trp Phe 725 730 735 Lys Gly Asp Leu Glu Leu Arg Pro Ser Thr Phe Leu Ile Ile Asp Pro 740 745 750 Leu Leu Gly Leu Leu Lys Ile Gln Glu Thr Gln Asp Leu Asp Ala Gly 755 760 765 Asp Tyr Thr Cys Val Ala Ile Asn Glu Ala Gly Arg Ala Thr Gly Lys 770 775 780 Ile Thr Leu Asp Val Gly Ser Pro Pro Val Phe Ile Gln Glu Pro Ala 785 790 795 800 Asp Val Ser Met Glu Ile Gly Ser Asn Val Thr Leu Pro Cys Tyr Val 805 810 815 Gln Gly Tyr Pro Glu Pro Thr Ile Lys Trp Arg Arg Leu Asp Asn Met 820 825 830 Pro Ile Phe Ser Arg Xaa Phe Ser Val Ser Ser Ile Ser Gln Leu Arg 835 840 845 Thr Gly Ala Leu Phe Ile Leu Asn Leu Trp Ala Ser Asp Lys Gly Thr 850 855 860 Tyr Ile Cys Glu Ala Glu Asn Gln Phe Gly Lys Ile Gln Ser Glu Thr 865 870 875 880 Thr Val Thr Val Thr Gly Leu Val Ala Pro Leu Ile Gly Ile Ser Pro 885 890 895 Ser Val Ala Asn Val Ile Glu Gly Gln Gln Leu Thr Leu Pro Cys Thr 900 905 910 Leu Leu Ala Gly Asn Pro Ile Pro Glu Arg Arg Trp Ile Lys Asn Ser 915 920 925 Ala Met Leu Leu Gln Asn Pro Tyr Ile Thr Val Arg Ser Asp Gly Ser 930 935 940 Leu His Ile Glu Arg Val Gln Leu Gln Asp Gly Gly Glu Tyr Thr Cys 945 950 955 960 Val Ala Ser Asn Val Ala Gly Thr Asn Asn Lys Thr Thr Ser Val Val 965 970 975 Val His Val Leu Pro Thr Ile Gln His Gly Gln Gln Ile Leu Ser Thr 980 985 990 Ile Glu Gly Ile Pro Val Thr Leu Pro Cys Lys Ala Ser Gly Asn Pro 995 1000 1005 Lys Pro Ser Val Ile Trp Ser Lys Lys Gly Glu Leu Ile Ser Thr Ser 1010 1015 1020 Ser Ala Lys Phe Ser Ala Gly Ala Asp Gly Ser Leu Tyr Val Val Ser 1025 1030 1035 1040 Pro Gly Gly Glu Glu Ser Gly Glu Tyr Val Cys Thr Ala Thr Asn Thr 1045 1050 1055 Ala Gly Tyr Ala Lys Arg Lys Val Gln Leu Thr Val Tyr Val Arg Pro 1060 1065 1070 Arg Val Phe Gly Asp Gln Arg Gly Leu Xaa Gln Asp Lys Pro Val Glu 1075 1080 1085 Ile Ser Val Leu Ala Gly Glu Glu Val Thr Leu Pro Cys Glu Val Lys 1090 1095 1100 Ser Leu Pro Pro Pro Ile Ile Thr Trp Ala Lys Glu Thr Gln Leu Ile 1105 1110 1115 1120 Ser Pro Phe Ser Pro Arg His Thr Phe Leu Pro Ser Gly Ser Met Lys 1125 1130 1135 Ile Thr Glu Thr Arg Thr Ser Asp Ser Gly Met Tyr Leu Cys Val Ala 1140 1145 1150 Thr Asn Ile Ala Gly Asn Val Thr Gln Ala Val Lys Leu Asn Val His 1155 1160 1165 Val Pro Pro Lys Ile Gln Arg Gly Pro Lys His Leu Lys Val Gln Val 1170 1175 1180 Gly Gln Arg Val Asp Ile Pro Cys Asn Ala Gln Gly Thr Pro Leu Pro 1185 1190 1195 1200 Val Ile Thr Trp Ser Lys Gly Gly Ser Thr Met Leu Val Asp Gly Glu 1205 1210 1215 His His Val Ser Asn Pro Asp Gly Thr Leu Ser Ile Asp Gln Ala Thr 1220 1225 1230 Pro Ser Asp Ala Gly Ile Tyr Thr Cys Val Ala Thr Asn Ile Ala Gly 1235 1240 1245 Thr Asp Glu Thr Glu Ile Thr Leu His Val Gln Glu Pro Pro Xaa Val 1250 1255 1260 Glu Asp Leu Glu Pro Pro Tyr Asn Thr Thr Phe Gln Glu Arg Val Ala 1265 1270 1275 1280 Asn Gln Arg Ile Glu Phe Pro Cys Pro Ala Lys Gly Thr Pro Lys Pro 1285 1290 1295 Thr Ile Lys Trp Leu His Asn Gly Arg Glu Leu Thr Gly Arg Glu Pro 1300 1305 1310 Gly Ile Ser Ile Leu Glu Asp Gly Thr Leu Leu Val Ile Ala Ser Val 1315 1320 1325 Thr Pro Tyr Asp Asn Gly Glu Tyr Ile Cys Val Ala Val Asn Glu Ala 1330 1335 1340 Gly Thr Thr Glu Arg Lys Tyr Asn Leu Lys Val His Val Pro Pro Val 1345 1350 1355 1360 Ile Lys Asp Lys Glu Gln Val Thr Asn Val Ser Val Leu Leu Asn Gln 1365 1370 1375 Leu Thr Asn Leu Phe Cys Glu Val Glu Gly Thr Pro Ser Pro Ile Ile 1380 1385 1390 Met Trp Tyr Lys Asp Asn Val Gln Val Thr Glu Ser Ser Thr Ile Gln 1395 1400 1405 Thr Val Asn Asn Gly Lys Ile Leu Lys Leu Phe Arg Ala Thr Pro Glu 1410 1415 1420 Asp Ala Gly Arg Tyr Ser Cys Lys Ala Ile Asn Ile Ala Gly Thr Ser 1425 1430 1435 1440 Gln Lys Tyr Phe Asn Ile Asp Val Leu Val Pro Pro Thr Ile Ile Gly 1445 1450 1455 Thr Asn Phe Pro Asn Glu Val Ser Val Val Leu Asn Arg Asp Val Ala 1460 1465 1470 Leu Glu Cys Gln Val Lys Gly Thr Pro Phe Pro Asp Ile His Trp Phe 1475 1480 1485 Lys Asp Gly Lys Pro Leu Phe Leu Gly Asp Pro Asn Val Glu Leu Leu 1490 1495 1500 Asp Arg Gly Gln Val Leu His Leu Lys Asn Ala Arg Arg Asn Asp Lys 1505 1510 1515 1520 Gly Arg Tyr Gln Cys Thr Val Ser Asn Ala Ala Gly Lys Gln Ala Lys 1525 1530 1535 Asp Ile Lys Leu Thr Ile Tyr Ile Pro Pro Ser Ile Lys Gly Gly Asn 1540 1545 1550 Val Thr Thr Xaa Ile Ser Val Leu Ile Asn Ser Leu Ile Lys Leu Glu 1555 1560 1565 Cys Glu Thr Arg Gly Leu Pro Met Pro Ala Ile Thr Trp Tyr Lys Asp 1570 1575 1580 Gly Gln Pro Ile Met Ser Ser Ser Gln Ala Leu Tyr Ile Asp Lys Gly 1585 1590 1595 1600 Gln Tyr Leu His Ile Pro Arg Ala Gln Val Ser Asp Ser Ala Thr Tyr 1605 1610 1615 Thr Cys His Val Ala Asn Val Ala Gly Thr Ala Glu Lys Ser Phe His 1620 1625 1630 Val Asp Val Tyr Val Pro Pro Met Ile Glu Gly Asn Leu Ala Thr Pro 1635 1640 1645 Leu Asn Lys Gln Val Val Ile Ala His Ser Leu Thr Leu Glu Cys Lys 1650 1655 1660 Ala Ala Gly Asn Pro Ser Pro Ile Leu Thr Trp Leu Lys Asp Gly Val 1665 1670 1675 1680 Pro Val Lys Ala Asn Asp Asn Ile Arg Ile Glu Ala Gly Gly Lys Lys 1685 1690 1695 Leu Glu Ile Met Ser Ala Gln Glu Ile Asp Arg Gly Gln Tyr Ile Cys 1700 1705 1710 Val Ala Thr Ser Val Ala Gly Glu Lys Glu Ile Lys Tyr Glu Val Asp 1715 1720 1725 Val Leu Val Pro Pro Ala Ile Glu Gly Gly Asp Glu Thr Ser Tyr Phe 1730 1735 1740 Ile Val Met Val Asn Asn Leu Leu Glu Leu Asp Cys His Val Thr Gly 1745 1750 1755 1760 Ser Pro Pro Pro Thr Ile Met Trp Leu Lys Asp Gly Gln Leu Ile Asp 1765 1770 1775 Glu Arg Asp Gly Phe Lys Ile Leu Leu Asn Gly Arg Lys Leu Val Ile 1780 1785 1790 Ala Gln Ala Gln Val Ser Asn Thr Gly Leu Tyr Arg Cys Met Ala Ala 1795 1800 1805 Asn Thr Ala Gly Asp His Lys Lys Glu Phe Glu Val Thr Val His Val 1810 1815 1820 Pro Pro Thr Ile Lys Ser Ser Gly Leu Ser Glu Arg Val Val Val Lys 1825 1830 1835 1840 Tyr Lys Pro Val Ala Leu Gln Cys Ile Ala Asn Gly Ile Pro Asn Pro 1845 1850 1855 Ser Ile Thr Trp Leu Lys Asp Asp Gln Pro Val Asn Thr Ala Gln Gly 1860 1865 1870 Asn Leu Lys Ile Gln Ser Ser Gly Arg Val Leu Gln Ile Ala Lys Thr 1875 1880 1885 Leu Leu Glu Asp Ala Gly Arg Tyr Thr Cys Val Ala Thr Asn Ala Ala 1890 1895 1900 Gly Glu Thr Gln Gln His Ile Gln Leu His Val His Glu Pro Pro Ser 1905 1910 1915 1920 Leu Glu Asp Ala Gly Lys Met Leu Asn Glu Thr Val Leu Val Ser Asn 1925 1930 1935 Pro Val Gln Leu Glu Cys Lys Ala Ala Gly Asn Pro Val Pro Val Ile 1940 1945 1950 Thr Trp Tyr Lys Asp Asn Arg Leu Leu Ser Gly Ser Thr Ser Met Thr 1955 1960 1965 Phe Leu Asn Arg Gly Gln Ile Ile Asp Ile Glu Ser Ala Gln Ile Ser 1970 1975 1980 Asp Ala Gly Ile Tyr Lys Cys Val Ala Ile Asn Ser Ala Gly Ala Thr 1985 1990 1995 2000 Glu Leu Phe Tyr Ser Leu Gln Val His Val Ala Pro Ser Ile Ser Gly 2005 2010 2015 Ser Asn Asn Met Val Ala Val Val Val Asn Asn Pro Val Arg Leu Glu 2020 2025 2030 Cys Glu Ala Arg Gly Ile Pro Ala Pro Ser Leu Thr Trp Leu Lys Asp 2035 2040 2045 Gly Ser Pro Val Ser Ser Phe Ser Asn Gly Leu Gln Val Leu Ser Gly 2050 2055 2060 Gly Arg Ile Leu Ala Leu Thr Ser Ala Gln Ile Ser Asp Thr Gly Arg 2065 2070 2075 2080 Tyr Thr Cys Val Ala Val Asn Ala Ala Gly Glu Lys Gln Arg Asp Ile 2085 2090 2095 Asp Leu Arg Val Tyr Val Pro Pro Asn Ile Met Gly Glu Glu Gln Asn 2100 2105 2110 Val Ser Val Leu Ile Ser Gln Ala Val Glu Leu Leu Cys Gln Ser Asp 2115 2120 2125 Ala Ile Pro Pro Pro Thr Leu Thr Trp Leu Lys Asp Gly His Pro Leu 2130 2135 2140 Leu Lys Lys Pro Gly Leu Ser Ile Ser Glu Asn Arg Ser Val Leu Lys 2145 2150 2155 2160 Ile Glu Asp Ala Gln Val Gln Asp Thr Gly Arg Tyr Thr Cys Glu Ala 2165

