NOVEL KINASES AND USES THEREOF

Abstract

s, proteins, and nucleic acid molecules are disclosed. In addition to isolated, full-length kinase proteins, the invention further provides isolated kinase fusion proteins, antigenic peptides, and anti-kinase antibodies. The invention also provides kinase nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a kinase gene has been introduced or disrupted. Diagnostic, screening, and therapeutic methods utilizing compositions of the invention are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. patent application Ser. No. 12/151,520, filed on May 7, 2008 (pending), which is a divisional of U.S. patent application Ser. No. 11/358,419, filed on Feb. 21, 2006, now U.S. Pat. No. 7,425,424, which is a continuation of U.S. patent application Ser. No. 10/989,228, filed on Nov. 15, 2004 (abandoned), which is a divisional of U.S. patent application Ser. No. 09/862,027, filed on May 21, 2001, now U.S. Pat. No. 6,858,418, which is a divisional of U.S. application Ser. No. 09/345,473, filed Jun. 30, 1999, now U.S. Pat. No. 6,558,903. The entire contents of each of these applications are herein incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to novel kinase nucleic acid sequences and proteins. Also provided are vectors, host cells, and recombinant methods for making and using the novel molecules.

BACKGROUND OF THE INVENTION

[0003] Phosphate tightly associated with a molecule, e.g., a protein, has been known since the late nineteenth century. Since then, a variety of covalent linkages of phosphate to proteins have been found. The most common involve esterification of phosphate to serine, threonine, and tyrosine with smaller amounts being linked to lysine, arginine, histidine, aspartic acid, glutamic acid, and cysteine. The occurrence of phosphorylated molecules, e.g., proteins, implies the existence of one or more kinases, e.g., protein kinases, capable of phosphorylating various molecules, e.g., amino acid residues on proteins, and also of phosphatases, e.g., protein phosphatases, capable of hydrolyzing various phosphorylated molecules, e.g., phosphorylated amino acid residues on proteins.

[0004] Protein kinases play critical roles in the regulation of biochemical and morphological changes associated with cellular growth and division (D'Urso et al. (1990) Science 250:786-791; Birchmeier et al. (1993) Bioessays 15:185-189). They serve as growth factor receptors and signal transducers and have been implicated in cellular transformation and malignancy (Hunter et al. (1992) Cell 70:375-387; Posada et al. (1992) Mol. Biol. Cell 3:583-592; Hunter et al. (1994) Cell 79:573-582). For example, protein kinases have been shown to participate in the transmission of signals from growth-factor receptors (Sturgill et al. (1988) Nature 344:715-718; Gomez et al. (1991) Nature 353:170-173), control of entry of cells into mitosis (Nurse (1990) Nature 344:503-508; Maller (1991) Curr. Opin. Cell Biol. 3:269-275) and regulation of actin bundling (Husain-Chishti et al. (1988) Nature 334:718-721).

[0005] Protein kinases can be divided into different groups based on either amino acid sequence similarity or specificity for either serine/threonine or tyrosine residues. A small number of dual-specificity kinases have also been described. Within the broad classification, kinases can be further subdivided into families whose members share a higher degree of catalytic domain amino acid sequence identity and also have similar biochemical properties. Most protein kinase family members also share structural features outside the kinase domain that reflect their particular cellular roles. These include regulatory domains that control kinase activity or interaction with other proteins (Hanks et al. (1988) Science 241:42-52).

[0006] Kinases play critical roles in cellular growth. Therefore, novel kinase polynucleotides and proteins are useful for modulating cellular growth, differentiation and/or development.

SUMMARY OF THE INVENTION

[0007] Isolated nucleic acid molecules corresponding to kinase nucleic acid sequences are provided. Additionally amino acid sequences corresponding to the polynucleotides are encompassed. In particular, the present invention provides for isolated nucleic acid molecules comprising nucleotide sequences encoding the amino acid sequences shown in SEQ ID NOs:2, 4, 6, 8, 10, 12, and 14. Further provided are kinase polypeptides having an amino acid sequence encoded by a nucleic acid molecule described herein.

[0008] The present invention also provides vectors and host cells for recombinant expression of the nucleic acid molecules described herein, as well as methods of making such vectors and host cells and for using them for production of the polypeptides or peptides of the invention by recombinant techniques.

[0009] The kinase molecules of the present invention are useful for modulating cellular growth and/or cellular metabolic pathways particularly for regulating one or more proteins involved in growth and metabolism. Accordingly, in one aspect, this invention provides isolated nucleic acid molecules encoding kinase proteins or biologically active portions thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of kinase-encoding nucleic acids.

[0010] Another aspect of this invention features isolated or recombinant kinase proteins and polypeptides. Preferred kinase proteins and polypeptides possess at least one biological activity possessed by naturally occurring kinase proteins.

[0011] Variant nucleic acid molecules and polypeptides substantially homologous to the nucleotide and amino acid sequences set forth in the sequence listings are encompassed by the present invention. Additionally, fragments and substantially homologous fragments of the nucleotide and amino acid sequences are provided.

[0012] Antibodies and antibody fragments that selectively bind the kinase polypeptides and fragments are provided. Such antibodies are useful in detecting the kinase polypeptides as well as in modulating cellular growth and metabolism.

[0013] In another aspect, the present invention provides a method for detecting the presence of kinase activity or expression in a biological sample by contacting the biological sample with an agent capable of detecting an indicator of kinase activity such that the presence of kinase activity is detected in the biological sample.

[0014] In yet another aspect, the invention provides a method for modulating kinase activity comprising contacting a cell with an agent that modulates (inhibits or stimulates) kinase activity or expression such that kinase activity or expression in the cell is modulated. In one embodiment, the agent is an antibody that specifically binds to kinase protein. In another embodiment, the agent modulates expression of kinase protein by modulating transcription of a kinase gene, splicing of a kinase mRNA, or translation of a kinase mRNA. In yet another embodiment, the agent is a nucleic acid molecule having a nucleotide sequence that is antisense to the coding strand of the kinase mRNA or the kinase gene.

[0015] In one embodiment, the methods of the present invention are used to treat a subject having a disorder characterized by aberrant kinase protein activity or nucleic acid expression by administering an agent that is a kinase modulator to the subject. In one embodiment, the kinase modulator is a kinase protein. In another embodiment, the kinase modulator is a kinase nucleic acid molecule. In other embodiments, the kinase modulator is a peptide, peptidomimetic, or other small molecule.

[0016] The present invention also provides a diagnostic assay for identifying the presence or absence of a genetic lesion or mutation characterized by at least one of the following: (1) aberrant modification or mutation of a gene encoding a kinase protein; (2) misregulation of a gene encoding a kinase protein; and (3) aberrant post-translational modification of a kinase protein, wherein a wild-type form of the gene encodes a protein with a kinase activity.

[0017] In another aspect, the invention provides a method for identifying a compound that binds to or modulates the activity of a kinase protein. In general, such methods entail measuring a biological activity of a kinase protein in the presence and absence of a test compound and identifying those compounds that alter the activity of the kinase protein.

[0018] The invention also features methods for identifying a compound that modulates the expression of kinase genes by measuring the expression of the kinase sequences in the presence and absence of the compound.

[0019] Other features and advantages of the invention will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIGS. 1A-1C provide the nucleotide (SEQ ID NO:1) and amino acid (SEQ ID NO:2) sequences for h12832.

[0021] FIGS. 2A-2G show the amino acid sequence alignment for the protein (h12832; SEQ ID NO:2) encoded by human 12832 (SEQ ID NO:1) with the Arabidopsis thaliana protein kinase homologue (A. thal. protein kinase homolog; GenBank Accession Number AAB71975; SEQ ID NO:15), the Arabidopsis thaliana putative receptor kinase (A. thal. putative Rc. Kinase; GenBank Accession Number AAB71975; SEQ ID NO:16), the Arabidopsis thaliana receptor-kinase isolog (A. thal. Rc. kinase isolog; GenBank Accession Number AAB65490; SEQ ID NO:17), the C. elegans tyrosine kinase (C. ele. Tyr. Kinase; GenBank Accession Number AAC47047; SEQ ID NO:18) and the human mixed lineage kinase 1 (hMLK1; SP Accession Number P80192; SEQ ID NO:19).

[0022] FIG. 3 shows a dendrogram for the h12832 gene.

[0023] FIGS. 4A-4B provide the nucleotide (SEQ ID NO:3) and amino acid (SEQ ID NO:4) sequences for h14138.

[0024] FIGS. 5A-5L show the amino acid sequence alignment for the protein (h14138; SEQ ID NO:4) encoded by human 14138 (SEQ ID NO:3) with the Dictyostelium discoideum PkgA protein (Di. Dis. PkgA; GenBank Accession Number AAB70848, SEQ ID NO:77), the hypothetical human serine-threonine protein kinase R31240_--1 (h19p13.2; GenBank Accession Number AAB51171; SEQ ID NO:78), the human KIAA0561 protein (hKIAA0561; DBJ Accession Number BAA20762; SEQ ID NO:79), the human KIAA0807 protein (hKIAA0807; DBJ Accession Number BAA34527; SEQ ID NO:80), the mouse protein kinase (mMAST205; GenBank Accession Number AAC04132; SEQ ID NO:81) and the S. pombe protein kinase CEK1 (CEK1, SP Accession Number P38938; SEQ ID NO:82).

[0025] FIG. 6 shows a dendrogram for the h14138 gene.

[0026] FIGS. 7A-7C provide the nucleotide (SEQ ID NO:5) and amino acid (SEQ ID NO:6) sequences for h14833.

[0027] FIGS. 8A-8G show the amino acid sequence alignment for the protein (h14833; SEQ ID NO:6) encoded by human 14833 (SEQ ID NO:5) with the avian erythroblastosis virus (strain S13) sea tyrosine-protein kinase transforming protein (Avi. SEA Tyr. Pro. Kin.; SP Accession Number P23049; SEQ ID NO:20), the avian erythroblastosis virus env-sea polyprotein (Avi. Tyr. Kinase env-sea; NB Accession Number A33902; SEQ ID NO:21), the Caenorhabditis elegans protein containing similarity to protein kinase domains (C. ele. P. Kin. Domains; GenBank Accession Number AAC19211; SEQ ID NO:22), the putative fruit fly (Drosophila melanogaster) torso tyrosine-protein kinase receptor (Dros. TOR Tyr. Kinase Rc.; SP Accession Number P18475; SEQ ID NO:23), the c-sea chicken (gallus gallus) transmembrane protein-tyrosine kinase (Gal. Proto. T.M. Tyr. Kinase; GenBank Accession Number AAA48729; SEQ ID NO:24), and the Hydra vulgaris receptor protein-tyrosine kinase (Hyd. Rc. Pro. Kinase; GenBank Accession Number AAA65223; SEQ ID NO:25). The sequence alignment was generated using the Clustal method with PAM 250 residue weight table.

[0028] FIG. 9 shows a dendrogram for the h14833 gene.

[0029] FIGS. 10A-10C provide the nucleotide (SEQ ID NO:7) and amino acid (SEQ ID NO:8) sequences for h15590.

[0030] FIGS. 11A-11H show the amino acid sequence alignment for the protein (h15990; SEQ ID NO:8) encoded by human 15990 (SEQ ID NO:7) with the Arabidopsis thaliana putative protein kinase (A. thal. BAC clone; GenBank Accession Number AAD30583; SEQ ID NO:26), the Arabidopsis thaliana serine/threonine kinase-like protein (A. thal. Ser/Thr kin-like pro; EMB Accession Number CAB43919; SEQ ID NO:27), the human serine/threonine kinase RICK (hBAC clone; GenBank Accession Number AAC24561; SEQ ID NO:28), the human serine/threonine kinase receptor interacting protein (hSer/Thr Kin. RIP; SP Accession Number Q13546; SEQ ID NO:29), the murine serine/threonine kinase receptor interacting protein (mSer/Thr Pro. Kin. RIP; SP Accession Number Q60855; SEQ ID NO:30), and the Rattus norvegicus homocysteine respondent protein (GenBank Accession Number AAD02059; SEQ ID NO:31). The sequence alignment was generated using the Clustal method.

[0031] FIG. 12 shows a dendrogram for the h15990 gene.

[0032] FIGS. 13A-13B provide the nucleotide (SEQ ID NO:9) and amino acid (SEQ ID NO:10) sequences for h15993.

[0033] FIGS. 14A-14Q show the amino acid sequence alignment for the protein (h15993; SEQ ID NO:10) encoded by human 15993 (SEQ ID NO:9) with the Arabidopsis thaliana putative MAP kinase (A. thal. MAPK; EMB Accession Number CAB43520; SEQ ID NO:32), the Arabidopsis thaliana Ste20-like kinase homolog (A. tha. Sete20-like Kinase homo.; GenBank Accession Number AAC18797; SEQ ID NO:33), the Arabidopsis thaliana protein kinase-like protein (A. thal. cosmid; EMB Accession Number CAB41172; SEQ ID NO:34), the C. elegans protein having weak similarity with many protein kinases (C. ele. Kinase-like; EMB Accession Number CAA99887; SEQ ID NO:35), the C. elegans tyrosine-protein kinase-like protein (C. ele. Tyr. Kinase-like; EMB Accession Number CAA15621; SEQ ID NO:36), the human putative mitogen-activated protein kinase kinase kinase (hMAPKKK; EMB Accession Number CAB44308; SEQ ID NO:37), the Oryza sativa mitogen activated protein kinase kinase (O. sat. MEK1; GenBank Accession Number AAC32599; SEQ ID NO:38), the Phycomyces blakesleeanus serine/threonine protein kinase pkpa (P. bla. PKPA; SP Accession Number Q01577; SEQ ID NO:39), and the C. elegans serine/threonine-protein kinase-like protein (C. ele. Ser/thr Kinase-like; EMB Accession Number CAA92591; SEQ ID NO:40). The sequence alignment was generated using the Clustal method.