2170 2175 Thr Asn Val Ala Gly Lys Thr Glu Lys Asn Tyr Asn Val Asn Ile Trp 2180 2185 2190 Val Pro Pro Asn Ile Gly Gly Ser Asp Glu Leu Thr Gln Leu Thr Val 2195 2200 2205 Ile Glu Gly Asn Leu Ile Ser Leu Leu Cys Glu Ser Ser Gly Ile Pro 2210 2215 2220 Pro Pro Asn Leu Ile Trp Lys Lys Lys Gly Ser Pro Val Leu Thr Asp 2225 2230 2235 2240 Ser Met Gly Arg Xaa Arg Ile Leu Ser Gly Gly Arg Gln Leu Gln Ile 2245 2250 2255 Ser Ile Ala Glu Lys Ser Asp Ala Ala Leu Tyr Ser Cys Val Ala Ser 2260 2265 2270 Asn Val Ala Gly Thr Ala Lys Lys Glu Tyr Asn Leu Gln Val Tyr Ile 2275 2280 2285 Arg Pro Thr Ile Thr Asn Ser Gly Ser His Pro Thr Glu Ile Ile Val 2290 2295 2300 Thr Arg Gly Lys Ser Ile Ser Leu Glu Cys Glu Val Gln Gly Ile Pro 2305 2310 2315 2320 Pro Pro Thr Val Thr Trp Met Lys Asp Gly His Pro Leu Ile Lys Ala 2325 2330 2335 Lys Gly Val Glu Ile Leu Asp Glu Gly His Ile Leu Gln Leu Lys Asn 2340 2345 2350 Ile His Val Ser Asp Thr Gly Arg Tyr Val Cys Val Ala Val Asn Val 2355 2360 2365 Ala Gly Met Thr Asp Lys Lys Tyr Asp Leu Ser Val His Ala Pro Pro 2370 2375 2380 Ser Ile Ile Gly Asn His Arg Ser Pro Glu Asn Ile Ser Val Val Glu 2385 2390 2395 2400 Lys Asn Ser Val Ser Leu Thr Cys Glu Ala Ser Gly Ile Pro Leu Pro 2405 2410 2415 Ser Xaa Thr Trp Phe Lys Asp Gly Trp Pro Val Ser Leu Ser Asn Ser 2420 2425 2430 Val Arg Ile Leu Ser Gly Gly Arg Met Leu Arg Leu Met Gln Thr Thr 2435 2440 2445 Met Glu Asp Ala Gly Gln Tyr Thr Cys Val Val Arg Asn Ala Ala Gly 2450 2455 2460 Glu Glu Arg Lys Ile Phe Gly Leu Ser Val Leu Val Pro Pro His Ile 2465 2470 2475 2480 Val Gly Glu Asn Thr Leu Glu Asp Val Lys Val Lys Glu Lys Gln Ser 2485 2490 2495 Val Thr Leu Thr Cys Glu Val Thr Gly Asn Pro Val Pro Glu Ile Thr 2500 2505 2510 Trp His Lys Asp Gly Gln Pro Leu Gln Glu Asp Glu Ala His His Ile 2515 2520 2525 Ile Ser Gly Gly Arg Phe Leu Gln Ile Thr Asn Val Gln Val Pro His 2530 2535 2540 Thr Gly Arg Tyr Thr Cys Leu Ala Ser Ser Pro Ala Gly His Lys Ser 2545 2550 2555 2560 Arg Ser Phe Ser Leu Asn Val Phe Val Ser Pro Thr Ile Ala Gly Val 2565 2570 2575 Gly Ser Asp Gly Asn Pro Glu Asp Val Thr Val Ile Leu Asn Ser Pro 2580 2585 2590 Thr Ser Leu Val Cys Glu Ala Tyr Ser Tyr Pro Pro Ala Thr Ile Thr 2595 2600 2605 Trp Phe Lys Asp Gly Thr Pro Leu Glu Ser Asn Arg Asn Ile Arg Ile 2610 2615 2620 Leu Pro Gly Gly Arg Thr Leu Gln Ile Leu Asn Ala Gln Glu Asp Asn 2625 2630 2635 2640 Ala Gly Arg Tyr Ser Cys Val Ala Thr Asn Glu Ala Gly Glu Met Ile 2645 2650 2655 Lys His Tyr Glu Val Lys Val Tyr Ile Pro Pro Ile Ile Asn Lys Gly 2660 2665 2670 Asp Leu Trp Gly Pro Gly Leu Ser Pro Lys Glu Val Lys Ile Lys Val 2675 2680 2685 Asn Asn Thr Leu Thr Leu Glu Cys Glu Ala Tyr Ala Ile Pro Ser Ala 2690 2695 2700 Ser Leu Ser Trp Tyr Lys Asp Gly Gln Pro Leu Lys Ser Asp Asp His 2705 2710 2715 2720 Val Asn Ile Ala Ala Asn Gly His Thr Leu Gln Ile Lys Glu Ala Gln 2725 2730 2735 Ile Ser Asp Thr Gly Arg Tyr Thr Cys Val Ala Ser Asn Ile Ala Gly 2740 2745 2750 Glu Asp Glu Leu Asp Phe Asp Val Asn Ile Gln Val Pro Pro Ser Phe 2755 2760 2765 Gln Lys Leu Trp Glu Ile Gly Asn Met Leu Asp Thr Gly Arg Asn Gly 2770 2775 2780 Glu Ala Lys Asp Val Ile Ile Asn Asn Pro Ile Ser Leu Tyr Cys Glu 2785 2790 2795 2800 Thr Asn Ala Ala Pro Pro Pro Thr Leu Thr Trp Tyr Lys Asp Gly His 2805 2810 2815 Pro Leu Thr Ser Ser Asp Lys Val Leu Ile Leu Pro Gly Gly Arg Val 2820 2825 2830 Leu Gln Ile Pro Arg Ala Lys Val Glu Asp Ala Gly Arg Tyr Thr Cys 2835 2840 2845 Val Ala Val Asn Glu Ala Gly Glu Asp Ser Leu Gln Tyr Asp Val Arg 2850 2855 2860 Val Leu Val Pro Pro Ile Ile Lys Gly Ala Asn Ser Asp Leu Pro Glu 2865 2870 2875 2880 Glu Val Thr Val Leu Val Asn Lys Ser Ala Leu Ile Glu Cys Leu Ser 2885 2890 2895 Ser Gly Ser Pro Ala Pro Arg Asn Ser Trp Gln Lys Asp Gly Gln Pro 2900 2905 2910 Leu Leu Glu Asp Asp His His Lys Phe Leu Ser Asn Gly Arg Ile Leu 2915 2920 2925 Gln Ile Leu Asn Thr Gln Ile Thr Asp Ile Gly Arg Tyr Val Cys Val 2930 2935 2940 Ala Glu Asn Thr Ala Gly Ser Ala Lys Lys Tyr Phe Asn Leu Asn Val 2945 2950 2955 2960 His Val Pro Pro Ser Val Ile Gly Pro Lys Ser Glu Asn Leu Thr Val 2965 2970 2975 Val Val Asn Asn Phe Ile Ser Leu Thr Cys Glu Val Ser Gly Phe Pro 2980 2985 2990 Pro Pro Asp Leu Ser Trp Leu Lys Asn Glu Gln Pro Ile Lys Leu Asn 2995 3000 3005 Thr Asn Thr Leu Ile Val Pro Gly Gly Arg Thr Leu Gln Ile Ile Arg 3010 3015 3020 Ala Lys Val Ser Asp Gly Gly Glu Tyr Thr Cys Ile Ala Ile Asn Gln 3025 3030 3035 3040 Ala Gly Glu Ser Lys Lys Lys Phe Ser Leu Thr Val Tyr Val Pro Pro 3045 3050 3055 Ser Ile Lys Asp His Asp Ser Glu Ser Leu Ser Val Val Asn Val Arg 3060 3065 3070 Glu Gly Thr Ser Val Ser Leu Glu Cys Glu Ser Asn Ala Val Pro Pro 3075 3080 3085 Pro Val Ile Thr Trp Tyr Lys Asn Gly Arg Met Ile Thr Glu Ser Thr 3090 3095 3100 His Val Glu Ile Leu Ala Asp Gly Gln Met Leu His Ile Lys Lys Ala 3105 3110 3115 3120 Glu Val Ser Asp Thr Gly Gln Tyr Val Cys Arg Ala Ile Asn Val Ala 3125 3130 3135 Gly Arg Asp Asp Lys Asn Phe His Leu Asn Val Tyr Val Pro Pro Ser 3140 3145 3150 Ile Glu Gly Pro Glu Arg Glu Val Ile Val Glu Thr Ile Ser Asn Pro 3155 3160 3165 Val Thr Leu Thr Cys Asp Ala Thr Gly Ile Pro Pro Pro Thr Ile Ala 3170 3175 3180 Trp Leu Lys Asn His Lys Arg Ile Glu Asn Ser Asp Ser Leu Glu Val 3185 3190 3195 3200 Arg Ile Leu Ser Gly Gly Ser Lys Leu Gln Ile Ala Arg Ser Gln His 3205 3210 3215 Ser Asp Ser Gly Asn Tyr Thr Cys Ile Ala Ser Asn Met Glu Gly Lys 3220 3225 3230 Ala Gln Lys Tyr Tyr Phe Leu Ser Ile Gln Val Pro Pro Ser Val Ala 3235 3240 3245 Gly Ala Glu Ile Pro Ser Asp Val Ser Val Leu Leu Gly Glu Asn Val 3250 3255 3260 Glu Leu Val Cys Asn Ala Asn Gly Ile Pro Thr Pro Leu Ile Gln Trp 3265 3270 3275 3280 Leu Lys Asp Gly Lys Pro Ile Ala Ser Gly Glu Thr Glu Arg Ile Arg 3285 3290 3295 Val Ser Ala Asn Gly Ser Thr Leu Asn Ile Tyr Gly Ala Leu Thr Ser 3300 3305 3310 Asp Thr Gly Lys Tyr Thr Cys Val Ala Thr Asn Pro Ala Gly Glu Glu 3315 3320 3325 Asp Arg Ile Phe Asn Leu Asn Val Tyr Val Thr Pro Thr Ile Arg Gly 3330 3335 3340 Asn Lys Asp Glu Ala Glu Lys Leu Met Thr Leu Val Asp Thr Ser Ile 3345 3350 3355 3360 Asn Ile Glu Cys Arg Ala Thr Gly Thr Pro Pro Pro Gln Ile Asn Trp 3365 3370 3375 Leu Lys Asn Gly Leu Pro Leu Pro Leu Ser Ser His Ile Arg Leu Leu 3380 3385 3390 Ala Ala Gly Gln Val Ile Arg Ile Val Arg Ala Gln Val Ser Asp Val 3395 3400 3405 Ala Val Tyr Thr Cys Val Ala Ser Asn Arg Ala Gly Val Asp Asn Lys 3410 3415 3420 His Tyr Asn Leu Gln Val Phe Ala Pro Pro Asn Met Asp Asn Ser Met 3425 3430 3435 3440 Gly Thr Glu Glu Ile Thr Val Leu Lys Gly Ser Ser Thr Ser Met Ala 3445 3450 3455 Cys Ile Thr Asp Gly Thr Pro Ala Pro Ser Met Ala Trp Leu Arg Asp 3460 3465 3470 Gly Gln Pro Leu Gly Leu Asp Ala His Leu Thr Val Ser Thr His Gly 3475 3480 3485 Met Val Leu Gln Leu Leu Lys Ala Glu Thr Glu Asp Ser Gly Lys Tyr 3490 3495 3500 Thr Cys Ile Ala Ser Asn Glu Ala Gly Glu Val Ser Lys His Phe Ile 3505 3510 3515 3520 Leu Lys Val Leu Glu Pro Pro His Ile Asn Gly Ser Glu Glu His Glu 3525 3530 3535 Glu Ile Ser Val Ile Val Asn Asn Pro Leu Glu Leu Thr Cys Ile Ala 3540 3545 3550 Ser Gly Ile Pro Ala Pro Lys Met Thr Trp Met Lys Asp Gly Arg Pro 3555 3560 3565 Leu Pro Gln Thr Asp Gln Val Gln Thr Leu Gly Gly Gly Glu Val Leu 3570 3575 3580 Arg Ile Ser Thr Ala Gln Val Glu Asp Thr Gly Arg Tyr Thr Cys Leu 3585 3590 3595 3600 Ala Ser Ser Pro Ala Gly Asp Asp Asp Lys Glu Tyr Leu Val Arg Val 3605 3610 3615 His Val Pro Pro Asn Ile Ala Gly Thr Asp Glu Pro Arg Asp Ile Thr 3620 3625 3630 Val Leu Arg Asn Arg Gln Val Thr Leu Glu Cys Lys Ser Asp Ala Val 3635 3640 3645 Pro Pro Pro Val Ile Thr Trp Leu Arg Asn Gly Glu Arg Leu Gln Ala 3650 3655 3660 Thr Pro Arg Val Arg Ile Leu Ser Gly Gly Arg Tyr Leu Gln Ile Asn 3665 3670 3675 3680 Asn Ala Asp Leu Gly Asp Thr Ala Asn Tyr Thr Cys Val Ala Ser Asn 3685 3690 3695 Ile Ala Gly Lys Thr Thr Arg Glu Phe Ile Leu Thr Val Asn Val Pro 3700 3705 3710 Pro Asn Ile Lys Gly Gly Pro Gln Ser Leu Val Ile Leu Leu Asn Lys 3715 3720 3725 Ser Thr Val Leu Glu Cys Ile Ala Glu Gly Val Pro Thr Pro Arg Ile 3730 3735 3740 Thr Trp Arg Lys Asp Gly Ala Val Leu Ala Gly Asn His Ala Arg Tyr 3745 3750 3755 3760 Ser Ile Leu Glu Asn Gly Phe Leu His Ile Gln Ser Ala His Val Thr 3765 3770 3775 Asp Thr Gly Arg Tyr Leu Cys Met Ala Thr Asn Ala Ala Gly Thr Asp 3780 3785 3790 Arg Arg Arg Ile Asp Leu Gln Val His Val Pro Pro Ser Ile Ala Pro 3795 3800 3805 Gly Pro Thr Asn Met Thr Val Ile Val Asn Val Gln Thr Thr Leu Ala 3810 3815 3820 Cys Glu Ala Thr Gly Ile Pro Lys Pro Ser Ile Asn Trp Arg Lys Asn 3825 3830 3835 3840 Gly His Leu Leu Asn Val Asp Gln Asn Gln Asn Ser Tyr Arg Leu Leu 3845 3850 3855 Ser Ser Gly Ser Leu Val Ile Ile Ser Pro Ser Val Asp Asp Thr Ala 3860 3865 3870 Thr Tyr Glu Cys Thr Val Thr Asn Gly Ala Gly Asp Asp Lys Arg Thr 3875 3880 3885 Val Asp Leu Thr Val Gln Val Pro Pro Ser Ile Ala Asp Glu Pro Thr 3890 3895 3900 Asp Phe Leu Val Thr Lys His Ala Pro Ala Val Ile Thr Cys Thr Ala 3905 3910 3915 3920 Ser Gly Val Pro Phe Pro Ser Ile His Trp Thr Lys Asn Gly Ile Arg 3925 3930 3935 Leu Leu Pro Arg Gly Asp Gly Tyr Arg Ile Leu Ser Ser Gly Ala Ile 3940 3945 3950 Glu Ile Leu Ala Thr Gln Leu Asn His Ala Gly Arg Tyr Thr Cys Val 3955 3960 3965 Ala Arg Asn Ala Ala Gly Ser Ala His Arg His Val Thr Leu His Val 3970 3975 3980 His Glu Pro Pro Val Ile Gln Pro Gln Pro Ser Glu Leu His Val Ile 3985 3990 3995 4000 Leu Asn Asn Pro Ile Leu Leu Pro Cys Glu Ala Thr Gly Thr Pro Ser 4005 4010 4015 Pro Phe Ile Thr Trp Gln Lys Glu Gly Ile Asn Val Asn Thr Ser Gly 4020 4025 4030 Arg Asn His Ala Val Leu Pro Ser Gly Gly Leu Gln Ile Xaa Arg Ala 4035 4040 4045 Val Arg Glu Asp Ala Gly Thr Tyr Met Cys Val Ala Gln Asn Pro Ala 4050 4055 4060 Gly Thr Ala Leu Gly Lys Ile Lys Leu Asn Val Gln Val Pro Pro Val 4065 4070 4075 4080 Ile Ser Pro His Leu Lys Glu Tyr Val Ile Ala Val Asp Lys Pro Ile 4085 4090 4095 Thr Leu Ser Cys Glu Ala Asp Gly Leu Pro Pro Pro Asp Ile Thr Trp 4100 4105 4110 His Lys Asp Gly Arg Ala Ile Val Glu Ser Ile Arg Gln Arg Val Leu 4115 4120 4125 Ser Ser Gly Ser Leu Gln Ile Ala Phe Val Gln Pro Gly Asp Ala Gly 4130 4135 4140 His Tyr Thr Cys Met Ala Ala Asn Val Ala Gly Ser Ser Ser Thr Ser 4145 4150 4155 4160 Thr Lys Leu Thr Val His Val Pro Pro Arg Ile Arg Ser Thr Glu Gly 4165 4170 4175 His Tyr Thr Val Asn Glu Asn Ser Gln Ala Ile Leu Pro Cys Val Ala 4180 4185 4190 Asp Gly Ile Pro Thr Pro Ala Ile Asn Trp Lys Lys Asp Asn Val Leu 4195 4200 4205 Leu Ala Asn Leu Leu Gly Lys Tyr Thr Ala Glu Pro Tyr Gly Glu Leu 4210 4215 4220 Ile Leu Glu Asn Val Val Leu Glu Asp Ser Gly Phe Tyr Thr Cys Val 4225 4230 4235 4240 Ala Asn Asn Ala Ala Gly Glu Asp Thr His Thr Val Ser Leu Thr Val 4245 4250 4255 His Val Leu Pro Thr Phe Thr Glu Leu Pro Gly Asp Val Ser Leu Asn 4260 4265 4270 Lys Gly Glu Gln Leu Arg Leu Ser Cys Lys Ala Thr Gly Ile Pro Leu 4275 4280 4285 Pro Lys Leu Thr Trp Thr Phe Asn Asn Asn Ile Ile Pro Ala His Phe 4290 4295 4300 Asp Ser Val Asn Gly His Ser Glu Leu Val Ile Glu Arg Val Ser Lys 4305 4310 4315 4320 Glu Asp Ser Gly Thr Tyr Val Cys Thr Ala Glu Asn Ser Val Gly Phe 4325 4330 4335 Val Lys Ala Ile Gly Phe Val Tyr Val Lys Glu Pro Pro Val Phe Lys 4340 4345 4350 Gly Asp Tyr Pro Ser Asn Trp Ile Glu Pro Leu Gly Gly Asn Ala Ile 4355 4360 4365 Leu Asn Cys Glu Val Lys Gly Asp Pro Thr Pro Thr Ile Gln Trp Asn 4370 4375 4380 Arg Lys Gly Val Asp Ile Glu Ile Ser His Arg Ile Arg Gln Leu Gly 4385 4390 4395 4400 Asn Gly Ser Leu Ala Ile Tyr Gly Thr Val Asn Glu Asp Ala Gly Asp 4405 4410 4415 Tyr Thr Cys Val Ala Thr Asn Glu Ala Gly Val Val Glu Arg Ser Met 4420 4425 4430 Ser Leu Thr Leu Gln Ser Pro Pro Ile Ile Thr Leu Glu Pro Val Glu 4435 4440 4445 Thr Val Ile Asn Ala Gly Gly Lys Ile Ile Leu Asn Cys Gln Ala Thr 4450 4455 4460 Gly Glu Pro Gln Pro Thr Ile Thr Trp Ser Arg Gln Gly His Ser Ile 4465 4470 4475 4480 Ser Trp Asp Asp Arg Val Asn Val Leu Ser Asn Asn Ser Leu Tyr Ile 4485 4490 4495 Ala Asp Ala Gln Lys Glu Asp Thr Ser Glu Phe Glu Cys Val Ala Arg 4500 4505 4510 Asn Leu Met Gly Ser Val Leu Val Arg Val Pro Val Ile Val Gln Val 4515 4520 4525 His Gly Gly Phe Ser Gln Trp Ser Ala Trp Arg Ala Cys Ser Val Thr 4530 4535 4540 Cys Gly Lys Gly Ile Gln Lys Arg Ser Arg Leu Cys Asn Gln Pro Leu 4545 4550 4555 4560 Pro Ala Asn Gly Gly Lys Pro Cys Gln Gly Ser Asp Leu Glu Met Arg 4565 4570 4575 Asn Cys Gln Asn Lys Pro Cys Pro Val Asp Gly Ser

Trp Ser Glu Trp 4580 4585 4590 Ser Leu Trp Glu Glu Cys Thr Arg Ser Cys Gly Arg Gly Asn Gln Thr 4595 4600 4605 Arg Thr Arg Thr Cys Asn Asn Pro Ser Val Gln His Gly Gly Arg Pro 4610 4615 4620 Cys Glu Gly Asn Ala Val Glu Ile Ile Met Cys Asn Ile Arg Pro Cys 4625 4630 4635 4640 Pro Val His Gly Ala Trp Ser Ala Trp Gln Pro Trp Gly Thr Cys Ser 4645 4650 4655 Glu Ser Cys Gly Lys Gly Thr Gln Thr Arg Ala Arg Leu Cys Asn Asn 4660 4665 4670 Pro Pro Pro Ala Phe Gly Gly Ser Tyr Cys Asp Gly Ala Glu Thr Gln 4675 4680 4685 Met Gln Val Cys Asn Glu Arg Asn Cys Pro Ile His Gly Lys Trp Ala 4690 4695 4700 Thr Trp Ala Ser Trp Ser Ala Cys Ser Val Ser Cys Gly Gly Gly Ala 4705 4710 4715 4720 Arg Gln Arg Thr Arg Gly Cys Ser Asp Pro Val Pro Gln Tyr Gly Gly 4725 4730 4735 Arg Lys Cys Glu Gly Ser Asp Val Gln Ser Asp Phe Cys Asn Ser Asp 4740 4745 4750 Pro Cys Pro Thr His Gly Asn Trp Ser Pro Trp Ser Gly Trp Gly Thr 4755 4760 4765 Cys Ser Arg Thr Cys Asn Gly Gly Gln Met Arg Arg Tyr Arg Thr Cys 4770 4775 4780 Asp Asn Pro Pro Pro Ser Asn Gly Gly Arg Ala Cys Gly Gly Pro Asp 4785 4790 4795 4800 Ser Gln Ile Gln Arg Cys Asn Thr Asp Met Cys Pro Val Asp Gly Ser 4805 4810 4815 Trp Gly Ser Trp His Ser Trp Ser Gln Cys Ser Ala Ser Cys Gly Gly 4820 4825 4830 Gly Glu Lys Thr Arg Lys Arg Leu Cys Asp His Pro Val Pro Val Lys 4835 4840 4845 Gly Gly Arg Pro Cys Pro Gly Asp Thr Thr Gln Val Thr Arg Cys Asn 4850 4855 4860 Val Gln Ala Cys Pro Gly Gly Pro Gln Arg Ala Arg Gly Ser Val Ile 4865 4870 4875 4880 Gly Asn Ile Asn Asp Val Glu Phe Gly Ile Ala Phe Leu Asn Ala Thr 4885 4890 4895 Ile Thr Asp Ser Pro Asn Ser Asp Thr Arg Ile Ile Arg Ala Lys Ile 4900 4905 4910 Thr Asn Val Pro Arg Ser Leu Gly Ser Ala Met Arg Lys Ile Val Ser 4915 4920 4925 Ile Leu Asn Pro Ile Tyr Trp Thr Thr Ala Lys Glu Ile Gly Glu Ala 4930 4935 4940 Val Asn Gly Phe Thr Leu Thr Asn Ala Val Phe Lys Arg Glu Thr Gln 4945 4950 4955 4960 Val Glu Phe Ala Thr Gly Glu Ile Leu Gln Met Ser His Ile Ala Arg 4965 4970 4975 Gly Leu Asp Ser Asp Gly Ser Leu Leu Leu Asp Ile Val Val Ser Gly 4980 4985 4990 Tyr Val Leu Gln Leu Gln Ser Pro Ala Glu Val Thr Val Lys Asp Tyr 4995 5000 5005 Thr Glu Asp Tyr Ile Gln Thr Gly Pro Gly Gln Leu Tyr Ala Tyr Ser 5010 5015 5020 Thr Arg Leu Phe Thr Ile Asp Gly Ile Ser Ile Pro Tyr Thr Trp Asn 5025 5030 5035 5040 His Thr Val Phe Tyr Asp Gln Ala Gln Gly Arg Met Pro Phe Leu Val 5045 5050 5055 Glu Thr Leu His Ala Ser Ser Val Glu Ser Asp Tyr Asn Gln Ile Glu 5060 5065 5070 Glu Thr Leu Gly Phe Lys Ile His Ala Ser Ile Ser Lys Gly Asp Arg 5075 5080 5085 Ser Asn Gln Cys Pro Ser Gly Phe Thr Leu Asp Ser Val Gly Pro Phe 5090 5095 5100 Cys Ala Asp Glu Asp Glu Cys Ala Ala Gly Asn Pro Cys Ser His Ser 5105 5110 5115 5120 Cys His Asn Ala Met Gly Thr Tyr Tyr Cys Ser Cys Pro Lys Gly Leu 5125 5130 5135 Thr Ile Ala Ala Asp Gly Arg Thr Cys Gln Asp Ile Asp Glu Cys Ala 5140 5145 5150 Leu Gly Arg His Thr Cys His Ala Gly Gln Asp Cys Asp Asn Thr Ile 5155 5160 5165 Gly Ser Tyr Arg Cys Val Val Arg Cys Gly Ser Gly Phe Arg Arg Thr 5170 5175 5180 Ser Asp Gly Leu Ser Cys Gln Asp Ile Asn Glu Cys