[0034] FIG. 15 shows a dendrogram for the h15993 gene.

[0035] FIG. 16 provides the nucleotide (SEQ ID NO:11) and amino acid (SEQ ID NO:12) sequences for h16341.

[0036] FIGS. 17A-17I show the amino acid sequence alignment for the protein (h16341; SEQ ID NO:12) encoded by human 16341 (SEQ ID NO:11) with the human lim domain kinase 2 (hLIK2; SP accession Number P53671; SEQ ID NO:41), the human lim kinase (hLim Kinase; GenBank Accession Number AAB54055; SEQ ID NO:42), the human testis-specific protein kinase 1 (hTESK; SP accession Number Q15569; SEQ ID NO:43), the murine lim kinase 2b (mLIMK2b; DBJ Accession Number BAA24489; SEQ ID NO:44), the murine testis-specific lim-kinase 2 (mLimk2t; DBJ Accession Number BAA31147; SEQ ID NO:45), the murine testis-specific protein kinase 1 (mTESK1; DBJ Accession Number BAA25124; SEQ ID NO:46), and mTESK1.1; DBJ Accession Number BAA25125; SEQ ID NO:47), the R. norvegicus testis-specific protein kinase 1 (rTESK; SP Accession Number Q63572; SEQ ID NO:48), and Xenopus laevis LIM motif-containing protein kinase, Xlimk1 (S. lae. Xlimk1; DBJ Accession Number BAA21488; SEQ ID NO:49). The sequence alignment was generated using the Clustal method.

[0037] FIG. 18 shows a dendrogram for the h16341 gene.

[0038] FIGS. 19A-19D provide the nucleotide (SEQ ID NO:13) and amino acid (SEQ ID NO:14) sequences for h2252.

[0039] FIGS. 20A-20G show the amino acid sequence alignment for the protein (h2252; SEQ ID NO:14) encoded by human 2252 (SEQ ID NO:13) with the C. elegans serine/threonine kinase (C. ele. cosmid, GenBank Accession Number AAC69038; SEQ ID NO:50), the Diclyostelium discoideum severin kinase (Disto. Disc. Severin Kinase., GenBank Accession Number AAC24522; SEQ ID NO: 51), the human Ste20-like kinase (hSTE20-like Kinase; EMB Accession Number CAA67700; SEQ ID NO:52), the human Ste20-like kinase 3 (hSTE20-like Kinase-3; GenBank Accession Number AAB82560; SEQ ID NO:53), the human YSK1 protein (hYSK1, DBJ Accession Number BAA20420; SEQ ID NO:54) and the mouse Ste20-like kinase (mSTE20-like Kinase; GenBank Accession Number AAD01208; SEQ ID NO:55).

[0040] FIG. 21 shows a dendrogram for the h2252 gene.

[0041] FIG. 22 shows expression of h12832 in various tissues and cell types relative to expression in human CD14.

[0042] FIG. 23 shows expression of h14138 in various tissues and cell types relative to expression in human mPB leukocytes.

[0043] FIG. 24 shows expression of h14833 in various tissues and cell types relative to expression in human CD14.

[0044] FIG. 25 shows expression of h15990 in various tissues and cell types relative to expression in human HEK 293.

[0045] FIG. 26 shows expression of h16341 in various tissues and cell types relative to expression in human liver fibrosis 194.

[0046] FIG. 27 shows expression of h2252 in various tissues and cell types relative to expression in human brain tissue.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention is based, at least in part, on the discovery of novel molecules, referred to herein as "kinase" nucleic acid and polypeptide molecules, which play a role in, or function in, signaling pathways associated with cellular growth and/or cellular metabolic pathways. These growth and metabolic pathways are described in Lodish et al. (1995) Molecular Cell Biology (Scientific American Books Inc., New York, N.Y.) and Stryer Biochemistry, (W. H. Freeman, New York), the contents of which are incorporated herein by reference. In one embodiment, the kinase molecules modulate the activity of one or more proteins involved in cellular growth or differentiation, e.g., cardiac, epithelial, or neuronal cell growth or differentiation. In another embodiment, the kinase molecules of the present invention are capable of modulating the phosphorylation state of a kinase molecule or the phosphorylation state of one or more proteins involved in cellular growth or differentiation, e.g., cardiac, epithelial, or neuronal cell growth or differentiation, as described in, for example, Lodish et al. and Stryer, supra. In addition, kinases of the present invention are targets of drugs described in Goodman and Gilman (1996), The Pharmacological Basis of Therapeutics (9^th ed.) Hartman & Limbard Editors, the contents of which are incorporated herein by reference. Particularly, the kinases of the invention may modulate phosphorylation in tissues and cells including lymph node, spleen, thymus, brain, lung, skeletal muscle, fetal liver, tonsil, colon, heart, liver, immune cells, including T cells, Th1 and Th2 cells, leukocytes, blood marrow, etc.

[0048] As used herein, the term "kinase" includes a protein, polypeptide, or other non-proteinaceous molecule that is capable of modulating its own phosphorylation state or the phosphorylation state of a different protein, polypeptide, or other non-proteinaceous molecule. Kinases can have a specificity for (i.e., a specificity to phosphorylate) serine/threonine residues, tyrosine residues, or both serine/threonine and tyrosine residues, e.g., the dual-specificity kinases. As referred to herein, kinases such as protein kinases preferably include a catalytic domain of about 200-400 amino acid residues in length, preferably about 200-300 amino acid residues in length, or more preferably about 250-300 amino acid residues in length, which includes preferably 5-20, more preferably 5-15, or most preferably 11 highly conserved motifs or subdomains separated by sequences of amino acids with reduced or minimal conservation. Specificity of a kinase for phosphorylation of either tyrosine or serine/threonine can be predicted by the sequence of two of the subdomains (VIb and VIII) in which different residues are conserved in each class (as described in, for example, Hanks et al. (1988) Science 241:42-52, the contents of which are incorporated herein by reference). These subdomains are also described in further detail herein.

[0049] Kinases play a role in signaling pathways associated with cellular growth. For example, protein kinases are involved in the regulation of signal transmission from cellular receptors, e.g., growth-factor receptors, entry of cells into mitosis, and the regulation of cytoskeleton function, e.g., actin bundling.

[0050] Assays for measuring Kinase activity are well known in the art depending on the particular kinase. Specific assay protocols are available in standard sources known to the ordinarily skilled artisan. For example, see "Kinases" in Ausueel et al., eds. (1994-1998) Current Protocols in Molecular Biology (3) and references cited therein.

[0051] Inhibition or over stimulation of the activity of kinases involved in signaling pathways associated with cellular growth can lead to perturbed cellular growth, which can in turn lead to cellular growth related-disorders. As used herein, a "cellular growth-related disorder" includes a disorder, disease, or condition characterized by a deregulation, e.g., an upregulation or a downregulation, of cellular growth. Cellular growth deregulation may be due to a deregulation of cellular proliferation, cell cycle progression, cellular differentiation and/or cellular hypertrophy. Examples of cellular growth related disorders include cardiovascular disorders such as heart failure, hypertension, atrial fibrillation, dilated cardiomyopathy, idiopathic cardiomyopathy, or angina; proliferative disorders or differentiative disorders such as cancer, e.g., melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, or sarcoma. Disorders associated with the following cells or tissues are also encompassed: lymph node, spleen, thymus, brain, lung, skeletal muscle, fetal liver, tonsil, colon, heart, liver, immune cells, including T cells, Th1 and Th2 cells, leukocytes, blood marrow, etc. The compositions are also useful for the treatment of liver fibrosis and other liver-related disorders.

[0052] The disclosed invention relates to methods and compositions for the modulation, diagnosis, and treatment of immune, inflammatory, respiratory, and hematological disorders. Such immune disorders include, but are not limited to, chronic inflammatory diseases and disorders, such as Crohn's disease, reactive arthritis, including Lyme disease, insulin-dependent diabetes, organ-specific autoimmunity, including multiple sclerosis, Hashimoto's thyroiditis and Grave's disease, contact dermatitis, psoriasis, graft rejection, graft versus host disease, sarcoidosis, atopic conditions, such as asthma and allergy, including allergic rhinitis, gastrointestinal allergies, including food allergies, eosinophilia, conjunctivitis, glomerular nephritis, certain pathogen susceptibilities such as helminthic (e.g., leishmaniasis), certain viral infections, including HIV, and bacterial infections, including tuberculosis and lepromatous leprosy.

[0053] Respiratory disorders include, but are not limited to, apnea, asthma, particularly bronchial asthma, berillium disease, bronchiectasis, bronchitis, bronchopneumonia, cystic fibrosis, diphtheria, dyspnea, emphysema, chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, pneumonia, acute pulmonary edema, pertussis, pharyngitis, atelectasis, Wegener's granulomatosis, Legionnaires disease, pleurisy, rheumatic fever, and sinusitis.

[0054] Hematologic disorders include but are not limited to anemias including sickle cell and hemolytic anemia, hemophilias including types A and B, leukemias, thalassemias, spherocytosis, Von Willebrand disease, chronic granulomatous disease, glucose-6-phosphate dehydrogenase deficiency, thrombosis, clotting factor abnormalities and deficiencies including factor VIII and IX deficiencies, hemarthrosis, hematemesis, hematomas, hematuria, hemochromatosis, hemoglobinuria, hemolytic-uremic syndrome, thrombocytopenias including HIV-associated thrombocytopenia, hemorrhagic telangiectasia, idiopathic thrombocytopenic purpura, thrombotic microangiopathy, hemosiderosis.

[0055] The present invention is based, at least in part, on the discovery of novel molecules, referred to herein as kinase protein and nucleic acid molecules, that comprise a family of molecules having certain conserved structural and functional features. The term "family" when referring to the protein and nucleic acid molecules of the invention is intended to mean two or more proteins or nucleic acid molecules having a common structural domain or motif and having sufficient amino acid or nucleotide sequence identity as defined herein. Such family members can be naturally or non-naturally occurring and can be from either the same or different species. For example, a family can contain a first protein of human origin, as well as other, distinct proteins of human origin or alternatively, can contain homologues of non-human origin. Members of a family may also have common functional characteristics.

[0056] One embodiment of the invention features kinase nucleic acid molecules, preferably human kinase molecules, that were identified based on a consensus motif or protein domain characteristic of a kinase family of proteins. Specifically, seven novel human genes, termed clones h12832, h14138 (partial-length), h14833, h15990 (partial length), 15993 (partial length), h16341 (partial length), and h2252, are provided. Such sequences are referred to as "kinase" sequences indicating that the genes and the partial gene sequences share sequence similarity with kinase genes. The kinases of the invention fall within the eukaryotic protein kinase family.

A. The Eukaryotic Protein Kinase Nucleic Acid and Polypeptide Molecules

[0057] In one embodiment, the isolated nucleic acid molecules of the present invention encode eukaryotic protein kinase polypeptides. Eukaryotic protein kinases (described in, for example, Hanks et al. (1995) FASEB J. 9:576-596) are enzymes that belong to an extensive family of proteins that share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. One of these regions, located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. Another region, located in the central part of the catalytic domain, contains a conserved aspartic acid residue which is important for the catalytic activity of the enzyme (Knighton et al. (1991) Science 253:407-414). Two signature patterns have been described for this region: one specific for serine/threonine kinases and one for tyrosine kinases.

[0058] Eukaryotic protein kinase polypeptides of the present invention preferably include one of the following consensus sequences:

TABLE-US-00001 (SEQ ID NO: 83) [LIV]-G-{P}-G-{P}-[FYWMGSTNH]-[SGA]-{PW}- [LIVCAT]-{PD}-x-[GSTACLIVMFY]-x(5, 18)- [LIVMFYWCSTAR]-[AIVP]-[LIVMFAGCKR]-K [K bindsATP] (SEQ ID NO: 84) [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-K-x(2)-N- [LIVMFYCT](3) [D is an active site residue] (SEQ ID NO: 85) [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-[RSTAC]-x(2)-N- [LIVMFYC](3) [D is an active site residue]

B. The Adenylate Kinase Nucleic Acid and Polypeptide Molecules

[0059] In one embodiment, the isolated nucleic acid molecules of the present invention encode adenylate kinase polypeptides. Adenylate kinase (AK) (described in Schulz (1987) Cold Spring Harbor Symp. Quant. Biol. 52:429-439) is a monomeric enzyme that catalyzes the reversible transfer of MgATP to AMP (MgATP+AMP=MgADP+ADP).

[0060] In mammals there are three different isozymes: AK1 (or myokinase), which is cytosolic; AK2, which is located in the outer compartment of mitochondria; and AK3 (or GTP:AMP phosphotransferase), which is located in the mitochondrial matrix and which uses MgGTP instead of MgATP.

[0061] Several regions of AK family enzymes are well conserved, including the ATP-binding domains. This region includes an aspartic acid residue that is part of the catalytic cleft of the enzyme and is involved in a salt bridge.

[0062] It also includes an arginine residue whose modification leads to inactivation of the enzyme. Adenylate kinase polypeptides of the present invention preferably include the following consensus sequence:

TABLE-US-00002 (SEQ ID NO: 86) [LIVMFYW](3)-D-G-[FYI]-P-R-x(3)-[NQ]

C. The Guanylate Kinase Nucleic Acid and Polypeptide Molecules

[0063] In one embodiment, the isolated nucleic acid molecules of the present invention encode guanylate kinase polypeptides. Guanylate kinase (described in Stehle (1992) J. Mol. Biol. 224:1127-1141) catalyzes the ATP-dependent phosphorylation of GMP into GDP and it is essential for recycling GMP and indirectly, cGMP. In prokaryotes (such as Escherichia coli), lower eukaryotes (such as yeast) and in vertebrates, guanylate kinase is a highly conserved monomeric protein of about 200 amino acids.