Gln Glu Ser Ser 5185 5190 5195 5200 Pro Cys His Gln Arg Cys Phe Asn Ala Ile Gly Ser Phe His Cys Gly 5205 5210 5215 Cys Glu Pro Gly Tyr Gln Leu Lys Gly Arg Lys Cys Met Asp Val Asn 5220 5225 5230 Glu Cys Arg Gln Asn Val Cys Arg Pro Asp Gln His Cys Lys Asn Thr 5235 5240 5245 Arg Gly Gly Tyr Lys Cys Ile Asp Leu Cys Pro Asn Gly Met Thr Lys 5250 5255 5260 Ala Glu Asn Gly Thr Cys Ile Asp Ile Asp Glu Cys Lys Asp Gly Thr 5265 5270 5275 5280 His Gln Cys Arg Tyr Asn Gln Ile Cys Glu Asn Thr Arg Gly Ser Tyr 5285 5290 5295 Arg Cys Val Cys Pro Arg Gly Tyr Arg Ser Gln Gly Val Gly Arg Pro 5300 5305 5310 Cys Met Asp Ile Asp Glu Cys Glu Asn Thr Asp Ala Cys Gln His Glu 5315 5320 5325 Cys Lys Asn Thr Phe Gly Ser Tyr Gln Cys Ile Cys Pro Pro Gly Tyr 5330 5335 5340 Gln Leu Thr His Asn Gly Lys Thr Cys Gln Asp Ile Asp Glu Cys Leu 5345 5350 5355 5360 Glu Gln Asn Val His Cys Gly Pro Asn Arg Met Cys Phe Asn Met Arg 5365 5370 5375 Gly Ser Tyr Gln Cys Ile Asp Thr Pro Cys Pro Pro Asn Tyr Gln Arg 5380 5385 5390 Asp Pro Val Ser Gly Phe Cys Leu Lys Asn Cys Pro Pro Asn Asp Leu 5395 5400 5405 Glu Cys Ala Leu Ser Pro Tyr Ala Leu Glu Tyr Lys Leu Val Ser Leu 5410 5415 5420 Pro Phe Gly Ile Ala Thr Asn Gln Asp Leu Ile Arg Leu Val Ala Tyr 5425 5430 5435 5440 Thr Gln Asp Gly Val Met His Pro Arg Thr Thr Phe Leu Met Val Asp 5445 5450 5455 Glu Glu Gln Thr Val Pro Phe Ala Leu Arg Asp Glu Asn Leu Lys Gly 5460 5465 5470 Val Val Tyr Thr Thr Arg Pro Leu Arg Glu Ala Glu Thr Tyr Arg Met 5475 5480 5485 Arg Val Arg Ala Ser Ser Tyr Ser Ala Asn Gly Thr Ile Glu Tyr Gln 5490 5495 5500 Thr Thr Phe Ile Val Tyr Ile Ala Val Ser Ala Tyr Pro Tyr 5505 5510 5515 3 12381 DNA homo sapiens 3 atgtggtata aagataatgt ccaggtgact gaaagcagca ctattcagac tgtgaacaat 60 gggaagatac tgaagctctt cagagccact ccagaggatg caggaagata ttcctgcaaa 120 gcaattaata ttgcaggcac ttctcagaag tactttaaca ttgatgtgct agttccaccc 180 accataatag gtaccaactt cccaaatgaa gtctcagttg tcctcaaccg tgacgtcgcc 240 cttgaatgcc aggtcaaagg cactcccttt cctgatattc attggttcaa agatggcaag 300 cctttatttt tgggcgatcc taatgttgaa cttctagaca gaggacaagt cttacattta 360 aagaatgcac ggagaaatga caaggggcgc taccaatgta ctgtgtctaa tgcagctggc 420 aaacaagcca aggatataaa actgactatc tatattccac ctagtattaa aggaggaaat 480 gtcaccacrg mcatatcagt attgatcaac agccttatta aactggaatg tgaaacacgg 540 ggacttccaa tgcctgccat tacttggtat aaggacgggc agccaatcat gtccagctca 600 caagcacttt atattgataa aggacaatat cttcatattc ctcgagcaca ggtctctgat 660 tcagcaacat atacgtgtca ygtagccaat gttgctggaa ctgctgaaaa atcattccat 720 gtggatgtct atgttcctcc aatgattgaa ggcaacttgg ccacgccttt gaataagcaa 780 gtagttattg ctcattctct gacactggag tgcaaagctg ctggaaaccc ttctcccatt 840 ctcacctggt tgaaagatgg tgtacctgtg aaagctaatg acaatatccg catagaagct 900 ggtgggaaga aactcgaaat catgagtgcc caagaaattg atcgaggaca gtacatatgc 960 gtggctacca gtgtggcagg agaaaaggaa atcaaatatg aagttgatgt cttggtgcca 1020 ccagctatag aaggaggaga tgaaacatct tacttcattg tgatggttaa taacttactg 1080 gagctagatt gtcatgtgac aggctctccc ccaccaacta tcatgtggct gaaggatggc 1140 cagttaattg atgaaaggga tggattcaag attttattaa atggacgcaa actggttatt 1200 gctcaggctc aagtgtcaaa cacaggcctt tatcggtgca tggcagcaaa tactgctgga 1260 gaccacaaga aggaatttga agtgactgtt catgttcctc caacaatcaa gtcctcaggc 1320 ctttctgaga gagttgtggt aaaatacaag cctgtcgcct tgcagtgcat agccaatggg 1380 attccaaatc cttccattac atggttaaaa gatgaccagc ctgtgaacac tgcccaagga 1440 aaccttaaaa tacagtcttc tggtcgagtt ctacaaattg ccaaaaccct gttggaagat 1500 gctggcagat acacatgtgt ggctaccaac gcagctggag aaacacaaca gcacattcaa 1560 ctgcatgttc atgaaccacc tagtctggaa gatgctggaa aaatgctgaa tgagactgtg 1620 ttggtgagca accctgtaca gctggagtgt aaggcagctg gaaatcctgt gcctgttatt 1680 acatggtaca aagataatcg tctactctca ggttccacca gcatgacttt cttgaacaga 1740 ggacagatca ttgatattga aagtgcccag atctcagatg ctggcatata taaatgcgtg 1800 gccatcaact cagctggagc tacagagtta ttttacagtc tgcaagttca tgtggcccca 1860 tcaatttctg gcagcaataa catggtggca gtggtggtta ataacccggt gaggttagaa 1920 tgtgaagcca gaggtattcc tgccccaagt ctgacctggt tgaaagatgg gagtcctgtt 1980 tctagttttt ctaatggatt acaggttctc tctggtggtc gaatcctagc attgaccagt 2040 gcacaaatca gcgacacagg aaggtacacc tgcgtggcag tgaatgctgc tggagaaaag 2100 caaagggaca ttgacctccg agtatatgtt ccgccaaata ttatgggaga agaacagaat 2160 gtctctgtcc tcattagcca agctgtggaa ttactatgtc aaagtgatgc tattccccca 2220 cctactctta cttggttaaa agacggccac cccttgctga agaaaccagg cctcagtata 2280 tctgaaaata gaagtgtgtt aaagattgaa gatgctcagg ttcaagacac tggtcgttac 2340 acttgtgaag caacaaatgt tgctggaaaa actgaaaaaa actacaatgt caacatttgg 2400 gtccccccaa atattggtgg ttctgatgaa cttactcaac ttacagtcat tgaagggaat 2460 ctcattagtc tgttgtgtga atcaagtggt attccacccc caaatctcat ctggaagaag 2520 aaaggctctc cagtgctgac tgattccatg gggcgagyta gaattttatc tgggggcagg 2580 caattacaaa tttcaattgc tgaaaagtct gatgcagcac tctattcatg tgtggcgtcg 2640 aatgttgctg ggactgcaaa gaaagaatac aatctgcaag tttacattag accaaccata 2700 accaacagtg gcagccaccc tactgaaatt attgtgaccc gagggaagag tatctccttg 2760 gagtgtgagg tgcagggtat tccaccacca acagtgacct ggatgaaaga tggccacccc 2820 ttgatcaagg caaagggagt agaaatactg gatgaaggtc acatccttca gctgaagaac 2880 attcatgtat ctgacacagg ccgttatgtg tgtgttgctg tgaatgtagc aggaatgact 2940 gacaaaaaat atgacttaag tgtccatgct cctccaagca tcataggaaa ccacaggtca 3000 cctgaaaata ttagtgtggt agaaaagaac tcagtatctt tgacttgtga agcttctgga 3060 attcccctgc cttccayaac ctggttcaaa gatgggtggc ctgtcagcct tagcaattct 3120 gtgaggattc tttcaggagg caggatgcta cggctgatgc agaccacaat ggaagatgct 3180 ggccaatata cttgcgttgt aaggaatgca gctggtgaag aaagaaaaat ctttgggctt 3240 tcagtattag taccacctca tattgtgggt gaaaatacat tggaagatgt gaaggtaaaa 3300 gagaaacaga gtgttacgct gacttgtgaa gtgacaggga atccagtgcc agaaattaca 3360 tggcacaaag atgggcagcc cctccaagaa gatgaagccc atcacattat atctggtggc 3420 cgttttcttc aaattaccaa tgtccaggtg ccacacactg gaagatatac atgtttggct 3480 tccagtccag ctggccacaa gagcaggagc ttcagtctta atgtatttgt atctcctaca 3540 attgctggtg taggtagtga tggcaaccct gaagatgtca ctgtcatcct taacagccct 3600 acatctttgg tctgtgaagc ttattcatat cctccagcta ccatcacctg gtttaaggat 3660 ggcactcctt tagaatctaa ccgaaatatt cgtattcttc caggaggcag aactctgcag 3720 atcctcaatg cacaggagga caatgctgga agatactctt gtgtagccac gaatgaggct 3780 ggagaaatga taaagcacta tgaagtgaag gtgtacattc cacccataat caataaaggg 3840 gacctttggg ggccaggtct ttcccctaaa gaagtgaaga tcaaagtaaa caacactctg 3900 accttggaat gtgaagcgta tgcaattcct tctgcctccc tcagctggta caaggatgga 3960 cagcccctta aatccgatga tcatgttaat attgctgcga atggacacac acttcaaata 4020 aaggaggctc aaatatcaga caccggacga tatacttgtg tagcatctaa cattgcaggt 4080 gaagatgagt tggattttga tgtgaatatt caagttcctc caagttttca gaaactctgg 4140 gaaataggaa acatgctaga tactggcagg aatggtgaag ccaaagatgt gatcatcaac 4200 aatcccattt ctctttactg tgagacaaat gctgctcccc ctcctacact gacatggtac 4260 aaagatggcc accctctgac ctcaagtgat aaagtattga ttttgccagg agggcgagtg 4320 ttgcagattc ctcgggctaa agtagaagat gctgggagat acacatgtgt ggctgtgaat 4380 gaggctggag aagattccct tcaatatgat gtccgtgtac tcgtgccgcc aattatcaag 4440 ggagcaaata gtgatctccc tgaagaggtc accgtgctgg tgaacaagag tgcactgata 4500 gagtgtttat ccagtggcag cccagcacca aggaattcct ggcagaaaga tggacagccc 4560 ttgctagaag atgaccatca taaatttcta tctaatggac gaattctgca gattctgaat 4620 actcaaataa cagatatcgg caggtatgtg tgtgttgctg agaacacagc tgggagtgcc 4680 aaaaaatatt ttaacctcaa tgttcatgtt cctccaagtg tcattggtcc taaatctgaa 4740 aatcttaccg tcgtggtgaa caatttcatc tctttgacct gtgaggtctc tggttttcca 4800 cctcctgacc tcagctggct caagaatgaa cagcccatca aactgaacac aaatactctc 4860 attgtgcctg gtggtcgaac tctacagatt