[0064] Guanylate kinases are characterized by the presence of one or more of a DHR domain, and an SH3 domain (Woods et al. (1994) Mech. Dev. 44:85-89). There is also an ATP-binding site (P-loop) in the N-terminal section of guanylate kinases. Guanylate kinase polypeptides of the present invention contain a highly conserved region that contains two arginine residues and a tyrosine residue, which are involved in GMP-binding. This conserved region is shown below:

TABLE-US-00003 (SEQ ID NO: 87) T[ST]-R-x(2)-[KR]-x(2)-[DE]-x(2)-G-x(2)-Y-x-[FY]- [LIVMK]

D. The Pyruvate Kinase Nucleic Acid and Polypeptide Molecules

[0065] In one embodiment, the isolated nucleic acid molecules of the present invention encode pyruvate kinase polypeptides. Pyruvate kinase (PK) (described in Muirhead (1990) Biochem. Soc. Trans. 18:193-196) catalyzes the final step in glycolysis, the conversion of phosphoenolpyruvate to pyruvate with the concomitant phosphorylation of ADP to ATP. PK requires both magnesium and potassium ions for its activity. PK is found in all living organisms. In vertebrates there are four, tissue-specific isozymes: (L) liver, R (red cells), M1 (muscle, heart, and brain), and M2 (early fetal tissues).

[0066] All PK isozymes appear to be tetramers of identical subunits of about 500 amino acid residues. PKs contain a conserved region that includes a lysine residue that appears to be the acid/base catalyst responsible for the interconversion of pyruvate and enolpyruvate, and a glutamic acid residue implicated in the binding of the magnesium ion.

[0067] The pyruvate kinase polypeptides of the present invention preferably include the following consensus sequence:

TABLE-US-00004 (SEQ ID NO: 88) [LIVAC]-x-[LIVM](2)-[SAPCV]-K-[LIV]-E-[NKRST]-x- [DEQH]-[GSTA]-[LIVM] [K is the active site residue] [E is a magnesium ligand]

E. The Phosphatidylinositol-3 Kinase Nucleic Acid and Polypeptide Molecules

[0068] In one embodiment, the isolated nucleic acid molecules of the present invention encode phosphatidylinositol 3-kinase polypeptides. Phosphatidylinositol 3-kinase (PI3-kinase) (described in Hiles et al. (1992) Cell 70:419-429) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring.

[0069] The three products of PI3-kinase [PI-3-P, PI-3,4-P(2), and PI-3,4,5-P(3)] function as second messengers in cell signaling. The mammalian PI3 kinase is a heterodimer of a 110 kDa catalytic chain (p110) and an 85 kDa subunit (p85) which allows it to bind to activated tyrosine protein kinases. The PI3-kinases share a well conserved domain at their C-terminal section (Kunz et al. (1993) Cell 73:585-596).

[0070] The phosphatidylinositol 3-kinase polypeptides of the present invention preferably include the following consensus domains:

TABLE-US-00005 (SEQ ID NO: 89) [LIVMFAC]-K-x(1, 3)-[DEA]-[DE]-[LIVMC]-R-Q-[DE]-x (4)-Q[GS]-x-[AV]-x(3)-[LIVM]-x(2)-[FYH]-[LIVM] (2)-x-[LIVMF]-x-D-R-H-x(2)-N

Novel Kinase Sequences

[0071] The kinase genes and partial gene sequences of the invention were identified in a variety of cell or tissue libraries including Th2 cell library (h12832, h15993, h16341); natural killer T cell library (h14833, h2252); microvascular endothelial cells (h14138); mixed lymphocyte reaction (h15990). The first of these clones, h12832, encodes an approximately 1.6 kb mRNA transcript having the corresponding cDNA sequence set forth in SEQ ID NO:1. This transcript has a 966 nucleotide open reading frame (nucleotides 191-1156 of SEQ ID NO:1), which encodes a 322 amino acid protein (SEQ ID NO:2). The molecule may have transmembrane segments from amino acids (aa) 19-35 and 230-250 as predicted by MEMSAT. Prosite program analysis was used to predict various sites within the h12832 protein. N-glycosylation sites were predicted at aa 196-199 and 249-252. A cAMP- and cGMP-dependent protein kinase phosphorylation site was predicted at aa 16-19. Protein kinase C phosphorylation sites were predicted at aa 14-16, 52-54, 181-183, and 225-227. Casein kinase II phosphorylation sites were predicted at aa 122-125, 198-201, 236-239, 251-254, 260-263, 264-267, and 301-304. N-myristoylation sites were predicted at aa 41-46 and 118-123. A serine/threonine protein kinase active-site signature sequence was predicted at aa 163-175. The h12832 protein possesses a eukaryotic protein kinase domain, from aa 32 to aa 316, as predicted by HMMer, Version 2. Within this domain, critical residues are conserved at amino acid (aa) positions 39, 41, 46, 62, 64, 85, 94, 96, 116, 123, 153, 156-158, 165, 167, 169, 172, 183, 186, 188, 208, 209, 216, 229, 234, 237, 239, 246, 296, 304, 305, and 308. Critical residues are missing at aa positions 166, 187, 214, and 215, while important residues are missing at aa positions 44, 121, 149, 173, 174, 212, 231, 232, and 284. "Critical residues" are those residues that are recognized as important for activity and are highly conserved in known kinases. "Important residues" are those residues generally conserved among kinases.

[0072] The h12832 protein shares similarity with several protein kinases (see FIGS. 2A-2G). Dendrogram analysis of this gene indicates it shares closest homology with C. elegans tyrosine kinase (C. ele. Tyr. Kinase; GenBank Accession Number AAC47047; SEQ ID NO:18). The h12832 protein shares approximately 26% identity with this protein kinase receptor as determined by pairwise alignment (see Needleman and Wunsch (1970) J. Mol. Biol. 48:444). (see FIG. 3).

[0073] The partial gene sequence designated clone h14138 encodes an approximately 0.83 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:3. This transcript has a 522 nucleotide open reading frame (nucleotides 1-522 of SEQ ID NO:3), which encodes a 174 amino acid polypeptide (SEQ ID NO:4). An analysis of the disclosed h14138 polypeptide sequence (SEQ ID NO:4) using the MEMSAT program predicts a transmembrane segment from aa 56-73. Prosite program analysis was also used to predict various sites within this partial-length protein sequence. Protein kinase C phosphorylation sites were predicted at aa 12-14, 17-19, 20-22, and 116-118. Casein kinase II phosphorylation sites were predicted at aa 12-15, 105-108, 112-115, 131-134, and 156-159. An N-myristoylation site was predicted at aa 9-14. The partial-length h14138 protein possesses a eukaryotic protein kinase domain, from aa 35-130, and a protein kinase C terminal domain, from aa 131-159, as predicted by HMMer Version 2.

[0074] The partial length h14138 protein displays similarity to several protein kinases (see FIGS. 5A-5L). Dendrogram analysis of this gene indicates it shares closest homology with human KIAA0807 protein; DBJ Accession Number BAA34527; SEQ ID NO: 80). The h14138 protein shares approximately 35% identity with this protein kinase receptor as determined by pairwise alignment (see Needleman and Wunsch (1970) J. Mol. Biol. 48:444). (see FIG. 6).

[0075] The third novel gene, designated clone h14833, encodes an approximately 2.1 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:5. This transcript has a 627 nucleotide open reading frame (nucleotides 154-780 of SEQ ID NO:5), which encodes a 209 amino acid protein (SEQ ID NO:6) having a molecular weight of approximately 23.8 kDa. An analysis of the full-length h14833 protein sequence using the MEMSAT program predicted no transmembrane domains. Prosite program analysis of this protein predicted an N-glycosylation site at amino acid (aa) 205-208 and a cAMP- and cGMP-dependent protein kinase phosphorylation site at aa 133-136. Protein kinase C phosphorylation sites were predicted at aa 11-13, 51-53, 91-93, and 159-161. Casein kinase II phosphorylation sites were predicted at aa 121-124, 159-162, and 173-176. N-myristoylation sites were predicted at aa 56-61 and 67-72. A tyrosine protein kinase specific active-site signature was predicted at aa 34-46. The h14833 protein possesses a eukaryotic protein kinase domain from aa 10 to aa 163.

[0076] The h14833 protein displays similarity to several protein kinases (see FIGS. 8A-8G). Dendrogram analysis of this gene indicates that the encoded h14833 protein shares closest homology with a putative fruit fly (Drosophila melanogaster) torso tyrosine-protein kinase receptor (SP Accession Number P18475; SEQ ID NO:23) (see FIG. 9). The h14833 protein shares approximately 34% identity over a 209 amino-acid overlap with this protein kinase receptor as determined by pairwise alignment (see Needleman and Wunsch (1970) J. Mol. Biol. 48:444).

[0077] The partial gene sequence designated clone h15990 encodes an approximately 1.7 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:7. This transcript has a 1491 nucleotide open reading frame (nucleotides 2-1492 of SEQ ID NO:7), which encodes a 497 amino acid polypeptide (SEQ ID NO:8). An analysis of the partial-length h15990 protein sequence using the MEMSAT program predicted no transmembrane domains. Prosite program analysis of this partial-length protein predicted N-glycosylation sites at amino acids (aa) 78-81, 412-415, 433-436, and 493-496. Glycosaminoglycan attachment sites were predicted at aa 151-154, 299-302, and 461-464. cAMP- and cGMP-dependent protein kinase phosphorylation sites were predicted at aa 175-178 and 292-295. Protein kinase C phosphorylation sites were predicted at aa 279-281, 290-292, 348-350, 382-384, 414-416, 424-426, 461-463, and 495-497. Casein kinase II phosphorylation sites were predicted at aa 179-182, 220-223, 254-257, 279-282, 295-298, 304-307, 318-321, and 366-369. N-myristoylation sites were predicted at aa 9-14, 79-84, 147-152, 159-164, 300-305, 402-407, 410-415, 436-441, and 457-462. A protein kinase ATP-binding region signature sequence was predicted at aa 6-14. A serine/threonine protein kinase active-site signature sequence was predicted at aa 117-129. The partial-length h15990 protein possesses a eukaryotic protein kinase domain, from aa 1-259, as predicted by HMMer Version 2.

[0078] The partial-length h15990 protein displays similarity to several protein kinases (see FIGS. 11A-11H). Dendrogram analysis of this gene indicates that the encoded h15990 protein shares closest homology with a Rattus norvegicus homocysteine respondent protein (GenBank Accession Number AAD02059; SEQ ID NO:31) (see FIG. 12). The partial-length h15990 protein shares approximately 74.3% identity over a 142 amino-acid overlap with this homocysteine respondent protein as determined by pairwise alignment.

[0079] The partial gene sequence designated clone h15993 encodes an approximately 0.98 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:9. This transcript has a 978 nucleotide open reading frame (nucleotides 2-979 of SEQ ID NO:9), which encodes a 326 amino acid polypeptide (SEQ ID NO:10) having a molecular weight of approximately 37.2 kDa. Transmembrane segments from amino acids (aa) 168-185 and 247-263 were predicted by MEMSAT. Prosite program analysis of the partial-length h15993 protein predicted an N-glycosylation site at aa 186-189, and a cAMP and cGMP-dependent protein kinase phosphorylation site at aa 304-307. Protein kinase C phosphorylation sites were predicted at aa 141-143 and 149-151. Casein kinase H phosphorylation sites were predicted at aa 33-36, 100-103, 246-249, 267-270, and 284-287. N-myristoylation sites were predicted at aa 58-63 and 185-190. The partial-length h15993 protein possesses two eukaryotic protein kinase domains, from aa 108 to 203 and from aa 283 to 314, as predicted by HMMer Version 2.

[0080] The partial-length h15993 protein displays similarity to several protein kinases (see FIGS. 14A-14Q). Dendrogram analysis of this gene indicates that the encoded h15993 protein shares closest homology with a C. elegans tyrosine-protein kinase-like protein (EMB Accession Number CAA15621; SEQ ID NO:36) (see FIG. 15). The partial-length h15993 protein shares approximately 45.1% identity over a 231 amino-acid overlap with this tyrosine-protein kinase-like protein as determined by pairwise alignment.

[0081] The partial gene sequence designated clone h16341 encodes an approximately 0.52 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:9. This transcript has a 516 nucleotide open reading frame (nucleotides 2-517 of SEQ ID NO:9), which encodes a 172 amino acid polypeptide (SEQ ID NO:10) having a molecular weight of approximately 19.5 kDa. An analysis of the partial-length h16341 protein sequence using the MEMSAT program predicted no transmembrane domains. Prosite program analysis of this partial-length protein predicted an N-glycosylation site at amino acids (aa) 27-30, and protein kinase C phosphorylation sites at aa 38-40, 89-91, and 147-149. Casein kinase II phosphorylation sites were predicted at aa 13-16 and 50-53. N-myristoylation sites were predicted at aa 20-25, 77-82, and 120-125. A protein kinase ATP-binding region signature sequence was predicted at aa 60-68. The partial-length h16341 protein possesses a eukaryotic protein kinase domain, from aa 58 to aa 172, as predicted by HMMer Version 2.

[0082] The partial-length h16341 protein displays similarity to several protein kinases (see FIGS. 17A-17I). Dendrogram analysis of this gene indicates that the encoded partial-length h16341 protein shares closest homology with a murine testis-specific protein kinase 1 (DBJ Accession Number BAA25124; SEQ ID NO:46) (see FIG. 18). The partial-length h16341 protein shares approximately 91.7% identity over a 172 amino-acid overlap with this tyrosine-protein kinase-like protein as determined by pairwise alignment.

[0083] The last of these novel genes, designated clone h2252, encodes an approximately 1.7 kb transcript mRNA having the corresponding cDNA set forth in SEQ ID NO:13. This transcript has a 1248 nucleotide open reading frame (nucleotides 275-1522 of SEQ ID NO:13), which encodes a 416 amino acid protein (SEQ ID NO:14). Transmembrane segments were predicted at aa 95-111 and 346-362 using the MEMSAT program. Prosite analysis of the full-length h2252 protein predicted N-glycosylation sites at aa 44-47, 318-321, and 371-374. cAMP- and cGMP-dependent protein kinase phosphorylation sites were predicted at aa 175-178 and aa 279-282. Protein kinase C phosphorylation sites were predicted at aa 137-139, 246-248, 260-262, 264-266, 278-280, 314-316, 328-330, and 396-398. Casein kinase II phosphorylation sites were predicted at aa 25-28, 34-37, 75-78, 106-109, 194-197, 198-201, 208-211, 246-249, 264-267, 300-303, 304-307, 309-312, 314-317, 320-323, and 411-414. N-myristoylation sites were predicted at aa 12-17 and 103-108. A protein kinase ATP-binding region signature sequence was predicted at aa 30-38. The h2252 protein possesses a eukaryotic protein kinase domain, from aa 24-274, and a phosphofructokinase domain, from aa 385-406, as predicted by HMMer Version 2.0.

[0084] The partial length h2252 protein displays similarity to several protein kinases (see FIGS. 20A-20G). Dendrogram analysis of this gene indicates it shares closest homology with the human Ste20-like kinase 3 (hSTE20-like Kinase-3; GenBank Accession Number AAB82560; SEQ ID NO:53). The h2252 protein shares approximately 73% identity with this protein kinase receptor as determined by pairwise alignment (see Needleman and Wunsch (1970) J. Mol. Biol. 48:444). (see FIG. 21).

[0085] Preferred kinase polypeptides of the present invention have an amino acid sequence sufficiently identical to the amino acid sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, or a domain thereof. The term "sufficiently identical" is used herein to refer to a first amino acid or nucleotide sequence that contains a sufficient or minimum number of identical or equivalent (e.g., with a similar side chain) amino acid residues or nucleotides to a second amino acid or nucleotide sequence such that the first and second amino acid or nucleotide sequences have a common structural domain and/or common functional activity. For example, amino acid or nucleotide sequences that contain a common structural domain having at least about 45%, 55%, or 65% identity, preferably 75% identity, more preferably 85%, 95%, or 98% identity are defined herein as sufficiently identical.

[0086] To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., percent identity=number of identical positions/total number of positions (e.g., overlapping positions)×100). In one embodiment, the two sequences are the same length. The percent identity between two sequences can be determined using techniques similar to those described below, with or without allowing gaps. In calculating percent identity, typically exact matches are counted.

[0087] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm. A preferred, nonlimiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Nati. Acad. Sci. USA 87:2264, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al. (1990) J. Mol. Biol. 215:403. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to kinase nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to kinase protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389. Alternatively, PSI-Blast can be used to perform an iterated search that detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (accessible at the website maintained by the National Center for Biotechnology Information, Bethesda, Md.). Another preferred, example of an algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. A preferred program is the Pairwise Alignment Program (Sequence Explorer), using default parameters.

[0088] Accordingly, another embodiment of the invention features isolated kinase proteins and polypeptides having a kinase protein activity. As used interchangeably herein, a "kinase protein activity", "biological activity of a kinase protein", or "functional activity of a kinase protein" refers to an activity exerted by a kinase protein, polypeptide, or nucleic acid molecule on a kinase-responsive cell as determined in vivo, or in vitro, according to standard assay techniques. A kinase activity can be a direct activity, such as an association with or an enzymatic activity on a second protein, or an indirect activity, such as a cellular signaling activity mediated by interaction of the kinase protein with a second protein. In a preferred embodiment, a kinase activity includes at least one or more of the following activities: (1) modulating (stimulating and/or enhancing or inhibiting) cellular proliferation, growth and/or metabolism (e.g. in those cells in which the sequence is expressed, including, lymph node, spleen, thymus, brain, lung, skeletal muscle, fetal liver, tonsil, colon, heart, liver, immune cells, including Th1, Th2, T cells, natural killer T cells, lymphocytes, leukocytes, blood marrow, etc.); (2) the regulation of transmission of signals from cellular receptors, e.g., growth factor receptors; (3) the modulation of the entry of cells into mitosis; (4) the modulation of cellular differentiation; (5) the modulation of cell death; and (6) the regulation of cytoskeleton function, e.g., actin bundling.

[0089] An "isolated" or "purified" kinase nucleic acid molecule or protein, or biologically active portion thereof, is substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. Preferably, an "isolated" nucleic acid is free of sequences (preferably protein-encoding sequences) that naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For purposes of the invention, "isolated"

[0090] when used to refer to nucleic acid molecules excludes isolated chromosomes. For example, in various embodiments, the isolated kinase nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb, or 0.1 kb of nucleotide sequences that naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. A kinase protein that is substantially free of cellular material includes preparations of kinase protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of non-kinase protein (also referred to herein as a "contaminating protein"). When the kinase protein or biologically active portion thereof is recombinantly produced, preferably, culture medium represents less than about 30%, 20%, 10%, or 5% of the volume of the protein preparation. When kinase protein is produced by chemical synthesis, preferably the protein preparations have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or non-kinase chemicals.

[0091] Various aspects of the invention are described in further detail in the following subsections.

I. Isolated Nucleic Acid Molecules

[0092] One aspect of the invention pertains to isolated nucleic acid molecules comprising nucleotide sequences encoding kinase proteins or biologically active portions thereof, as well as nucleic acid molecules sufficient for use as hybridization probes to identify kinase-encoding nucleic acids (e.g., kinase mRNA) and fragments for use as PCR primers for the amplification or mutation of kinase nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.

[0093] Nucleotide sequences encoding the kinase proteins of the present invention include sequences set forth in SEQ ID NOs: 1, 3, 5, 7, 9, 11, and 13, and complements thereof. By "complement" is intended a nucleotide sequence that is sufficiently complementary to a given nucleotide sequence such that it can hybridize to the given nucleotide sequence to thereby form a stable duplex. The corresponding amino acid sequences for the kinase proteins encoded by these nucleotide sequences are set forth in SEQ ID NOs:2, 4, 6, 8, 10, 12, and 14, respectively.

[0094] Nucleic acid molecules that are fragments of these kinase nucleotide sequences are also encompassed by the present invention. By "fragment" is intended a portion of the nucleotide sequence encoding a kinase protein of the invention. A fragment of a kinase nucleotide sequence may encode a biologically active portion of a kinase protein, or it may be a fragment that can be used as a hybridization probe or PCR primer using methods disclosed below. A biologically active portion of a kinase protein can be prepared by isolating a portion of one of the kinase nucleotide sequences of the invention, expressing the encoded portion of the kinase protein (e.g., by recombinant expression in vitro), and assessing the activity of the encoded portion of the kinase protein. Generally, nucleic acid molecules that are fragments of a kinase nucleotide sequence comprise at least 15, 20, 50, 75, 100, 325, 350, 375, 400, 425, 450 or 500 nucleotides, or up to the number of nucleotides present in a full-length kinase nucleotide sequence disclosed herein (for example, 1586, 831, 2060, 1697, 981, 518 or 1737 nucleotides for SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, respectively) depending upon the intended use.

[0095] It is understood that isolated fragments include any contiguous sequence not disclosed prior to the invention as well as sequences that are substantially the same and which are not disclosed. Accordingly, if a fragment is disclosed prior to the present invention, that fragment is not intended to be encompassed by the invention. When a sequence is not disclosed prior to the present invention, an isolated nucleic acid fragment is at least about 12, 15, 20, 25, or 30 contiguous nucleotides. Other regions of the nucleotide sequence may comprise fragments of various sizes, depending upon potential homology with previously disclosed sequences.

[0096] A fragment of a kinase nucleotide sequence that encodes a biologically active portion of a kinase protein of the invention will encode at least 15, 25, 30, 50, 75, 100, 125, 150, 160, or 170 contiguous amino acids, or up to the total number of amino acids present in a full-length kinase protein of the invention (for example, 322, 174, 209, 503, 326, 172, or 416 amino acids for SEQ ID NO:2, 4, 6, 8, 10, 12, or 14, respectively). Fragments of a kinase nucleotide sequence that are useful as hybridization probes for PCR primers generally need not encode a biologically active portion of a kinase protein.

[0097] Nucleic acid molecules that are variants of the kinase nucleotide sequences disclosed herein are also encompassed by the present invention. "Variants" of the kinase nucleotide sequences include those sequences that encode the kinase proteins disclosed herein but that differ conservatively because of the degeneracy of the genetic code. These naturally-occurring allelic variants can be identified with the use of well-known molecular biology techniques, such as polymerase chain reaction (PCR) and hybridization techniques as outlined below. Variant nucleotide sequences also include synthetically-derived nucleotide sequences that have been generated, for example, by using site-directed mutagenesis but which still encode the kinase proteins disclosed in the present invention as discussed below. Generally, nucleotide sequence variants of the invention will have at least 45%, 55%, 65%, 75%, 85%, 95%, or 98% identity to the nucleotide sequences disclosed herein. A variant kinase nucleotide sequence will encode a kinase protein that has an amino acid sequence having at least 45%, 55%, 65%, 75%, 85%, 95%, or 98% identity to an amino acid sequence of a kinase protein disclosed herein.

[0098] In addition to the kinase nucleotide sequences shown in SEQ ID NOs:1, 3, 5, 7, 9, 11, and 13, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of kinase proteins may exist within a population (e.g., the human population). Such genetic polymorphism in a kinase gene may exist among individuals within a population due to natural allelic variation. An allele is one of a group of genes that occur alternatively at a given genetic locus. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding a kinase protein, preferably a mammalian kinase protein. As used herein, the phrase "allelic variant" refers to a nucleotide sequence that occurs at a kinase locus or to a polypeptide encoded by the nucleotide sequence. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the kinase gene. Any and all such nucleotide variations and resulting amino acid polymorphisms or variations in a kinase sequence that are the result of natural allelic variation and that do not alter the functional activity of kinase proteins are intended to be within the scope of the invention.

[0099] Moreover, nucleic acid molecules encoding kinase proteins from other species (kinase homologues), which have a nucleotide sequence differing from that of the kinase sequences disclosed herein, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the kinase cDNAs of the invention can be isolated based on their identity to the mouse kinase nucleic acids disclosed herein using the mouse cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions as disclosed below.

[0100] In addition to naturally-occurring allelic variants of the kinase sequence that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of the invention thereby leading to changes in the amino acid sequence of the encoded kinase protein, without altering the biological activity of the kinase protein. Thus, an isolated nucleic acid molecule encoding a kinase protein having a sequence that differs from that of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14 can be created by introducing one or more nucleotide substitutions, additions, or deletions into the nucleotide sequences disclosed herein, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Such variant nucleotide sequences are also encompassed by the present invention.

[0101] For example, preferably, conservative amino acid substitutions may be made at one or more predicted, preferably nonessential amino acid residues. A "nonessential" amino acid residue is a residue that can be altered from the wild-type sequence of a kinase protein (e.g., the sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, or 14) without altering the biological activity, whereas an "essential" amino acid residue is required for biological activity. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, praline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Such substitutions would not be made for conserved amino acid residues or for amino acid residues residing within a conserved protein domain, such as the critical eukaryotic protein kinase domain of all disclosed clones, and the phosphofructo-kinase domain of clone h2252, where such residues are essential for protein activity.

[0102] Alternatively, variant kinase nucleotide sequences can be made by introducing mutations randomly along all or part of a kinase coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for kinase biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed recombinantly, and the activity of the protein can be determined using standard assay techniques.

[0103] Thus the nucleotide sequences of the invention include those sequences disclosed herein as well as fragments and variants thereof. The kinase nucleotide sequences of the invention, and fragments and variants thereof, can be used as probes and/or primers to identify and/or clone kinase homologues in other cell types, e.g., from other tissues, as well as kinase homologues from other mammals. Such probes can be used to detect transcripts or genomic sequences encoding the same or identical proteins. These probes can be used as part of a diagnostic test kit for identifying cells or tissues that misexpress a kinase protein, such as by measuring levels of a kinase-encoding nucleic acid in a sample of cells from a subject, e.g., detecting kinase mRNA levels or determining whether a genomic kinase gene has been mutated or deleted.

[0104] In this manner, methods such as PCR, hybridization, and the like can be used to identify such sequences having substantial identity to the sequences of the invention. See, for example, Sambrook et al. (1989) Molecular Cloning: Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.) and Innis, et al. (1990) PCR Protocols: A Guide to Methods and Applications (Academic Press, NY). Kinase nucleotide sequences isolated based on their sequence identity to the kinase nucleotide sequences set forth herein or to fragments and variants thereof are encompassed by the present invention.

[0105] In a hybridization method, all or part of a known kinase nucleotide sequence can be used to screen cDNA or genomic libraries. Methods for construction of such cDNA and genomic libraries are generally known in the art and are disclosed in Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.). The so-called hybridization probes may be genomic DNA fragments, cDNA fragments, RNA fragments, or other oligonucleotides, and may be labeled with a detectable group such as ³²P, or any other detectable marker, such as other radioisotopes, a fluorescent compound, an enzyme, or an enzyme co-factor. Probes for hybridization can be made by labeling synthetic oligonucleotides based on the known kinase nucleotide sequences disclosed herein. Degenerate primers designed on the basis of conserved nucleotides or amino acid residues in a known kinase nucleotide sequence or encoded amino acid sequence can additionally be used. The probe typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, preferably about 25, more preferably about 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 consecutive nucleotides of a kinase nucleotide sequence of the invention or a fragment or variant thereof. Preparation of probes for hybridization is generally known in the art and is disclosed in Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.), herein incorporated by reference.