attcgggcca aggtatcaga tggtggtgaa 4920 tacacttgta tagctatcaa tcaagctggc gaaagcaaga aaaagttttc cctgactgtt 4980 tatgtgcccc caagcattaa agaccatgac agtgaatctc tttctgtagt taatgtaaga 5040 gagggaactt ctgtgtcttt ggagtgtgag tcgaacgctg tgccacctcc agtcatcact 5100 tggtataaga atgggcggat gataacagag tctactcatg tggagatttt agctgatgga 5160 caaatgctac acattaagaa agctgaggta tctgacacag gccagtatgt atgtagagct 5220 ataaatgtag caggacggga tgataaaaat ttccacctca atgtatatgt gccacccagt 5280 attgaaggac ctgaaagaga agtgattgtg gagacgatca gcaatcctgt gacattaaca 5340 tgtgatgcca ctgggatccc acctcccacg atagcatggt taaagaacca caagcgcata 5400 gaaaattctg actcactgga agttcgtatt ttgtctggag gtagcaaact ccagattgcc 5460 cggtctcagc attcagatag tggaaactat acatgtattg cttcaaatat ggagggaaaa 5520 gcccagaaat attactttct ttcaattcaa gttcctccaa gtgttgctgg tgctgaaatt 5580 ccaagtgatg tcagtgtcct tctaggagaa aatgttgagc tggtctgcaa tgcaaatggc 5640 attcctactc cacttattca atggcttaaa gatggaaagc ccatagctag tggtgaaaca 5700 gaaagaatcc gagtgagtgc aaatggcagc acattaaaca tttatggagc tcttacatct 5760 gacacgggga aatacacatg tgttgctact aatcccgctg gagaagaaga ccgaattttt 5820 aacttgaatg tctatgttac acctacaatt aggggtaata aagatgaagc agagaaacta 5880 atgactttag tggatacttc aataaatatt gaatgcagag ccacagggac gcctccacca 5940 cagataaact ggctgaagaa tggacttcct ctgcctctct cctcccatat ccggttactg 6000 gcagcaggac aagttatcag gattgtgaga gctcaggtgt ctgatgtcgc tgtgtatact 6060 tgtgtggcct ccaacagagc tggggtggat aataagcatt acaatcttca agtgtttgca 6120 ccaccaaata tggacaattc aatggggaca gaggaaatca cagttctcaa aggtagttcc 6180 acctctatgg catgcattac tgatggaacc ccagctccca gtatggcctg gcttagagat 6240 ggccagcctc tggggcttga tgcccatctg acagtcagca cccatggaat ggtcctgcag 6300 ctcctcaaag cagagactga agattcggga aagtacacct gcattgcctc aaatgaagct 6360 ggagaagtca gcaagcactt tatcctcaag gtcctagaac cacctcacat taatggatct 6420 gaagaacatg aagagatatc agtaattgtt aataacccac ttgaacttac ctgcattgct 6480 tctggaatcc cagcccctaa aatgacctgg atgaaagatg gccggcccct tccacagacg 6540 gatcaagtgc aaactctagg aggaggagag gttcttcgaa tttctactgc tcaggtggag 6600 gatacaggaa gatatacatg tctggcatcc agtcctgcag gagatgatga taaggaatat 6660 ctagtgagag tgcatgtacc tcctaatatt gctggaactg atgagccccg ggatatcact 6720 gtgttacgga acagacaagt gacattggaa tgcaagtcag atgcagtgcc cccacctgta 6780 attacttggc tcagaaatgg agaacggtta caggcaacac ctcgagtgcg aatcctatct 6840 ggagggagat acttgcaaat caacaatgct gacctaggtg atacagccaa ttatacctgt 6900 gttgccagca acattgcagg aaagactaca agagaattta ttctcactgt aaatgttcct 6960 ccaaacataa aggggggccc ccagagcctt gtaattcttt taaataagtc aactgtattg 7020 gaatgcatcg ctgaaggtgt gccaactcca aggataacat ggagaaagga tggagctgtt 7080 ctagctggga atcatgcaag atattccatc ttggaaaatg gattccttca tattcaatca 7140 gcacatgtca ctgacactgg acggtatttg tgtatggcca ccaatgctgc tggaacagat 7200 cgcaggcgaa tagatttaca ggtccatgtt cctccatcta ttgctccggg tcctaccaac 7260 atgactgtaa tagtaaatgt tcaaactact ctggcttgtg aggctactgg gataccaaaa 7320 ccatcaatca attggagaaa aaatgggcat cttcttaatg tggatcaaaa tcagaactca 7380 tacaggctcc tttcttcagg ttcactagta attatttccc cttctgtgga tgacactgca 7440 acctatgaat gtactgtgac aaacggtgct ggagatgata aaagaactgt ggatctcact 7500 gtccaagttc caccttccat agctgatgag cctacagatt tcctagtaac caaacatgcc 7560 ccagcagtaa ttacctgcac tgcttcggga gttccatttc cctcaattca ctggaccaaa 7620 aatggtataa gactgcttcc caggggagat ggctatagaa ttctgtcctc aggagcaatt 7680 gaaatacttg ccacccaatt aaaccatgct ggaagataca cttgtgtcgc taggaatgcg 7740 gctggctctg cacatcgaca cgtsaccctt catgttcatg agcctccagt cattcagccc 7800 caaccaagtg aactacacgt cattctgaac aatcctattt tattaccatg tgaagcaaca 7860 gggacaccca gtcctttcat tacttggcaa aaagaaggca tcaatgttaa cacttcaggc 7920 agaaaccatg cagttcttcc tagtggcggc ttacagatcw ccagagctgt ccgagaggat 7980 gctggcactt acatgtgtgt ggcccagaac ccggctggta cagccttggg caaaatcaag 8040 ttaaatgtcc aagttcctcc agtcattagc cctcatctaa aggaatatgt tattgctgtg 8100 gacaagccca tcacgttatc ctgtgaagca gatggcctcc ctccgcctga cattacatgg 8160 cataaagatg ggcgtgcaat tgtggaatct atccgccagc gcgtcctcag ctctggctct 8220 ctgcaaatag catttgtcca gcctggtgat gctggccatt acacgtgcat ggcagccaat 8280 gtagcaggat caagcagcac aagcaccaag ctcaccgtcc atgtaccacc caggatcaga 8340 agtacagaag gacactacac ggtcaatgag aattcacaag ccattcttcc atgcgtagct 8400 gatggaatcc ccacaccagc aattaactgg aaaaaagaca atgttctttt agctaacttg 8460 ttaggaaaat acactgctga accatatgga gaactcattt tagaaaatgt tgtgctggag 8520 gattctggct tctatacctg tgttgctaac aatgctgcag gtgaagatac acacactgtc 8580 agcctgactg tgcatgttct ccccactttt actgaacttc ctggagacgt gtcattaaat 8640 aaaggagaac agctacgatt aagctgtaaa gctactggta ttccattgcc caaattaaca 8700 tggaccttca ataacaatat tattccagcc cactttgaca gtgtgaatgg acacagtgaa 8760 cttgttattg aaagagtgtc aaaagaggat tcaggtactt atgtgtgcac cgcagagaac 8820 agcgttggct ttgtgaaggc aattggattt gtttatgtga aagaacctcc agtcttcaaa 8880 ggtgattatc cttctaactg gattgaacca cttggtggga atgcaatcct gaattgtgag 8940 gtgaaaggag accccacccc aaccatccag tggaacagaa agggagtgga tattgaaatt 9000 agccacagaa tccggcaact gggcaatggc tccctggcca tctatggcac tgttaatgaa 9060 gatgccggtg actatacatg tgtagctacc aatgaagctg gggtggtgga gcgcagcatg 9120 agtctgactc tgcaaagtcc tcctattatc actcttgagc cagtggaaac tgttattaat 9180 gctggtggca aaatcatatt

gaattgtcag gcaactggag agcctcaacc aaccattaca 9240 tggtcccgtc aagggcactc tatttcctgg gatgaccggg ttaacgtgtt gtccaacaac 9300 tcattatata ttgctgatgc tcagaaagaa gatacctctg aatttgaatg tgttgctcga 9360 aacttaatgg gttctgtcct tgtcagagtg ccagtcatag tccaggttca tggtggattt 9420 tcccagtggt ctgcatggag agcctgcagt gtcacctgtg gaaaaggcat ccaaaagagg 9480 agtcgtctgt gcaaccagcc ccttccagcc aatggtggga agccctgcca aggttcagat 9540 ttggaaatgc gaaactgtca aaataagcct tgtccagtgg atggtagctg gtcggaatgg 9600 agtctttggg aagaatgcac aaggagctgt ggacgcggca accaaaccag gaccaggact 9660 tgcaataatc catcagttca gcatggtggg cggccatgtg aagggaatgc tgtggaaata 9720 attatgtgca acattaggcc ttgcccagtt catggagcat ggagcgcttg gcagccttgg 9780 ggaacatgca gcgaaagttg tgggaaaggt actcagacaa gagcaagact ttgtaataac 9840 ccaccaccag cgtttggtgg gtcctactgt gatggagcag aaacacagat gcaagtttgc 9900 aatgaaagaa attgtccaat tcatggcaag tgggcgactt gggccagttg gagtgcctgt 9960 tctgtgtcat gtggaggagg tgccagacag agaacaaggg gctgctccga ccctgtgccc 10020 cagtatggag gaaggaaatg cgaagggagt gatgtccaga gtgatttttg caacagtgac 10080 ccttgcccaa cccatggtaa ctggagtcct tggagtggct ggggaacatg cagccggacg 10140 tgtaacggag ggcagatgcg gcggtaccgc acatgtgata accctcctcc ctccaatggg 10200 ggaagagctt gtgggggacc agactcccag atccagaggt gcaacactga catgtgtcct 10260 gtggatggaa gttggggaag ctggcatagt tggagccagt gctctgcctc ctgtggagga 10320 ggtgaaaaga ctcggaagcg gctgtgcgac catcctgtgc cagttaaagg tggccgtccc 10380 tgtcccggag acactactca ggtgaccagg tgcaatgtac aagcatgtcc aggtgggccc 10440 cagcgagcca gaggaagtgt tattggaaat attaatgatg ttgaatttgg aattgctttc 10500 cttaatgcca caataactga tagccctaac tctgatacta gaataatacg tgccaaaatt 10560 accaatgtac ctcgtagtct tggttcagca atgagaaaga tagtttctat tctaaatccc 10620 atttattgga caacagcaaa ggaaatagga gaagcagtca atggctttac cctcaccaat 10680 gcagtcttca aaagagaaac tcaagtggaa tttgcaactg gagaaatctt gcagatgagt 10740 catattgccc ggggcttgga ttccgatggt tctttgctgc tagatatcgt tgtgagtggc 10800 tatgtcctac agcttcagtc acctgctgaa gtcactgtaa aggattacac agaggactac 10860 attcaaacag gtcctgggca gctgtacgcc tactcaaccc ggctgttcac cattgatggc 10920 atcagcatcc catacacatg gaaccacacc gttttctatg atcaggcaca gggaagaatg 10980 cctttcttgg ttgaaacact tcatgcatcc tctgtggaat ctgactataa ccagatagaa 11040 gagacactgg gttttaaaat tcatgcttca atatccaaag gagatcgcag taatcagtgc 11100 ccctccgggt ttaccttaga ctcagttgga cctttttgtg ctgatgagga tgaatgtgca 11160 gcagggaatc cctgctccca tagctgccac aatgccatgg ggacttacta ctgctcctgc 11220 cctaaaggcc tcaccatagc tgcagatgga agaacttgtc aagatattga tgagtgtgct 11280 ttgggtaggc atacctgcca cgctggtcag gactgtgaca atacgattgg atcttatcgc 11340 tgtgtggtcc gttgtggaag tggctttcga agaacctctg atgggctgag ttgtcaagat 11400 attaatgaat gtcaagaatc cagcccctgt caccagcgct gtttcaatgc cataggaagt 11460 ttccattgtg gatgtgaacc tgggtatcag ctcaaaggca gaaaatgcat ggatgtgaac 11520 gagtgtagac aaaatgtatg cagaccagat cagcactgta agaacacccg tggtggctat 11580 aagtgcattg atctttgtcc aaatggaatg accaaggcag aaaatggaac ctgtattgat 11640 attgatgaat gtaaagatgg gacccatcag tgcagatata accagatatg tgagaataca 11700 agaggcagct atcgttgtgt atgcccaaga ggttatcggt ctcaaggagt tggaagaccc 11760 tgcatggata ttgatgaatg tgaaaataca gatgcctgcc agcatgagtg taagaatacc 11820 tttggaagtt atcagtgcat ctgcccacct ggctatcaac tcacacacaa tggaaagaca 11880 tgccaagata tcgatgaatg tctggagcag aatgtgcact gtggacccaa tcgcatgtgc 11940 ttcaacatga gaggaagcta ccagtgcatc gatacaccct gtccacccaa ctaccaacgg 12000 gatcctgttt cagggttctg cctcaagaac tgtccaccca atgatttgga atgtgccttg 12060 agcccatatg ccttggaata caaactcgtc tccctcccat ttggaatagc caccaatcaa 12120 gatttaatcc ggctggttgc atacacacag gatggagtga tgcatcccag gacaactttc 12180 ctcatggtag atgaggaaca gactgttcct tttgccttga gggatgaaaa cctgaaagga 12240 gtggtgtata caacacgacc actacgagaa gcagagacct accgcatgag ggtccgagcc 12300 tcatcctaca gtgccaatgg gaccattgaa tatcagacca cattcatagt ttatatagct 12360 gtgtccgcct atccatacta a 12381 4 4126 PRT homo sapiens VARIANT (1)...(4126) Xaa = Any Amino Acid 4 Met Trp Tyr Lys Asp Asn Val Gln Val Thr Glu Ser Ser Thr Ile Gln 1 5 10 15 Thr Val Asn Asn Gly Lys Ile Leu Lys Leu Phe Arg Ala Thr Pro Glu 20 25 30 Asp Ala Gly Arg Tyr Ser Cys Lys Ala Ile Asn Ile Ala Gly Thr Ser 35 40 45 Gln Lys Tyr Phe Asn Ile Asp Val Leu Val Pro Pro Thr Ile Ile Gly 50 55 60 Thr Asn Phe Pro Asn Glu Val Ser Val Val Leu Asn Arg Asp Val Ala 65 70 75 80 Leu Glu Cys Gln Val Lys Gly Thr Pro Phe Pro Asp Ile His Trp Phe 85 90 95 Lys Asp Gly Lys Pro Leu Phe Leu Gly Asp Pro Asn Val Glu Leu Leu 100 105 110 Asp Arg Gly Gln Val Leu His Leu Lys Asn Ala Arg Arg Asn Asp Lys 115 120 125 Gly Arg Tyr Gln Cys Thr Val Ser Asn Ala Ala Gly Lys Gln Ala Lys 130 135 140 Asp Ile Lys Leu Thr Ile Tyr Ile Pro Pro Ser Ile Lys Gly Gly Asn 145 150 155 160 Val Thr Thr Xaa Ile Ser Val Leu Ile Asn Ser Leu Ile Lys Leu Glu 165 170 175 Cys Glu Thr Arg Gly Leu Pro Met Pro Ala Ile Thr Trp Tyr Lys Asp 180 185 190 Gly Gln Pro Ile Met Ser Ser Ser Gln Ala Leu Tyr Ile Asp Lys Gly 195 200 205 Gln Tyr Leu His Ile Pro Arg Ala Gln Val Ser Asp Ser Ala Thr Tyr 210 215 220 Thr Cys His Val Ala Asn Val Ala Gly Thr Ala Glu Lys Ser Phe His 225 230 235 240 Val Asp Val Tyr Val Pro Pro Met Ile Glu Gly Asn Leu Ala Thr Pro 245 250 255 Leu Asn Lys Gln Val Val Ile Ala His Ser Leu Thr Leu Glu Cys Lys 260 265 270 Ala Ala Gly Asn Pro Ser Pro Ile Leu Thr Trp Leu Lys Asp Gly Val 275 280 285 Pro Val Lys Ala Asn Asp Asn Ile Arg Ile Glu Ala Gly Gly Lys Lys 290 295 300 Leu Glu Ile Met Ser Ala Gln Glu Ile Asp Arg Gly Gln Tyr Ile Cys 305 310 315 320 Val Ala Thr Ser Val Ala Gly Glu Lys Glu Ile Lys Tyr Glu Val Asp 325 330 335 Val Leu Val Pro Pro Ala Ile Glu Gly Gly Asp Glu Thr Ser Tyr Phe 340 345 350 Ile Val Met Val Asn Asn Leu Leu Glu Leu Asp Cys His Val Thr Gly 355 360 365 Ser Pro Pro Pro Thr Ile Met Trp Leu Lys Asp Gly Gln Leu Ile Asp 370 375 380 Glu Arg Asp Gly Phe Lys Ile Leu Leu Asn Gly Arg Lys Leu Val Ile 385 390 395 400 Ala Gln Ala Gln Val Ser Asn Thr Gly Leu Tyr Arg Cys Met Ala Ala 405 410 415 Asn Thr Ala Gly Asp His Lys Lys Glu Phe Glu Val Thr Val His Val 420 425 430 Pro Pro Thr Ile Lys Ser Ser Gly Leu Ser Glu Arg Val Val Val Lys 435 440 445 Tyr Lys Pro Val Ala Leu Gln Cys Ile Ala Asn Gly Ile Pro Asn Pro 450 455 460 Ser Ile Thr Trp Leu Lys Asp Asp Gln Pro Val Asn Thr Ala Gln Gly 465 470 475 480 Asn Leu Lys Ile Gln Ser Ser Gly Arg Val Leu Gln Ile Ala Lys Thr 485 490 495 Leu Leu Glu Asp Ala Gly Arg Tyr Thr Cys Val Ala Thr Asn Ala Ala 500 505 510 Gly Glu Thr Gln Gln His Ile Gln Leu His Val His Glu Pro Pro Ser 515 520 525 Leu Glu Asp Ala Gly Lys Met Leu Asn Glu Thr Val Leu Val Ser Asn 530 535 540 Pro Val Gln Leu Glu Cys Lys Ala Ala Gly Asn Pro Val Pro Val Ile 545 550 555 560 Thr Trp Tyr Lys Asp Asn Arg Leu Leu Ser Gly Ser Thr Ser Met Thr 565 570 575 Phe Leu Asn Arg Gly Gln Ile Ile Asp Ile Glu Ser Ala Gln Ile Ser 580 585 590 Asp Ala Gly Ile Tyr Lys Cys Val Ala Ile Asn Ser Ala Gly Ala Thr 595 600 605 Glu Leu Phe Tyr Ser Leu Gln Val His Val Ala Pro Ser Ile Ser Gly 610 615 620 Ser Asn Asn Met Val Ala Val Val Val Asn Asn Pro Val Arg Leu Glu 625 630 635 640 Cys Glu Ala Arg Gly Ile Pro Ala Pro Ser Leu Thr Trp Leu Lys Asp 645 650 655 Gly Ser Pro Val Ser Ser Phe Ser Asn Gly Leu Gln Val Leu Ser Gly 660 665 670 Gly Arg Ile Leu Ala Leu Thr Ser Ala Gln Ile Ser Asp Thr Gly Arg 675 680 685 Tyr Thr Cys Val Ala Val Asn Ala Ala Gly Glu Lys Gln Arg Asp Ile 690 695 700 Asp Leu Arg Val Tyr Val Pro Pro Asn Ile Met Gly Glu Glu Gln Asn 705 710 715 720 Val Ser Val Leu Ile Ser Gln Ala Val Glu Leu Leu Cys Gln Ser Asp 725 730 735 Ala Ile Pro Pro Pro Thr Leu Thr Trp Leu Lys Asp Gly His Pro Leu 740 745 750 Leu Lys Lys Pro Gly Leu Ser Ile Ser Glu Asn Arg Ser Val Leu Lys 755 760 765 Ile Glu Asp Ala Gln Val Gln Asp Thr Gly Arg Tyr Thr Cys Glu Ala 770 775 780 Thr Asn Val Ala Gly Lys Thr Glu Lys Asn Tyr Asn Val Asn Ile Trp 785 790 795 800 Val Pro Pro Asn Ile Gly Gly Ser Asp Glu Leu Thr Gln Leu Thr Val 805 810 815 Ile Glu Gly Asn Leu Ile Ser Leu Leu Cys Glu Ser Ser Gly Ile Pro 820 825 830 Pro Pro Asn Leu Ile Trp Lys Lys Lys Gly Ser Pro Val Leu Thr Asp 835 840 845 Ser Met Gly Arg Xaa Arg Ile Leu Ser Gly Gly Arg Gln Leu Gln Ile 850 855 860 Ser Ile Ala Glu Lys Ser Asp Ala Ala Leu Tyr Ser Cys Val Ala Ser 865 870 875 880 Asn Val Ala Gly Thr Ala Lys Lys Glu Tyr Asn Leu Gln Val Tyr Ile 885 890 895 Arg Pro Thr Ile Thr Asn Ser Gly Ser His Pro Thr Glu Ile Ile Val 900 905 910 Thr Arg Gly Lys Ser Ile Ser Leu Glu Cys Glu Val Gln Gly Ile Pro 915 920 925 Pro Pro Thr Val Thr Trp Met Lys Asp Gly His Pro Leu Ile Lys Ala 930 935 940 Lys Gly Val Glu Ile Leu Asp Glu Gly His Ile Leu Gln Leu Lys Asn 945 950 955 960 Ile His Val Ser Asp Thr Gly Arg Tyr Val Cys Val Ala Val Asn Val 965 970 975 Ala Gly Met Thr Asp Lys Lys Tyr Asp Leu Ser Val His Ala Pro Pro 980 985 990 Ser Ile Ile Gly Asn His Arg Ser Pro Glu Asn Ile Ser Val Val Glu 995 1000 1005 Lys Asn Ser Val Ser Leu Thr Cys Glu Ala Ser Gly Ile Pro Leu Pro 1010 1015 1020 Ser Xaa Thr Trp Phe Lys Asp Gly Trp Pro Val Ser Leu Ser Asn Ser 1025 1030 1035 1040 Val Arg Ile Leu Ser Gly Gly Arg Met Leu Arg Leu Met Gln Thr Thr 1045 1050 1055 Met Glu Asp Ala Gly Gln Tyr Thr Cys Val Val Arg Asn Ala Ala Gly 1060 1065 1070 Glu Glu Arg Lys Ile Phe Gly Leu Ser Val Leu Val Pro Pro His Ile 1075 1080 1085 Val Gly Glu Asn Thr Leu Glu Asp Val Lys Val Lys Glu Lys Gln Ser 1090 1095 1100 Val Thr Leu Thr Cys Glu Val Thr Gly Asn Pro Val Pro Glu Ile Thr 1105 1110 1115 1120 Trp His Lys Asp Gly Gln Pro Leu Gln Glu Asp Glu Ala His His Ile 1125 1130 1135 Ile Ser Gly Gly Arg Phe Leu Gln Ile Thr Asn Val Gln Val Pro His 1140 1145 1150 Thr Gly Arg Tyr Thr Cys Leu Ala Ser Ser Pro Ala Gly His Lys Ser 1155 1160 1165 Arg Ser Phe Ser Leu Asn Val Phe Val Ser Pro Thr Ile Ala Gly Val 1170 1175 1180 Gly Ser Asp Gly Asn Pro Glu Asp Val Thr Val Ile Leu Asn Ser Pro 1185 1190 1195 1200 Thr Ser Leu Val Cys Glu Ala Tyr Ser Tyr Pro Pro Ala Thr Ile Thr 1205 1210 