[0106] For example, in one embodiment, a previously unidentified kinase nucleic acid molecule hybridizes under stringent conditions to a probe that is a nucleic acid molecule comprising one of the kinase nucleotide sequences of the invention or a fragment thereof. In another embodiment, the previously unknown kinase nucleic acid molecule is at least 300, 325, 350, 375, 400, 425, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 2,000, 3,000, or 4,000 nucleotides in length and hybridizes under stringent conditions to a probe that is a nucleic acid molecule comprising one of the kinase nucleotide sequences disclosed herein or a fragment thereof.

[0107] Accordingly, in another embodiment, an isolated previously unknown kinase nucleic acid molecule of the invention is at least 300, 325, 350, 375, 400, 425, 450, 500, 518, 550, 600, 650, 700, 800, 831, 900, 981, 1000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, or 2,060 nucleotides in length and hybridizes under stringent conditions to a probe that is a nucleic acid molecule comprising one of the nucleotide sequences of the invention, preferably the coding sequence set forth in SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, or a complement, fragment, or variant thereof.

[0108] As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences having at least 60%, 65%, 70%, preferably 75% identity to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology (John Wiley & Sons, New York (1989)), 6.3.1-6.3.6. A preferred, non-limiting example of stringent hybridization conditions is hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65° C. In another preferred embodiment, stringent conditions comprise hybridization in 6×SSC at 42° C., followed by washing with 1×SSC at 55° C. Preferably, an isolated nucleic acid molecule that hybridizes under stringent conditions to a kinase sequence of the invention corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

[0109] Thus, in addition to the kinase nucleotide sequences disclosed herein and fragments and variants thereof, the isolated nucleic acid molecules of the invention also encompass homologous DNA sequences identified and isolated from other cells and/or organisms by hybridization with entire or partial sequences obtained from the kinase nucleotide sequences disclosed herein or variants and fragments thereof.

[0110] The present invention also encompasses antisense nucleic acid molecules, i.e., molecules that are complementary to a sense nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule, or complementary to an mRNA sequence. Accordingly, an antisense nucleic acid can hydrogen bond to a sense nucleic acid. The antisense nucleic acid can be complementary to an entire kinase coding strand, or to only a portion thereof, e.g., all or part of the protein coding region (or open reading frame). An antisense nucleic acid molecule can be antisense to a noncoding region of the coding strand of a nucleotide sequence encoding a kinase protein. The noncoding regions are the 5' and 3' sequences that flank the coding region and are not translated into amino acids.

[0111] Given the coding-strand sequences encoding a kinase protein disclosed herein (e.g., SEQ ID NOs:1, 3, 5, 7, 9, 11, and 13), antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of kinase mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of kinase mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of kinase mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis and enzymatic ligation procedures known in the art.

[0112] For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, including, but not limited to, for example, phosphorothioate derivatives and acridine substituted nucleotides. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

[0113] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a kinase protein to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, antisense molecules can be linked to peptides or antibodies to form a complex that specifically binds to receptors or antigens expressed on a selected cell surface. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0114] An antisense nucleic acid molecule of the invention can be an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids Res. 15:6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (Inoue et al. (1987) Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al. (1987) FEBS Lett. 215:327-330).

[0115] The invention also encompasses ribozymes, which are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave kinase mRNA transcripts to thereby inhibit translation of kinase mRNA. A ribozyme having specificity for a kinase-encoding nucleic acid can be designed based upon the nucleotide sequence of a kinase cDNA disclosed herein (e.g., SEQ ID NO:1, 3, 5, 7, 9, 11, or 13). See, e.g., Cech et al., U.S. Pat. No. 4,987,071; and Cech et al., U.S. Pat. No. 5,116,742. Alternatively, kinase mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel and Szostak (1993) Science 261:1411-1418.

[0116] The invention also encompasses nucleic acid molecules that form triple helical structures. For example, kinase gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the kinase protein (e.g., the kinase promoter and/or enhancers) to form triple helical structures that prevent transcription of the kinase gene in target cells. See generally Helene (1991) Anticancer Drug Des. 6(6):569; Helene (1992) Ann. N.Y. Acad. Sci. 660:27; and Maher (1992) Bioassays 14(12):807.

[0117] In preferred embodiments, the nucleic acid molecules of the invention can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorganic & Medicinal Chemistry 4:5). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid-phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. USA 93:14670.

[0118] PNAs of a kinase molecule can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA-directed PCR clamping, as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup (1996), supra, or as probes or primers for DNA sequence and hybridization (Hyrup (1996), supra; Perry-O'Keefe et al. (1996), supra).

[0119] In another embodiment, PNAs of a kinase molecule can be modified, e.g., to enhance their stability, specificity, or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996), supra; Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63; Mag et al. (1989) Nucleic Acids Res. 17:5973; and Peterser et al. (1975) Bioorganic Med. Chem. Lett. 5:1119.

II. Isolated Kinase Proteins and Anti-Kinase Antibodies

[0120] Kinase proteins are also encompassed within the present invention. By "kinase protein" is intended proteins having the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, 10, 12, or 14, as well as fragments, biologically active portions, and variants thereof.

[0121] "Fragments" or "biologically active portions" include polypeptide fragments suitable for use as immunogens to raise anti-kinase antibodies. Fragments include peptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequences of a kinase protein of the invention and exhibiting at least one activity of a kinase protein, but which include fewer amino acids than the full-length kinase proteins disclosed herein. Typically, biologically active portions comprise a domain or motif with at least one activity of the kinase protein. A biologically active portion of a kinase protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Such biologically active portions can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native kinase protein.

[0122] By "variants" is intended proteins or polypeptides having an amino acid sequence that is at least about 45%, 55%, 65%, preferably about 75%, 85%, 95%, or 98% identical to the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, or 14. Variants also include variants of polypeptides encoded by a nucleic acid molecule that hybridizes to a nucleic acid molecule of SEQ ID NO: 1, 3, 5, 7, 9, 11, or 13, or a complement thereof under stringent conditions. Such variants generally retain the functional activity of the kinase proteins of the invention. Variants include polypeptides that differ in amino acid sequence due to natural allelic variation or mutagenesis.

[0123] The invention also provides kinase chimeric or fusion proteins. As used herein, a kinase "chimeric protein" or "fusion protein" comprises a kinase polypeptide operably linked to a non-kinase polypeptide. A "kinase polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a kinase protein, whereas a "non-kinase polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially identical to the kinase protein, e.g., a protein that is different from the kinase protein and which is derived from the same or a different organism. Within a kinase fusion protein, the kinase polypeptide can correspond to all or a portion of a kinase protein, preferably at least one biologically active portion of a kinase protein. Within the fusion protein, the term "operably linked" is intended to indicate that the kinase polypeptide and the non-kinase polypeptide are fused in-frame to each other. The non-kinase polypeptide can be fused to the N-terminus or C-terminus of the kinase polypeptide.

[0124] One useful fusion protein is a GST-kinase fusion protein in which the kinase sequences are fused to the C-terminus of the GST sequences. Such fusion proteins can facilitate the purification of recombinant kinase proteins.

[0125] In yet another embodiment, the fusion protein is a kinase-immunoglobulin fusion protein in which all or part of a kinase protein is fused to sequences derived from a member of the immunoglobulin protein family. The kinase-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a kinase ligand and a kinase protein on the surface of a cell, thereby suppressing kinase-mediated signal transduction in vivo. The kinase-immunoglobulin fusion proteins can be used to affect the bioavailability of a kinase cognate ligand. Inhibition of the kinase ligand/kinase interaction may be useful therapeutically, both for treating proliferative and differentiative disorders and for modulating (e.g., promoting or inhibiting) cell survival. Moreover, the kinase-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-kinase antibodies in a subject, to purify kinase ligands, and in screening assays to identify molecules that inhibit the interaction of a kinase protein with a kinase ligand.

[0126] Preferably, a kinase chimeric or fusion protein of the invention is produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences may be ligated together in-frame, or the fusion gene can be synthesized, such as with automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments, which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel et al., eds. (1995) Current Protocols in Molecular Biology) (Greene Publishing and Wiley-Interscience, NY). Moreover, a kinase-encoding nucleic acid can be cloned into a commercially available expression vector such that it is linked in-frame to an existing fusion moiety. Variants of the kinase proteins can function as either kinase agonists (mimetics) or as kinase antagonists. Variants of the kinase protein can be generated by mutagenesis, e.g., discrete point mutation or truncation of the kinase protein. An agonist of the kinase protein can retain substantially the same or a subset of the biological activities of the naturally-occurring form of the kinase protein. An antagonist of the kinase protein can inhibit one or more of the activities of the naturally-occurring form of the kinase protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade that includes the kinase protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. Treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein can have fewer side effects in a subject relative to treatment with the naturally occurring form of the kinase proteins.

[0127] Variants of the kinase protein that function as either kinase agonists or as kinase antagonists can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of the kinase protein for kinase protein agonist or antagonist activity. In one embodiment, a variegated library of kinase variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of kinase variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential kinase sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of kinase sequences therein. There are a variety of methods that can be used to produce libraries of potential kinase variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential kinase sequences. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang (1983) Tetrahedron 39:3; Itakura et al. (1984) Annu. Rev. Biochem. 53:323; Itakura et al. (1984) Science 198:1056; Ike et al. (1983) Nucleic Acid Res. 11:477).

[0128] In addition, libraries of fragments of the kinase protein coding sequence can be used to generate a variegated population of kinase fragments for screening and subsequent selection of variants of a kinase protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double-stranded PCR fragment of a kinase coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double-stranded DNA, renaturing the DNA to form double-stranded DNA which can include sense/antisense pairs from different nicked products, removing single-stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, one can derive an expression library that encodes N-terminal and internal fragments of various sizes of the kinase protein.

[0129] Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of kinase proteins. The most widely used techniques, which are amenable to high through-put analysis for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify kinase variants (Arkin and Yourvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave et al. (1993) Protein Engineering 6(3):327-331).

[0130] An isolated kinase polypeptide of the invention can be used as an immunogen to generate antibodies that bind kinase proteins using standard techniques for polyclonal and monoclonal antibody preparation. The full-length kinase protein can be used or, alternatively, the invention provides antigenic peptide fragments of kinase proteins for use as immunogens. The antigenic peptide of a kinase protein comprises at least 8, preferably 10, 15, 20, or 30 amino acid residues of the amino acid sequence shown in SEQ ID NO:2, 4, 6, 8, 10, 12, or 14 and encompasses an epitope of a kinase protein such that an antibody raised against the peptide forms a specific immune complex with the kinase protein. Preferred epitopes encompassed by the antigenic peptide are regions of a kinase protein that are located on the surface of the protein, e.g., hydrophilic regions.

[0131] Accordingly, another aspect of the invention pertains to anti-kinase polyclonal and monoclonal antibodies that bind a kinase protein. Polyclonal anti-kinase antibodies can be prepared by immunizing a suitable subject (e.g., rabbit, goat, mouse, or other mammal) with a kinase immunogen. The anti-kinase antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized kinase protein. At an appropriate time after immunization, e.g., when the anti-kinase antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497, the human B-cell hybridoma technique (Kozbor et al. (1983) Immunol. Today 4:72), the EBV-hybridoma technique (Cole et al. (1985) in Monoclonal Antibodies and Cancer Therapy, ed. Reisfeld and Sell (Alan R. Liss, Inc., New York, N.Y.), pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see generally Coligan et al., eds. (1994) Current Protocols in Immunology (John Wiley & Sons, Inc., New York, N.Y.); Galfre et al. (1977) Nature 266:550-52; Kenneth (1980) in Monoclonal Antibodies: A New Dimension In Biological Analyses (Plenum Publishing Corp., NY; and Lerner (1981) Yale J. Biol. Med., 54:387-402).

[0132] Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal anti-kinase antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with a kinase protein to thereby isolate immunoglobulin library members that bind the kinase protein. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP® Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication Nos. WO 92/18619; WO 91/17271; WO 92/20791; WO 92/15679; 93/01288; WO 92/01047; 92/09690; and 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734.

[0133] Additionally, recombinant anti-kinase antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and nonhuman portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication Nos. WO 86101533 and WO 87/02671; European Patent Application Nos. 184,187, 171,496, 125,023, and 173,494; U.S. Pat. Nos. 4,816,567 and 5,225,539; European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987) Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; Shaw et al. (1988) J. Natl. Cancer Inst. 80:1553-1559); Morrison (1985) Science 229:1202-1207; Oi et al. (1986) Bio/Techniques 4:214; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141:4053-4060.

[0134] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar (1995) Int. Rev. Immunol. 13:65-93); and U.S. Pat. Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, Calif.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0135] Completely human antibodies that recognize a selected epitope can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a murine antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. This technology is described by Jespers et al. (1994) Bio/Technology 12:899-903).

[0136] An anti-kinase antibody (e.g., monoclonal antibody) can be used to isolate kinase proteins by standard techniques, such as affinity chromatography or immunoprecipitation. An anti-kinase antibody can facilitate the purification of natural kinase protein from cells and of recombinantly produced kinase protein expressed in host cells. Moreover, an anti-kinase antibody can be used to detect kinase protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the kinase protein. Anti-kinase antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S, or ³H.

[0137] Further, an antibody (or fragment thereof) may be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine). The conjugates of the invention can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, α-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophase colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors.

[0138] Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.

[0139] 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982). Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.

III. Recombinant Expression Vectors and Host Cells

[0140] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a kinase protein (or a portion thereof). "Vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked, such as a "plasmid", a circular double-stranded DNA loop into which additional DNA segments can be ligated, or a viral vector, where additional DNA segments can be ligated into the viral genome. The vectors are useful for autonomous replication in a host cell or may be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome (e.g., nonepisomal mammalian vectors). Expression vectors are capable of directing the expression of genes to which they are operably linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication-defective retroviruses, adenoviruses, and adeno-associated viruses), that serve equivalent functions.

[0141] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell. This means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, operably linked to the nucleic acid sequence to be expressed. "Operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers, and other expression control elements (e.g., polyadenylation signals). See, for example, Goeddel (1990) in Gene Expression Technology: Methods in Enzymology 185 (Academic Press, San Diego, Calif.). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., kinase proteins, mutant forms of kinase proteins, fusion proteins, etc.).

[0142] The recombinant expression vectors of the invention can be designed for expression of kinase protein in prokaryotic or eukaryotic host cells. Expression of proteins in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or nonfusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson (1988) Gene 67:31-40), pMAL (New England Biolabs, Beverly, Mass.), and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible nonfusion E. coli expression vectors include pTrc (Amann et al. (1988) Gene 69:301-315) and pET 11d (Studier et al. (1990) in Gene Expression Technology: Methods in Enzymology 185 (Academic Press, San Diego, Calif.), pp. 60-89). Strategies to maximize recombinant protein expression in E. coli can be found in Gottesman (1990) in Gene Expression Technology: Methods in Enzymology 185 (Academic Press, CA), pp. 119-128 and Wada et al. (1992) Nucleic Acids Res. 20:2111-2118. Target gene expression from the pTrc vector relies on host RNA polymerase transcription from a hybrid trp-lac fusion promoter.

[0143] Suitable eukaryotic host cells include insect cells (examples of Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al. (1983) Mol. Cell Biol. 3:2156-2165) and the pVL series (Lucklow and Summers (1989) Virology 170:31-39)); yeast cells (examples of vectors for expression in yeast S. cerevisiae include pYepSecl (Baldari et al. (1987) EMBO J. 6:229-234), pMFa (Kurjan and Herskowitz (1982) Cell 30:933-943), pJRY88 (Schultz et al. (1987) Gene 54:113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and pPicZ (Invitrogen Corporation, San Diego, Calif.)); or mammalian cells (mammalian expression vectors include pCDM8 (Seed (1987) Nature 329:840) and pMT2PC (Kaufman et al. (1987) EMBO J. 6:187:195)). Suitable mammalian cells include Chinese hamster ovary cells (CHO) or COS cells. In mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus, and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells, see chapters 16 and 17 of Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.). See, Goeddel (1990) in Gene Expression Technology: Methods in Enzymology 185 (Academic Press, San Diego, Calif.). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0144] The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences,

[0145] such progeny may not, in fact, be identical to the parent cell but are still included within the scope of the term as used herein.

[0146] In one embodiment, the expression vector is a recombinant mammalian expression vector that comprises tissue-specific regulatory elements that direct expression of the nucleic acid preferentially in a particular cell type. Suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et al. (1987) Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol. 43:235-275), particular promoters of T-cell receptors (Winoto and Baltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Banerji et al. (1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund et al. (1985) Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Patent Publication No. 264,166). Developmentally-regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss (1990) Science 249:374-379), the α-fetoprotein promoter (Carves and Tilghman (1989) Genes Dev. 3:537-546), and the like.

[0147] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operably linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to kinase mRNA. Regulatory sequences operably linked to a nucleic acid cloned in the antisense orientation can be chosen to direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen to direct constitutive, tissue-specific, or cell-type-specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid, or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see Weintraub et al. (1986) Reviews--Trends in Genetics, Vol. 1(1).

[0148] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook et al. (1989) Molecular Cloning: A Laboraty Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.) and other laboratory manuals.

[0149] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin, and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding a kinase protein or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0150] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) kinase protein. Accordingly, the invention further provides methods for producing kinase protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of the invention, into which a recombinant expression vector encoding a kinase protein has been introduced, in a suitable medium such that kinase protein is produced. In another embodiment, the method further comprises isolating kinase protein from the medium or the host cell.

[0151] The host cells of the invention can also be used to produce nonhuman transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which kinase-coding sequences have been introduced. Such host cells can then be used to create nonhuman transgenic animals in which exogenous kinase sequences have been introduced into their genome or homologous recombinant animals in which endogenous kinase sequences have been altered. Such animals are useful for studying the function and/or activity of kinase genes and proteins and for identifying and/or evaluating modulators of kinase activity. As used herein, a "transgenic animal" is a nonhuman animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include nonhuman primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a nonhuman animal, preferably a mammal, more preferably a mouse, in which an endogenous kinase gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0152] A transgenic animal of the invention can be created by introducing kinase-encoding nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. The kinase cDNA sequence can be introduced as a transgene into the genome of a nonhuman animal. Alternatively, a homologue of the mouse kinase gene can be isolated based on hybridization and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably linked to the kinase transgene to direct expression of kinase protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866, 4,870,009, and 4,873,191 and in Hogan (1986) Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the kinase transgene in its genome and/or expression of kinase mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene encoding kinase gene can further be bred to other transgenic animals carrying other transgenes.

[0153] To create a homologous recombinant animal, one prepares a vector containing at least a portion of a kinase gene or a homologue of the gene into which a deletion, addition, or substitution has been introduced to thereby alter, e.g., functionally disrupt, the kinase gene. In a preferred embodiment, the vector is designed such that, upon homologous recombination, the endogenous kinase gene is functionally disrupted (i.e., no longer encodes a functional protein; such vectors are also referred to as "knock out" vectors). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous kinase gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous kinase protein). In the homologous recombination vector, the altered portion of the kinase gene is flanked at its 5' and 3' ends by additional nucleic acid of the kinase gene to allow for homologous recombination to occur between the exogenous kinase gene carried by the vector and an endogenous kinase gene in an embryonic stem cell. The additional flanking kinase nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5' and 3' ends) are included in the vector (see, e.g., Thomas and Capecchi (1987) Cell 51:503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (e.g., by electroporation), and cells in which the introduced kinase gene has homologously recombined with the endogenous kinase gene are selected (see, e.g., Li et al. (1992) Cell 69:915). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see, e.g., Bradley (1987) in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, ed. Robertson (IRL, Oxford), pp. 113-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley (1991) Current Opinion in Bio/Technology 2:823-829 and in PCT Publication Nos. WO 90/11354, WO 91/01140, WO 92/0968, and WO 93/04169.

[0154] In another embodiment, transgenic nonhuman animals containing selected systems that allow for regulated expression of the transgene can be produced. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. (1992) Proc. Natl. Acad. Sci. USA 89:6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae (O'Gorman et al. (1991) Science 251:1351-1355). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0155] Clones of the nonhuman transgenic animals described herein can also be produced according to the methods described in Wilmut et al. (1997) Nature 385:810-813 and PCT Publication Nos. WO 97/07668 and WO 97/07669.

IV. Pharmaceutical Compositions

[0156] The kinase nucleic acid molecules, kinase proteins, and anti-kinase antibodies (also referred to herein as "active compounds") of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0157] The compositions of the invention are useful to treat any of the disorders discussed herein. The compositions are provided in therapeutically effective amounts. By "therapeutically effective amounts" is intended an amount sufficient to modulate the desired response. As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about I to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.

[0158] The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments. In a preferred example, a subject is treated with antibody, protein, or polypeptide in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. It will also be appreciated that the effective dosage of antibody, protein, or polypeptide used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays as described herein.

[0159] The present invention encompasses agents which modulate expression or activity. An agent may, for example, be a small molecule. For example, such small molecules include, but are not limited to, peptides, peptidomimetics, amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e,. including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

[0160] It is understood that appropriate doses of small molecule agents depends upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher. The dose(s) of the small molecule will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the small molecule to, have upon the nucleic acid or polypeptide of the invention. Exemplary doses include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram. It is furthermore understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. Such appropriate doses may be determined using the assays described herein. When one or more of these small molecules is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid of the invention, a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0161] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0162] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF; Parsippany, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0163] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a kinase protein or anti-kinase antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0164] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0165] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0166] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including Liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0167] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated with each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Depending on the type and severity of the disease, about 1 pg/kg to about 15 mg/kg (e.g., 0.1 to 20 mg/kg) of antibody is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage might range from about 1 pg/kg to about 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays. An exemplary dosing regimen is disclosed in WO 94/04188. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0168] The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470), or by stereotactic injection (see, e.g., Chen et of. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

[0169] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

V. Uses and Methods of the Invention

[0170] The nucleic acid molecules, proteins, protein homologues, and antibodies described herein can be used in one or more of the following methods: (a) screening assays; (b) detection assays (e.g., chromosomal mapping, tissue typing, forensic biology); (c) predictive medicine (e.g., diagnostic assays, prognostic assays, monitoring clinical trials, and pharmacogenomics); and (d) methods of treatment (e.g., therapeutic and prophylactic). The isolated nucleic acid molecules of the invention can be used to express kinase protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect kinase mRNA (e.g., in a biological sample) or a genetic lesion in a kinase gene, and to modulate kinase activity. In addition, the kinase proteins can be used to screen drugs or compounds that modulate cellular growth and/or metabolism as well as to treat disorders characterized by insufficient or excessive production of kinase protein or production of kinase protein forms that have decreased or aberrant activity compared to kinase wild type protein. In addition, the anti-kinase antibodies of the invention can be used to detect and isolate kinase proteins and modulate kinase activity.

[0171] A. Screening Assays

[0172] The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules, or other drugs) that bind to kinase proteins or have a stimulatory or inhibitory effect on, for example, kinase expression or kinase activity.

[0173] The test compounds of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including biological libraries, spatially-addressable parallel solid phase or solution phase libraries, synthetic library methods requiring deconvolution, the "one-bead one-compound" library method, and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, nonpeptide oligomer, or small molecule libraries of compounds (Lam (1997) Anticancer Drug Des. 12:145).

[0174] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. USA 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and Gallop et al. (1994) J. Med. Chem. 37:1233.

[0175] Libraries of compounds may be presented in solution (e.g., Houghten (1992) Bio/Techniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (U.S. Pat. No. 5,223,409), spores (U.S. Pat. Nos. 5,571,698; 5,403,484; and 5,223,409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. USA 89:1865-1869), or phage (Scott and Smith (1990) Science 249:386-390; Devlin (1990) Science 249:404-406; Cwirla et al. (1990) Proc. Natl. Acad. Sci. USA 87:6378-6382; and Felici (1991) J. Mol. Biol. 222:301-310).

[0176] Determining the ability of the test compound to bind to the kinase protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the kinase protein or biologically active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemmission or by scintillation counting. Alternatively, test compounds can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.

[0177] In a similar manner, one may determine the ability of the kinase protein to bind to or interact with a kinase target molecule. By "target molecule" is intended a molecule with which a kinase protein binds or interacts in nature. In a preferred embodiment, the ability of the kinase protein to bind to or interact with a kinase target molecule can be determined by monitoring the activity of the target molecule. For example, the activity of the target molecule can be monitored by detecting induction of a cellular second messenger of the target (e.g., intracellular Ca2+, diacylglycerol, 1P3, etc.), detecting catalytic/enzymatic activity of the target on an appropriate substrate, detecting the induction of a reporter gene (e.g., a kinase-responsive regulatory element operably linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cellular differentiation or cell proliferation.

[0178] In yet another embodiment, an assay of the present invention is a cell-free assay comprising contacting a kinase protein or biologically active portion thereof with a test compound and determining the ability of the test compound to bind to the kinase protein or biologically active portion thereof. Binding of the test compound to the kinase protein can be determined either directly or indirectly as described above. In a preferred embodiment, the assay includes contacting the kinase protein or biologically active portion thereof with a known compound that binds kinase protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to preferentially bind to kinase protein or biologically active portion thereof as compared to the known compound.

[0179] In another embodiment, an assay is a cell-free assay comprising contacting kinase protein or biologically active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the kinase protein or biologically active portion thereof. Determining the ability of the test compound to modulate the activity of a kinase protein can be accomplished, for example, by determining the ability of the kinase protein to bind to a kinase target molecule as described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of a kinase protein can be accomplished by determining the ability of the kinase protein to further modulate a kinase target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as previously described.

[0180] In yet another embodiment, the cell-free assay comprises contacting the kinase protein or biologically active portion thereof with a known compound that binds a kinase protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to preferentially bind to or modulate the activity of a kinase target molecule.

[0181] In the above-mentioned assays, it may be desirable to immobilize either a kinase protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, glutathione-S-transferase/kinase fusion proteins or glutathione-S-transferase/target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione-derivatized microtitre plates, which are then combined with the test compound or the test compound and either the nonadsorbed target protein or kinase protein, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtitre plate wells are washed to remove any unbound components and complex formation is measured either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of kinase binding or activity determined using standard techniques.

[0182] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either kinase protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated kinase molecules or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96-well plates (Pierce Chemicals). Alternatively, antibodies reactive with a kinase protein or target molecules but which do not interfere with binding of the kinase protein to its target molecule can be derivatized to the wells of the plate, and unbound target or kinase protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the kinase protein or target molecule,as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the kinase protein or target molecule.

[0183] In another embodiment, modulators of kinase expression are identified in a method in which a cell is contacted with a candidate compound and the expression of kinase mRNA or protein in the cell is determined relative to expression of kinase mRNA or protein in a cell in the absence of the candidate compound. When expression is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of kinase mRNA or protein expression. Alternatively, when expression is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of kinase mRNA or protein expression. The level of kinase mRNA or protein expression in the cells can be determined by methods described herein for detecting kinase mRNA or protein.