1215 Trp Phe Lys Asp Gly Thr Pro Leu Glu Ser Asn Arg Asn Ile Arg Ile 1220 1225 1230 Leu Pro Gly Gly Arg Thr Leu Gln Ile Leu Asn Ala Gln Glu Asp Asn 1235 1240 1245 Ala Gly Arg Tyr Ser Cys Val Ala Thr Asn Glu Ala Gly Glu Met Ile 1250 1255 1260 Lys His Tyr Glu Val Lys Val Tyr Ile Pro Pro Ile Ile Asn Lys Gly 1265 1270 1275 1280 Asp Leu Trp Gly Pro Gly Leu Ser Pro Lys Glu Val Lys Ile Lys Val 1285 1290 1295 Asn Asn Thr Leu Thr Leu Glu Cys Glu Ala Tyr Ala Ile Pro Ser Ala 1300 1305 1310 Ser Leu Ser Trp Tyr Lys Asp Gly Gln Pro Leu Lys Ser Asp Asp His 1315 1320 1325 Val Asn Ile Ala Ala Asn Gly His Thr Leu Gln Ile Lys Glu Ala Gln 1330 1335 1340 Ile Ser Asp Thr Gly Arg Tyr Thr Cys Val Ala Ser Asn Ile Ala Gly 1345 1350 1355 1360 Glu Asp Glu Leu Asp Phe Asp Val Asn Ile Gln Val Pro Pro Ser Phe 1365 1370 1375 Gln Lys Leu Trp Glu Ile Gly Asn Met Leu Asp Thr Gly Arg Asn Gly 1380 1385 1390 Glu Ala Lys Asp Val Ile Ile Asn Asn Pro Ile Ser Leu Tyr Cys Glu 1395 1400 1405 Thr Asn Ala Ala Pro Pro Pro Thr Leu Thr Trp Tyr Lys Asp Gly His 1410 1415 1420 Pro Leu Thr Ser Ser Asp Lys Val Leu Ile Leu Pro Gly Gly Arg Val 1425 1430 1435 1440 Leu Gln Ile Pro Arg Ala Lys Val Glu Asp Ala Gly Arg Tyr Thr Cys 1445 1450 1455 Val Ala Val Asn Glu Ala Gly Glu Asp Ser Leu Gln Tyr Asp Val Arg 1460 1465 1470 Val Leu Val Pro Pro Ile Ile Lys Gly Ala Asn Ser Asp Leu Pro Glu 1475 1480 1485 Glu Val Thr Val Leu Val Asn Lys Ser Ala Leu Ile Glu Cys Leu Ser 1490 1495 1500 Ser Gly Ser Pro Ala Pro Arg Asn Ser Trp Gln Lys Asp Gly Gln Pro 1505 1510 1515 1520 Leu Leu Glu Asp Asp His His Lys Phe Leu Ser Asn Gly Arg Ile Leu 1525 1530 1535 Gln Ile Leu Asn Thr Gln Ile Thr Asp Ile Gly Arg Tyr Val Cys Val 1540 1545 1550 Ala Glu Asn Thr Ala Gly Ser Ala Lys Lys Tyr Phe Asn Leu Asn Val 1555 1560 1565 His Val Pro Pro Ser Val Ile Gly Pro Lys Ser Glu Asn Leu Thr Val 1570 1575 1580 Val Val Asn Asn Phe Ile Ser Leu Thr Cys Glu Val Ser Gly Phe Pro 1585 1590 1595 1600 Pro Pro Asp Leu Ser Trp Leu Lys Asn Glu Gln Pro Ile Lys Leu Asn 1605 1610 1615 Thr Asn Thr Leu Ile Val Pro Gly Gly Arg Thr Leu Gln Ile Ile Arg 1620 1625 1630 Ala Lys Val Ser Asp Gly Gly Glu Tyr Thr Cys Ile Ala Ile Asn Gln 1635 1640 1645 Ala Gly Glu Ser Lys Lys Lys Phe Ser Leu Thr Val Tyr Val Pro Pro 1650 1655 1660 Ser Ile Lys Asp His Asp Ser Glu Ser Leu Ser Val Val Asn Val Arg 1665 1670 1675 1680 Glu Gly Thr Ser Val Ser Leu Glu Cys Glu Ser Asn Ala Val Pro Pro 1685 1690 1695 Pro Val Ile Thr Trp Tyr Lys Asn Gly Arg Met Ile Thr Glu Ser Thr 1700 1705 1710 His Val Glu Ile Leu Ala Asp Gly Gln Met Leu His Ile Lys Lys Ala 1715 1720 1725 Glu Val Ser Asp Thr Gly Gln Tyr Val Cys Arg Ala Ile Asn Val Ala 1730 1735 1740 Gly Arg Asp Asp Lys Asn Phe His Leu Asn Val Tyr Val Pro Pro Ser 1745 1750 1755 1760 Ile Glu Gly Pro Glu Arg Glu Val Ile Val Glu Thr Ile Ser Asn Pro 1765 1770 1775 Val Thr Leu Thr Cys Asp Ala Thr Gly Ile Pro Pro Pro Thr Ile Ala 1780 1785 1790 Trp Leu Lys Asn His Lys Arg Ile Glu Asn Ser Asp Ser Leu Glu Val 1795 1800 1805 Arg Ile Leu Ser Gly Gly Ser Lys Leu Gln Ile Ala Arg Ser Gln His 1810 1815 1820 Ser Asp Ser Gly Asn Tyr Thr Cys Ile Ala Ser Asn Met Glu Gly Lys 1825 1830 1835 1840 Ala Gln Lys Tyr Tyr Phe Leu Ser Ile Gln Val Pro Pro Ser Val Ala 1845 1850 1855 Gly Ala Glu Ile Pro Ser Asp Val Ser Val Leu Leu Gly Glu Asn Val 1860 1865 1870 Glu Leu Val Cys Asn Ala Asn Gly Ile Pro Thr Pro Leu Ile Gln Trp 1875 1880 1885 Leu Lys Asp Gly Lys Pro Ile Ala Ser Gly Glu Thr Glu Arg Ile Arg 1890 1895

1900 Val Ser Ala Asn Gly Ser Thr Leu Asn Ile Tyr Gly Ala Leu Thr Ser 1905 1910 1915 1920 Asp Thr Gly Lys Tyr Thr Cys Val Ala Thr Asn Pro Ala Gly Glu Glu 1925 1930 1935 Asp Arg Ile Phe Asn Leu Asn Val Tyr Val Thr Pro Thr Ile Arg Gly 1940 1945 1950 Asn Lys Asp Glu Ala Glu Lys Leu Met Thr Leu Val Asp Thr Ser Ile 1955 1960 1965 Asn Ile Glu Cys Arg Ala Thr Gly Thr Pro Pro Pro Gln Ile Asn Trp 1970 1975 1980 Leu Lys Asn Gly Leu Pro Leu Pro Leu Ser Ser His Ile Arg Leu Leu 1985 1990 1995 2000 Ala Ala Gly Gln Val Ile Arg Ile Val Arg Ala Gln Val Ser Asp Val 2005 2010 2015 Ala Val Tyr Thr Cys Val Ala Ser Asn Arg Ala Gly Val Asp Asn Lys 2020 2025 2030 His Tyr Asn Leu Gln Val Phe Ala Pro Pro Asn Met Asp Asn Ser Met 2035 2040 2045 Gly Thr Glu Glu Ile Thr Val Leu Lys Gly Ser Ser Thr Ser Met Ala 2050 2055 2060 Cys Ile Thr Asp Gly Thr Pro Ala Pro Ser Met Ala Trp Leu Arg Asp 2065 2070 2075 2080 Gly Gln Pro Leu Gly Leu Asp Ala His Leu Thr Val Ser Thr His Gly 2085 2090 2095 Met Val Leu Gln Leu Leu Lys Ala Glu Thr Glu Asp Ser Gly Lys Tyr 2100 2105 2110 Thr Cys Ile Ala Ser Asn Glu Ala Gly Glu Val Ser Lys His Phe Ile 2115 2120 2125 Leu Lys Val Leu Glu Pro Pro His Ile Asn Gly Ser Glu Glu His Glu 2130 2135 2140 Glu Ile Ser Val Ile Val Asn Asn Pro Leu Glu Leu Thr Cys Ile Ala 2145 2150 2155 2160 Ser Gly Ile Pro Ala Pro Lys Met Thr Trp Met Lys Asp Gly Arg Pro 2165 2170 2175 Leu Pro Gln Thr Asp Gln Val Gln Thr Leu Gly Gly Gly Glu Val Leu 2180 2185 2190 Arg Ile Ser Thr Ala Gln Val Glu Asp Thr Gly Arg Tyr Thr Cys Leu 2195 2200 2205 Ala Ser Ser Pro Ala Gly Asp Asp Asp Lys Glu Tyr Leu Val Arg Val 2210 2215 2220 His Val Pro Pro Asn Ile Ala Gly Thr Asp Glu Pro Arg Asp Ile Thr 2225 2230 2235 2240 Val Leu Arg Asn Arg Gln Val Thr Leu Glu Cys Lys Ser Asp Ala Val 2245 2250 2255 Pro Pro Pro Val Ile Thr Trp Leu Arg Asn Gly Glu Arg Leu Gln Ala 2260 2265 2270 Thr Pro Arg Val Arg Ile Leu Ser Gly Gly Arg Tyr Leu Gln Ile Asn 2275 2280 2285 Asn Ala Asp Leu Gly Asp Thr Ala Asn Tyr Thr Cys Val Ala Ser Asn 2290 2295 2300 Ile Ala Gly Lys Thr Thr Arg Glu Phe Ile Leu Thr Val Asn Val Pro 2305 2310 2315 2320 Pro Asn Ile Lys Gly Gly Pro Gln Ser Leu Val Ile Leu Leu Asn Lys 2325 2330 2335 Ser Thr Val Leu Glu Cys Ile Ala Glu Gly Val Pro Thr Pro Arg Ile 2340 2345 2350 Thr Trp Arg Lys Asp Gly Ala Val Leu Ala Gly Asn His Ala Arg Tyr 2355 2360 2365 Ser Ile Leu Glu Asn Gly Phe Leu His Ile Gln Ser Ala His Val Thr 2370 2375 2380 Asp Thr Gly Arg Tyr Leu Cys Met Ala Thr Asn Ala Ala Gly Thr Asp 2385 2390 2395 2400 Arg Arg Arg Ile Asp Leu Gln Val His Val Pro Pro Ser Ile Ala Pro 2405 2410 2415 Gly Pro Thr Asn Met Thr Val Ile Val Asn Val Gln Thr Thr Leu Ala 2420 2425 2430 Cys Glu Ala Thr Gly Ile Pro Lys Pro Ser Ile Asn Trp Arg Lys Asn 2435 2440 2445 Gly His Leu Leu Asn Val Asp Gln Asn Gln Asn Ser Tyr Arg Leu Leu 2450 2455 2460 Ser Ser Gly Ser Leu Val Ile Ile Ser Pro Ser Val Asp Asp Thr Ala 2465 2470 2475 2480 Thr Tyr Glu Cys Thr Val Thr Asn Gly Ala Gly Asp Asp Lys Arg Thr 2485 2490 2495 Val Asp Leu Thr Val Gln Val Pro Pro Ser Ile Ala Asp Glu Pro Thr 2500 2505 2510 Asp Phe Leu Val Thr Lys His Ala Pro Ala Val Ile Thr Cys Thr Ala 2515 2520 2525 Ser Gly Val Pro Phe Pro Ser Ile His Trp Thr Lys Asn Gly Ile Arg 2530 2535 2540 Leu Leu Pro Arg Gly Asp Gly Tyr Arg Ile Leu Ser Ser Gly Ala Ile 2545 2550 2555 2560 Glu Ile Leu Ala Thr Gln Leu Asn His Ala Gly Arg Tyr Thr Cys Val 2565 2570 2575 Ala Arg Asn Ala Ala Gly Ser Ala His Arg His Val Thr Leu His Val 2580 2585 2590 His Glu Pro Pro Val Ile Gln Pro Gln Pro Ser Glu Leu His Val Ile 2595 2600 2605 Leu Asn Asn Pro Ile Leu Leu Pro Cys Glu Ala Thr Gly Thr Pro Ser 2610 2615 2620 Pro Phe Ile Thr Trp Gln Lys Glu Gly Ile Asn Val Asn Thr Ser Gly 2625 2630 2635 2640 Arg Asn His Ala Val Leu Pro Ser Gly Gly Leu Gln Ile Xaa Arg Ala 2645 2650 2655 Val Arg Glu Asp Ala Gly Thr Tyr Met Cys Val Ala Gln Asn Pro Ala 2660 2665 2670 Gly Thr Ala Leu Gly Lys Ile Lys Leu Asn Val Gln Val Pro Pro Val 2675 2680 2685 Ile Ser Pro His Leu Lys Glu Tyr Val Ile Ala Val Asp