[0184] In yet another aspect of the invention, the kinase proteins can be used as "bait proteins" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Bio/Techniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and PCT Publication No. WO 94/10300), to identify other proteins, which bind to or interact with kinase protein ("kinase-binding proteins" or "kinase-bp") and modulate kinase activity. Such kinase-binding proteins are also likely to be involved in the propagation of signals by the kinase proteins as, for example, upstream or downstream elements of a signaling pathway.

[0185] This invention further pertains to novel agents identified by the above-described screening assays and uses thereof for treatments as described herein.

[0186] B. Detection Assays

[0187] Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. For example, these sequences can be used to: (1) map their respective genes on a chromosome; (2) identify an individual from a minute biological sample (tissue typing); and (3) aid in forensic identification of a biological sample. These applications are described in the subsections below.

[0188] 1. Chromosome Mapping

[0189] The isolated complete or partial kinase gene sequences of the invention can be used to map their respective kinase genes on a chromosome, thereby facilitating the location of gene regions associated with genetic disease. Computer analysis of kinase sequences can be used to rapidly select PCR primers (preferably 15-25 by in length) that do not span more than one exon in the genomic DNA, thereby simplifying the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the kinase sequences will yield an amplified fragment.

[0190] Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow (because they lack a particular enzyme), but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes (D'Eustachio et al. (1983) Science 220:919-924). Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

[0191] Other mapping strategies that can similarly be used to map a kinase sequence to its chromosome include in situ hybridization (described in Fan et al. (1990) Proc. Natl. Acad. Sci. USA 87:6223-27), pre-screening with labeled flow-sorted chromosomes, and pre-selection by hybridization to chromosome specific cDNA libraries. Furthermore, fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can be used to provide a precise chromosomal location in one step. For a review of this technique, see Verma et al. (1988) Human Chromosomes: A Manual of Basic Techniques (Pergamon Press, N.Y.). The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection.

[0192] Preferably 1,000 bases, and more preferably 2,000 bases will suffice to get good results in a reasonable amount of time.

[0193] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

[0194] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. (Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland et al. (1987) Nature 325:783-787.

[0195] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the kinase gene can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

[0196] 2. Tissue Typing

[0197] The kinase sequences of the present invention can also be used to identify individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes and probed on a Southern blot to yield unique bands for identification. The sequences of the present invention are useful as additional DNA markers for RFLP (described in U.S. Pat. No. 5,272,057).

[0198] Furthermore, the sequences of the present invention can be used to provide an alternative technique for determining the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the kinase sequences of the invention can be used to prepare two PCR primers from the 5quadrature and 3quadrature ends of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

[0199] Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The kinase sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. The noncoding sequences of SEQ ID NO:1, 3, 5, 7, 9, 11, or 13 can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NO:1, 3 5, 7, 9, 11, or 13 are used, a more appropriate number of primers for positive individual identification would be 500 to 2,000.

[0200] 3. Use of Partial kinase Sequences in Forensic Biology

[0201] DNA-based identification techniques can also be used in forensic biology. In this manner, PCR technology can be used to amplify DNA sequences taken from very small biological samples such as tissues, e.g., hair, skin, or body fluids, e.g., blood, saliva, or semen found at a crime scene. The amplified sequence can then be compared to a standard, thereby allowing identification of the origin of the biological sample.

[0202] The sequences of the present invention can be used to provide polynucleotide reagents, e.g., PCR primers, targeted to specific loci in the human genome, which can enhance the reliability of DNA-based forensic identifications by, for example, providing another "identification marker" that is unique to a particular individual. As mentioned above, actual base sequence information can be used for identification as an accurate alternative to patterns formed by restriction enzyme generated fragments. Sequences targeted to noncoding regions of SEQ ID NO:I, 3, 5, 7, 9, 11, or 13 are particularly appropriate for this use as greater numbers of polymorphisms occur in the noncoding regions, making it easier to differentiate individuals using this technique. Examples of polynucleotide reagents include the kinase sequences or portions thereof, e.g., fragments derived from the noncoding regions of SEQ ID NO:1, 3, 5, 7, 9, 11, or 13 having a length of at least 20 or 30 bases.

[0203] The kinase sequences described herein can further be used to provide polynucleotide reagents, e.g., labeled or labelable probes that can be used in, for example, an in situ hybridization technique, to identify a specific tissue. This can be very useful in cases where a forensic pathologist is presented with a tissue of unknown origin. Panels of such kinase probes, can be used to identify tissue by species and/or by organ type.

[0204] In a similar fashion, these reagents, e.g., kinase primers or probes can be used to screen tissue culture for contamination (i.e., screen for the presence of a mixture of different types of cells in a culture).

[0205] C. Predictive Medicine

[0206] The present invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trails are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. These applications are described in the subsections below.

[0207] 1. Diagnostic Assays

[0208] One aspect of the present invention relates to diagnostic assays for detecting kinase protein and/or nucleic acid expression as well as kinase activity, in the context of a biological sample. An exemplary method for detecting the presence or absence of kinase proteins in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting kinase protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes kinase protein such that the presence of kinase protein is detected in the biological sample. Results obtained with a biological sample from the test subject may be compared to results obtained with a biological sample from a control subject.

[0209] A preferred agent for detecting kinase mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to kinase mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length or partial kinase nucleic acid, such as the nucleic acid of SEQ ID NO:1, 3, 5, 7, 9, 11, or 13, or a portion thereof, such as a nucleic acid molecule of at least 15, 30, 50, 100, 250, or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to kinase mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

[0210] A preferred agent for detecting kinase protein is an antibody capable of binding to kinase protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.

[0211] The term "biological sample" is intended to include tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells, and fluids present within a subject. That is, the detection method of the invention can be used to detect kinase mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of kinase xnRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of kinase protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of kinase genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of kinase protein include introducing into a subject a labeled anti-kinase antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0212] In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. Biological samples may be obtained from blood, serum, cells, or tissue of a subject.

[0213] The invention also encompasses kits for detecting the presence of kinase proteins in a biological sample (a test sample). Such kits can be used to determine if a subject is suffering from or is at increased risk of developing a disorder associated with aberrant expression of kinase protein. For example, the kit can comprise a labeled compound or agent capable of detecting kinase protein or mRNA in a biological sample and means for determining the amount of a kinase protein in the sample (e.g., an anti-kinase antibody or an oligonucleotide probe that binds to DNA encoding a kinase protein, e.g., SEQ ID NO:1, 3, 5, 7, 9, 11, or 13). Kits can also include instructions for observing that the tested subject is suffering from or is at risk of developing a disorder associated with aberrant expression of kinase sequences if the amount of kinase protein or mRNA is above or below a normal level.

[0214] For antibody-based kits, the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) that binds to kinase protein; and, optionally, (2) a second, different antibody that binds to kinase protein or the first antibody and is conjugated to a detectable agent. For oligonucleotide-based kits, the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, that hybridizes to a kinase nucleic acid sequence or (2) a pair of primers useful for amplifying a kinase nucleic acid molecule.

[0215] The kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent. The kit can also comprise components necessary for detecting the detectable agent (e.g., an enzyme or a substrate). The kit can also contain a control sample or a series of control samples that can be assayed and compared to the test sample contained. Each component of the kit is usually enclosed within an individual container, and all of the various containers are within a single package along with instructions for observing whether the tested subject is suffering from or is at risk of developing a disorder associated with aberrant expression of kinase proteins.

[0216] 2. Prognostic Assays

[0217] The methods described herein can furthermore be utilized as diagnostic or prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with kinase protein, kinase nucleic acid expression, or kinase activity. Prognostic assays can be used for prognostic or predictive purposes to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with kinase protein, kinase nucleic acid expression, or kinase activity.

[0218] Thus, the present invention provides a method in which a test sample is obtained from a subject, and kinase protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of kinase protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant kinase expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid cell sample, or tissue.

[0219] Furthermore, using the prognostic assays described herein, the present invention provides methods for determining whether a subject can be administered a specific agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) or class of agents (e.g., agents of a type that decrease kinase activity) to effectively treat a disease or disorder associated with aberrant kinase expression or activity. In this manner, a test sample is obtained and kinase protein or nucleic acid is detected. The presence of kinase protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant kinase expression or activity.

[0220] The methods of the invention can also be used to detect genetic lesions or mutations in a kinase gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In preferred embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion or mutation characterized by at least one of an alteration affecting the integrity of a gene encoding a kinase-protein, or the misexpression of the kinase gene. For example, such genetic lesions or mutations can be detected by ascertaining the existence of at least one of: (1) a deletion of one or more nucleotides from a kinase gene; (2) an addition of one or more nucleotides to a kinase gene; (3) a substitution of one or more nucleotides of a kinase gene; (4) a chromosomal rearrangement of a kinase gene; (5) an alteration in the level of a messenger RNA transcript of a kinase gene; (6) an aberrant modification of a kinase gene, such as of the methylation pattern of the genomic DNA; (7) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a kinase gene; (8) a non-wild-type level of a kinase-protein; (9) an allelic loss of a kinase gene; and (10) an inappropriate post-translational modification of a kinase-protein. As described herein, there are a large number of assay techniques known in the art that can be used for detecting lesions in a kinase gene. Any cell type or tissue in which kinase proteins are expressed may be utilized in the prognostic assays described herein.

[0221] In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) Proc. Natl. Acad. Sci. USA 91:360-364), the latter of which can be particularly useful for ,detecting point mutations in the kinase-gene (see, e.g., Abravaya et al. (1995) Nucleic Acids Res. 23:675-682). It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

[0222] Alternative amplification methods include self sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio/Technology 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

[0223] In an alternative embodiment, mutations in a kinase gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns of isolated test sample and control DNA digested with one or more restriction endonucleases. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

[0224] In other embodiments, genetic mutations in a kinase molecule can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing hundreds or thousands of oligonucleotides probes (Cronin et al. (1996) Human Mutation 7:244-255; Kozal et al. (1996) Nature Medicine 2:753-759). In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the kinase gene and detect mutations by comparing the sequence of the sample kinase gene with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert ((1977) Proc. Natl. Acad. Sci. USA 74:560) or Sanger ((1977) Proc. Natl. Acad. Sci. USA 74:5463). It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Bio/Techniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT Publication No. WO

[0225] 94/16101; Cohen et al. (1996) Adv. Chromatogr. 36:127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol. 38:147-159).

[0226] Other methods for detecting mutations in the kinase gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al. (1985) Science 230:1242). See, also Cotton et al. (1988) Proc. Natl. Acad. Sci. USA 85:4397; Saleeba et al. (1992) Methods Enzymol. 217:286-295. In a preferred embodiment, the control DNA or RNA can be labeled for detection.

[0227] In still another embodiment, the mismatch cleavage reaction employs one or more "DNA mismatch repair" enzymes that recognize mismatched base pairs in double-stranded DNA in defined systems for detecting and mapping point mutations in kinase cDNAs obtained from samples of cells. See, e.g., Hsu et al. (1994) Carcinogenesis 15:1657-1662. According to an exemplary embodiment, a probe based on a kinase sequence, e.g., a wild-type kinase sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Pat. No. 5,459,039.

[0228] In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in kinase genes. For example, single-strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild-type nucleic acids (Orita et al. (1989) Proc. Natl. Acad. Sci. USA 86:2766; see also Cotton (1993) Mutat. Res. 285:125-144; Hayashi (1992) Genet. Anal. Tech. Appl. 9:73-79). The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In a preferred embodiment, the subject method utilizes heteroduplex analysis to separate double-stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet. 7:5).

[0229] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 by of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys. Chem. 265:12753).

[0230] Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl. Acad. Sci. USA 86:6230). Such allele-specific oligonucleotides are hybridized to PCR-amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

[0231] Alternatively, allele-specific amplification technology, which depends on selective PCR amplification, may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule so that amplification depends on differential hybridization (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent or reduce polymerase extension (Prossner (1993) Tibtech 11:238). In addition, it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol. Cell Probes 6:1). It is anticipated that in certain embodiments amplification may also be performed using Tag ligase for amplification (Barany (1991) Proc. Natl. Acad. Sci. USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3' end of the 5' sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

[0232] The methods described herein may be performed, for example, by utilizing prepackaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a kinase gene.

[0233] 3. Pharmacogenomics

[0234] Agents or modulators that have a stimulatory or inhibitory effect on kinase activity (e.g., kinase gene expression) as identified by a screening assay described herein, can be administered to individuals to treat (prophylactically or therapeutically) disorders associated with aberrant kinase activity as well as to modulate the cellular growth, differentiation and/or metabolism. In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of kinase protein, expression of kinase nucleic acid, or mutation content of kinase genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

[0235] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, e.g., Linder (1997) Clin. Chem. 43(2):254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body are referred to as "altered drug action." Genetic conditions transmitted as single factors altering the way the body acts on drugs are referred to as "altered drug metabolism". These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common inherited enzymopathy in which the main clinical complication is haemolysis after ingestion of oxidant drugs (antimalarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0236] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, a PM will show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. The other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

[0237] Thus, the activity of kinase protein, expression of kinase nucleic acid, or mutation content of kinase genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a kinase modulator, such as a modulator identified by one of the exemplary screening assays described herein.

[0238] 4. Monitoring of Effects During Clinical Trials

[0239] Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of kinase genes (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening but also in clinical trials. For example, the effectiveness of an agent, as determined by a screening assay as described herein, to increase or decrease kinase gene expression, protein levels, or protein activity, can be monitored in clinical trials of subjects exhibiting decreased or increased kinase gene expression, protein levels, or protein activity. In such clinical trials, kinase expression or activity and preferably that of other genes that have been implicated in for example, a cellular proliferation disorder, can be used as a marker of cellular growth and differentiation.