Lys Pro Ile 2690 2695 2700 Thr Leu Ser Cys Glu Ala Asp Gly Leu Pro Pro Pro Asp Ile Thr Trp 2705 2710 2715 2720 His Lys Asp Gly Arg Ala Ile Val Glu Ser Ile Arg Gln Arg Val Leu 2725 2730 2735 Ser Ser Gly Ser Leu Gln Ile Ala Phe Val Gln Pro Gly Asp Ala Gly 2740 2745 2750 His Tyr Thr Cys Met Ala Ala Asn Val Ala Gly Ser Ser Ser Thr Ser 2755 2760 2765 Thr Lys Leu Thr Val His Val Pro Pro Arg Ile Arg Ser Thr Glu Gly 2770 2775 2780 His Tyr Thr Val Asn Glu Asn Ser Gln Ala Ile Leu Pro Cys Val Ala 2785 2790 2795 2800 Asp Gly Ile Pro Thr Pro Ala Ile Asn Trp Lys Lys Asp Asn Val Leu 2805 2810 2815 Leu Ala Asn Leu Leu Gly Lys Tyr Thr Ala Glu Pro Tyr Gly Glu Leu 2820 2825 2830 Ile Leu Glu Asn Val Val Leu Glu Asp Ser Gly Phe Tyr Thr Cys Val 2835 2840 2845 Ala Asn Asn Ala Ala Gly Glu Asp Thr His Thr Val Ser Leu Thr Val 2850 2855 2860 His Val Leu Pro Thr Phe Thr Glu Leu Pro Gly Asp Val Ser Leu Asn 2865 2870 2875 2880 Lys Gly Glu Gln Leu Arg Leu Ser Cys Lys Ala Thr Gly Ile Pro Leu 2885 2890 2895 Pro Lys Leu Thr Trp Thr Phe Asn Asn Asn Ile Ile Pro Ala His Phe 2900 2905 2910 Asp Ser Val Asn Gly His Ser Glu Leu Val Ile Glu Arg Val Ser Lys 2915 2920 2925 Glu Asp Ser Gly Thr Tyr Val Cys Thr Ala Glu Asn Ser Val Gly Phe 2930 2935 2940 Val Lys Ala Ile Gly Phe Val Tyr Val Lys Glu Pro Pro Val Phe Lys 2945 2950 2955 2960 Gly Asp Tyr Pro Ser Asn Trp Ile Glu Pro Leu Gly Gly Asn Ala Ile 2965 2970 2975 Leu Asn Cys Glu Val Lys Gly Asp Pro Thr Pro Thr Ile Gln Trp Asn 2980 2985 2990 Arg Lys Gly Val Asp Ile Glu Ile Ser His Arg Ile Arg Gln Leu Gly 2995 3000 3005 Asn Gly Ser Leu Ala Ile Tyr Gly Thr Val Asn Glu Asp Ala Gly Asp 3010 3015 3020 Tyr Thr Cys Val Ala Thr Asn Glu Ala Gly Val Val Glu Arg Ser Met 3025 3030 3035 3040 Ser Leu Thr Leu Gln Ser Pro Pro Ile Ile Thr Leu Glu Pro Val Glu 3045 3050 3055 Thr Val Ile Asn Ala Gly Gly Lys Ile Ile Leu Asn Cys Gln Ala Thr 3060 3065 3070 Gly Glu Pro Gln Pro Thr Ile Thr Trp Ser Arg Gln Gly His Ser Ile 3075 3080 3085 Ser Trp Asp Asp Arg Val Asn Val Leu Ser Asn Asn Ser Leu Tyr Ile 3090 3095 3100 Ala Asp Ala Gln Lys Glu Asp Thr Ser Glu Phe Glu Cys Val Ala Arg 3105 3110 3115 3120 Asn Leu Met Gly Ser Val Leu Val Arg Val Pro Val Ile Val Gln Val 3125 3130 3135 His Gly Gly Phe Ser Gln Trp Ser Ala Trp Arg Ala Cys Ser Val Thr 3140 3145 3150 Cys Gly Lys Gly Ile Gln Lys Arg Ser Arg Leu Cys Asn Gln Pro Leu 3155 3160 3165 Pro Ala Asn Gly Gly Lys Pro Cys Gln Gly Ser Asp Leu Glu Met Arg 3170 3175 3180 Asn Cys Gln Asn Lys Pro Cys Pro Val Asp Gly Ser Trp Ser Glu Trp 3185 3190 3195 3200 Ser Leu Trp Glu Glu Cys Thr Arg Ser Cys Gly Arg Gly Asn Gln Thr 3205 3210 3215 Arg Thr Arg Thr Cys Asn Asn Pro Ser Val Gln His Gly Gly Arg Pro 3220 3225 3230 Cys Glu Gly Asn Ala Val Glu Ile Ile Met Cys Asn Ile Arg Pro Cys 3235 3240 3245 Pro Val His Gly Ala Trp Ser Ala Trp Gln Pro Trp Gly Thr Cys Ser 3250 3255 3260 Glu Ser Cys Gly Lys Gly Thr Gln Thr Arg Ala Arg Leu Cys Asn Asn 3265 3270 3275 3280 Pro Pro Pro Ala Phe Gly Gly Ser Tyr Cys Asp Gly Ala Glu Thr Gln 3285 3290 3295 Met Gln Val Cys Asn Glu Arg Asn Cys Pro Ile His Gly Lys Trp Ala 3300 3305 3310 Thr Trp Ala Ser Trp Ser Ala Cys Ser Val Ser Cys Gly Gly Gly Ala 3315 3320 3325 Arg Gln Arg Thr Arg Gly Cys Ser Asp Pro Val Pro Gln Tyr Gly Gly 3330 3335 3340 Arg Lys Cys Glu Gly Ser Asp Val Gln Ser Asp Phe Cys Asn Ser Asp 3345 3350 3355 3360 Pro Cys Pro Thr His Gly Asn Trp Ser Pro Trp Ser Gly Trp Gly Thr 3365 3370 3375 Cys Ser Arg Thr Cys Asn Gly Gly Gln Met Arg Arg Tyr Arg Thr Cys 3380 3385 3390 Asp Asn Pro Pro Pro Ser Asn Gly Gly Arg Ala Cys Gly Gly Pro Asp 3395 3400 3405 Ser Gln Ile Gln Arg Cys Asn Thr Asp Met Cys Pro Val Asp Gly Ser 3410 3415 3420 Trp Gly Ser Trp His Ser Trp Ser Gln Cys Ser Ala Ser Cys Gly Gly 3425 3430 3435 3440 Gly Glu Lys Thr Arg Lys Arg Leu Cys Asp His Pro Val Pro Val Lys 3445 3450 3455 Gly Gly Arg Pro Cys Pro Gly Asp Thr Thr Gln Val Thr Arg Cys Asn 3460 3465 3470 Val Gln Ala Cys Pro Gly Gly Pro Gln Arg Ala Arg Gly Ser Val Ile 3475 3480 3485 Gly Asn Ile Asn Asp Val Glu Phe Gly Ile Ala Phe Leu Asn Ala Thr 3490 3495 3500 Ile Thr Asp Ser Pro Asn Ser Asp Thr Arg Ile Ile Arg Ala Lys Ile 3505 3510 3515 3520 Thr Asn Val Pro Arg Ser Leu Gly Ser Ala Met Arg Lys Ile Val Ser 3525 3530 3535 Ile Leu Asn Pro Ile Tyr Trp Thr Thr Ala Lys Glu Ile Gly Glu Ala 3540 3545 3550 Val Asn Gly Phe Thr Leu Thr Asn Ala Val Phe Lys Arg Glu Thr Gln 3555 3560 3565 Val Glu Phe Ala Thr Gly Glu Ile Leu Gln Met Ser His Ile Ala Arg 3570 3575 3580 Gly Leu Asp Ser Asp Gly Ser Leu Leu Leu Asp Ile Val Val Ser Gly 3585 3590 3595 3600 Tyr Val Leu Gln Leu Gln Ser Pro Ala Glu Val Thr Val Lys Asp Tyr 3605 3610 3615 Thr Glu Asp Tyr Ile Gln Thr Gly Pro Gly Gln Leu Tyr Ala Tyr Ser 3620 3625 3630 Thr Arg Leu Phe Thr Ile Asp Gly Ile Ser Ile Pro Tyr Thr Trp Asn 3635 3640 3645 His Thr Val Phe Tyr Asp Gln Ala Gln Gly Arg Met Pro Phe Leu Val 3650 3655 3660 Glu Thr Leu His Ala Ser Ser Val Glu Ser Asp Tyr Asn Gln Ile Glu 3665 3670 3675 3680 Glu Thr Leu Gly Phe Lys Ile His Ala Ser Ile Ser Lys Gly Asp Arg 3685 3690 3695 Ser Asn Gln Cys Pro Ser Gly Phe Thr Leu Asp Ser Val Gly Pro Phe 3700 3705 3710 Cys Ala Asp Glu Asp Glu Cys Ala Ala Gly Asn Pro Cys Ser His Ser 3715 3720 3725 Cys His Asn Ala Met Gly Thr Tyr Tyr Cys Ser Cys Pro Lys Gly Leu 3730 3735 3740 Thr Ile Ala Ala Asp Gly Arg Thr Cys Gln Asp Ile Asp Glu Cys Ala 3745 3750 3755 3760 Leu Gly Arg His Thr Cys His Ala Gly Gln Asp Cys Asp Asn Thr Ile 3765 3770 3775 Gly Ser Tyr Arg Cys Val Val Arg Cys Gly Ser Gly Phe Arg Arg Thr 3780 3785 3790 Ser Asp Gly Leu Ser Cys Gln Asp Ile Asn Glu Cys Gln Glu Ser Ser 3795 3800 3805 Pro Cys His Gln Arg Cys Phe Asn Ala Ile Gly Ser Phe His Cys Gly 3810 3815 3820 Cys Glu Pro Gly Tyr Gln Leu Lys Gly Arg Lys Cys Met Asp Val Asn 3825 3830 3835 3840 Glu Cys Arg Gln Asn Val Cys Arg Pro Asp Gln His Cys Lys Asn Thr 3845 3850 3855 Arg Gly Gly Tyr Lys Cys Ile Asp Leu Cys Pro Asn Gly Met Thr Lys 3860 3865 3870 Ala Glu Asn Gly Thr Cys Ile Asp Ile Asp Glu Cys Lys Asp Gly Thr 3875 3880 3885 His Gln Cys Arg Tyr Asn Gln Ile Cys Glu Asn Thr Arg Gly Ser Tyr 3890 3895 3900 Arg Cys Val Cys Pro Arg Gly Tyr Arg Ser Gln Gly Val Gly Arg Pro 3905 3910 3915 3920 Cys Met Asp Ile Asp Glu Cys Glu Asn Thr Asp Ala Cys Gln His Glu 3925 3930 3935 Cys Lys Asn Thr Phe Gly Ser Tyr Gln Cys Ile Cys Pro Pro Gly Tyr 3940 3945 3950 Gln Leu Thr His Asn Gly Lys Thr Cys Gln Asp Ile Asp Glu Cys Leu 3955 3960 3965 Glu Gln Asn Val His Cys Gly Pro Asn Arg Met Cys Phe Asn Met Arg 3970 3975 3980 Gly Ser Tyr Gln Cys Ile Asp Thr Pro Cys Pro Pro Asn Tyr Gln Arg 3985 3990 3995 4000 Asp Pro Val Ser Gly Phe Cys Leu Lys Asn Cys Pro Pro Asn Asp Leu 4005 4010 4015 Glu Cys Ala Leu Ser Pro Tyr Ala Leu Glu Tyr Lys Leu Val Ser Leu 4020 4025 4030 Pro Phe Gly Ile Ala Thr Asn Gln Asp Leu Ile Arg Leu Val Ala Tyr 4035 4040 4045 Thr Gln Asp Gly Val Met His Pro Arg Thr Thr Phe Leu Met Val Asp 4050 4055 4060 Glu Glu Gln Thr Val Pro Phe Ala Leu Arg Asp Glu Asn Leu Lys Gly 4065 4070 4075 4080 Val Val Tyr Thr Thr Arg Pro Leu Arg Glu Ala Glu Thr Tyr Arg Met 4085 4090 4095 Arg Val Arg Ala Ser Ser Tyr Ser Ala Asn Gly Thr Ile Glu Tyr Gln 4100 4105 4110 Thr Thr Phe Ile Val Tyr Ile Ala Val Ser Ala Tyr Pro Tyr 4115 4120 4125

Claims

1-4. (canceled)

5. A substantially isolated polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:4.

6. An isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3.

7. An antibody having immunospecificity for the polypeptide sequence of SEQ ID NO:2 or SEQ ID NO:4.