[0240] For example, and not by way of limitation, genes that are modulated in cells by treatment with an agent (e.g., compound, drug, or small molecule) that modulates kinase activity (e.g., as identified in a screening assay described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of kinase genes and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of kinase genes or other genes. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

[0241] In a preferred embodiment, the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (1) obtaining a preadministration sample from a subject prior to administration of the agent; (2) detecting the level of expression of a kinase protein, mRNA, or genomic DNA in the preadministration sample; (3) obtaining one or more postadministration samples from the subject; (4) detecting the level of expression or activity of the kinase protein, mRNA, or genomic DNA in the postadministration samples; (5) comparing the level of expression or activity of the kinase protein, mRNA, or genomic DNA in the preadministration sample with the kinase protein, mRNA, or genomic DNA in the postadministration sample or samples; and (vi) altering the administration of the agent to the subject accordingly to bring about the desired effect, i.e., for example, an increase or a decrease in the expression or activity of a kinase protein.

[0242] C. Methods of Treatment

[0243] The present invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant kinase expression or activity. Additionally, the compositions of the invention find use in the treatment of disorders described herein.

[0244] 1. Prophylactic Methods

[0245] In one aspect, the invention provides a method for preventing in a subject a disease or condition associated with an aberrant kinase expression or activity by administering to the subject an agent that modulates kinase expression or at least one kinase gene activity. Subjects at risk for a disease that is caused, or contributed to, by aberrant kinase expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the kinase aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending on the type of kinase aberrancy, for example, a kinase agonist or kinase antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein.

[0246] 2. Therapeutic Methods

[0247] Another aspect of the invention pertains to methods of modulating kinase expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of kinase protein activity associated with the cell. An agent that modulates kinase protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a kinase protein, a peptide, a kinase peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more of the biological activities of kinase protein. Examples of such stimulatory agents include active kinase protein and a nucleic acid molecule encoding a kinase protein that has been introduced into the cell. In another embodiment, the agent inhibits one or more of the biological activities of kinase protein. Examples of such inhibitory agents include antisense kinase nucleic acid molecules and anti-kinase antibodies.

[0248] These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the present invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a kinase protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or a combination of agents, that modulates (e.g., upregulates or downregulates) kinase expression or activity. In another embodiment, the method involves administering a kinase protein or nucleic acid molecule as therapy to compensate for reduced or aberrant kinase expression or activity.

[0249] Stimulation of kinase activity is desirable in situations in which a kinase protein is abnormally downregulated and/or in which increased kinase activity is likely to have a beneficial effect. Conversely, inhibition of kinase activity is desirable in situations in which kinase activity is abnormally upregulated and/or in which decreased kinase activity is likely to have a beneficial effect.

[0250] This invention is further illustrated by the following examples, which should not be construed as limiting.

EXAMPLES

Gene Expression Analysis

[0251] Total RNA was prepared from various human tissues by a single step extraction method using RNA STAT-60 according to the manufacturer's instructions (TelTest, Inc). Each RNA preparation was treated with DNase I (Ambion) at 37° C. for 1 hour. DNAse I treatment was determined to be complete if the sample required at least 38 PCR amplification cycles to reach a threshold level of flourescence using 13-2 microglobulin as an internal amplicon reference. The integrity of the RNA samples following DNase I treatment was confirmed by agarose gel electrophoresis and ethidium bromide staining. After phenol extraction cDNA was prepared from the sample using the SUPERSCRIPT® Choice System following the manufacturer's instructions (GibcoBRL). A negative control of RNA without reverse transcriptase was mock reverse transcribed for each RNA sample.

[0252] Novel kinase expression was measured by TaqMan® quantitative PCR (Perkin Elmer Applied Biosystems) in cDNA prepared from the following normal human tissues: lymph node, spleen, thymus, brain, lung, skeletal muscle, fetal liver, tonsil, colon, heart, and liver from one or two adult donors; fibrotic liver samples prepared from two to seven different donors; resting and phytohemaglutinin activated peripheral blood mononuclear cells (PBMC); CD3.sup.+, CD4.sup.+, and CD8.sup.+ T cells; Th1 and Th2 cells stimulated for six or 48 hours with anti-CD3 antibody; resting and lipopolysaccharide activated CD19.sup.+ B cells; CD34.sup.+ cells from mobilized peripheral blood (mPB CD34.sup.+), adult resting bone marrow (ABM CD34.sup.+), G-CSF mobilized bone marrow (mBM CD34.sup.+), and neonatal umbilical cord blood (CB CD34.sup.+); G-CSF mobilized peripheral blood leukocytes (mPB leukocytes) and CD34^cells purified from mPB leukocytes (mPB CD34.sup.-); CD 14.sup.+ cells; and granulocytes. Transformed human cell lines included K526, an erythroleukemia; HL60, an acute promyelocytic leukemia; Jurkat, a T cell leukemia; HEK 293, epithelial cells from embryonic kidney transformed with adenovirus 5 DNA; and Hep3B hepatocellular liver carcinoma cells cultured in normal (HepB normoxia) or reduced oxygen tension (Hep3B hypoxia).

[0253] Probes were designed by PrimerExpress software (PE Biosystems) based on the sequence of each kinase gene. The primers and probes for expression analysis of h12832, h14138, h14833, h15990, h16341, and h2252, respectively, and for β-2 microglobulin were as follows:

TABLE-US-00006 (SEQ ID NO: 56) h12832 Forward Primer: TTTTCACCTCCGACCTTTCCT (SEQ ID NO: 57) h12832 Reverse Primer: ATCCCTTCCATTGTGAAAGCC (SEQ ID NO: 58) h12832 TaqMan Probe: CCAGGCGGTGAGACTCTGGACTGAG (SEQ ID NO: 59) h14138 Forward Primer: CACGAGGCTAGACTAAAAGGAAAATT (SEQ ID NO: 60) h14138 Reverse Primer: TGAAGCCAGGAATACTGCTCAG h14138 TaqMan Prober: (SEQ ID NO: 61) TTGTGCTACAGACTAAATCCAGATACGGTCAG-GT (SEQ ID NO: 62) h14833 Forward Primer: CCTGCCTCCCACTCATCG (SEQ ID NO: 63) h14833 Reverse Primer: CAGCTGGTTCTGTAGAGGACGAA (SEQ ID NO: 64) h14833 TaqMan Probe: ATGCTCTGACTGCTCACTGCCTGGATC (SEQ ID NO: 65) h15990 Forward Primer: GGCAAAGGCGGGTTCG (SEQ ID NO: 66) h15990 Reverse Primer: TTGACCGCCACATCGTAGC (SEQ ID NO: 67) h15990 TaqMan Probe: CCGGGCGCAACATAGGAAGTGG (SEQ ID NO: 68) h16341 Forward Primer: CAGTTGCTAGACAGTAACCTGCATTT (SEQ ID NO: 69) h16341 Reverse Primer: TGAGGCCCACTGCTATGTCA (SEQ ID NO: 70) h16341 TaqMan Probe: CCTTGGACTGTGAGGGTAAAACTGGCC (SEQ ID NO: 71) h2252 Forward Primer: TCTGATTCCGAGGGCTCTGA (SEQ ID NO: 72) h2252 Reverse Primer: ACGGTGGTAAAGTCTCATTCA h2252 TaqMan Probe: (SEQ ID NO: 73) CGGAATCTACCAGCAGGGAAAACAATACTCAT-C β-2 microglobulin Forward Primer (SEQ ID NO: 74) CACCCCCACTGAAAAAGATGA β-2 microglobulin Reverse Primer (SEQ ID NO: 75) CTTAACTATCTTGGGCTGTGACAAAG β-2 microglobulin TaqMan Prober (SEQ ID NO: 76) TATGCCTGCCGTGTGAACCACGTG

[0254] Each kinase gene probe was labeled using FAM (6-carboxyfluorescein), and the β2-microglobulin reference probe was labeled with a different fluorescent dye, VIC. The differential labeling of the target gene and internal reference gene thus enabled measurement in same well. Forward and reverse primers and the probes for both β2-microglobulin and target gene were added to the TaqMan® Universal PCR Master Mix (PE Applied Biosystems). Although the final concentration of primer and probe could vary, each was internally consistent within a given experiment. A typical experiment contained 200 nM of forward and reverse primers plus 100 nM probe for β-2 microglobulin and 600 nM forward and reverse primers plus 200 nM probe for the target gene. TaqMan matrix experiments were carried out on an ABI PRISM 7700 Sequence Detection System (PE Applied Biosystems). The thermal cycler conditions were as follows: hold for 2 min at 50° C. and 10 min at 95° C., followed by two-step PCR for 40 cycles of 95° C. for 15 sec followed by 60° C. for 1 min.

[0255] The following method was used to quantitatively calculate kinase gene expression in the various tissues relative to β-2 microglobulin expression in the same tissue. The threshold cycle (Ct) value is defined as the cycle at which a statistically significant increase in flourescence is detected. A lower Ct value is indicative of a higher mRNA concentration. The Ct value of the kinase gene is normalized by subtracting the Ct value of the β-2 microglobulin gene to obtain a .sub.ΔCt value using the following formula: .sub.ΔCt=Ct.sub.kinase-Ct.sub.β-2 microglobulin. Expression is then calibrated against a cDNA sample showing a comparatively low level of expression of the kinase gene. The .sub.ΔCt value for the calibrator sample is then subtracted from .sub.ΔCt for each tissue sample according to the following formula: .sub.ΔΔCt=.sub.ΔCt-_sample-.sub.ΔCt-_cali- brator. Relative expression is then calculated using the arithmetic formula given by 2.sup.-ΔΔCt. Expression of the target kinase gene in each of the tissues tested is then graphically represented as discussed in more detail below.

[0256] FIG. 22 shows expression of h12832 in various tissues and cell lines as described above, relative to expression in CD14.sup.+ cells. The results indicate significant expression in thymus, fetal liver, B cells, Th1 and Th2 samples, and the K562, HL60, HEK 293, and Jurkat cell lines.

[0257] FIG. 23 shows expression of h14138 in various tissues and cell lines as described above, relative to expression in mPB leukocytes. The results indicate broad tissue expression and significant expression in Th1 and Th2 cells, and the K562, HL60, HEK 293, and Jurkat cell lines.

[0258] FIG. 24 shows expression of h14833 in various tissues and cell lines as described above, relative to expression in CD14.sup.+ cells. The results show broad tissue expression with high levels in skeletal muscle, fetal liver, and tonsil. Significantly high expression is seen in the CD34.sup.+ cells from mobilized peripheral blood and mobilized bone marrow, as well as in colon, and the Jurkat and HEK 293 cell lines.

[0259] FIG. 25 shows expression of h15990 in various tissues and cell lines as described above, relative to expression in HEK 293 cells. The results show that expression of h15990 is broadly distributed among the tissues examined with a significantly high level of expression in colon.

[0260] FIG. 26 shows expression of h16341 in various tissues and cell lines as described above, relative to expression in fibrotic liver cells (sample NDR 194). The results indicate expression at low or barely detectable levels in the tissues examined.

[0261] FIG. 27 shows expression of h2252 in various tissues and cell lines as described above, relative to brain tissue. The results indicate that h2252 is expressed lymphocytic cells, particularly in the T and B lymphocyte subpopulations, as well as in the HEK 293 and Jurkat cell lines.

[0262] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0263] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

[0264] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Sequence CWU 1

8911586DNAHomo sapiensCDS(191)...(1156) 1gtcgacccac gcgtccggtt cgaattgcaa cggcagctgc cgggcgtatg tgttggtgct 60agaggcagct gcagggtctc gctgggggcc gctcgggacc aattttgaag aggtacttgg 120ccacgactta ttttcacctc cgacctttcc ttccaggcgg tgagactctg gactgagagt 180ggctttcaca atg gaa ggg atc agt aat ttc aag aca cca agc aaa tta 229 Met Glu Gly Ile Ser Asn Phe Lys Thr Pro Ser Lys Leu 1 5 10tca gaa aaa aag aaa tct gta tta tgt tca act cca act ata aat atc 277Ser Glu Lys Lys Lys Ser Val Leu Cys Ser Thr Pro Thr Ile Asn Ile 15 20 25ccg gcc tct ccg ttt atg cag aag ctt ggc ttt ggt act ggg gta aat 325Pro Ala Ser Pro Phe Met Gln Lys Leu Gly Phe Gly Thr Gly Val Asn30 35 40 45gtg tac cta atg aaa aga tct cca aga ggt ttg tct cat tct cct tgg 373Val Tyr Leu Met Lys Arg Ser Pro Arg Gly Leu Ser His Ser Pro Trp 50 55 60gct gta aaa aag att aat cct ata tgt aat gat cat tat cga agt gtg 421Ala Val Lys Lys Ile Asn Pro Ile Cys Asn Asp His Tyr Arg Ser Val 65 70 75tat caa aag aga cta atg gat gaa gct aag att ttg aaa agc ctt cat 469Tyr Gln Lys Arg Leu Met Asp Glu Ala Lys Ile Leu Lys Ser Leu His 80 85 90cat cca aac att gtt ggt tat cgt gct ttt act gaa gcc aat gat ggc 517His Pro Asn Ile Val Gly Tyr Arg Ala Phe Thr Glu Ala Asn Asp Gly 95 100 105agt ctg tgt ctt gct atg gaa tat gga ggt gaa aag tct cta aat gac 565Ser Leu Cys Leu Ala Met Glu Tyr Gly Gly Glu Lys Ser Leu Asn Asp110 115 120 125tta ata gaa gaa cga tat aaa gcc agc caa gat cct ttt cca gca gcc 613Leu Ile Glu Glu Arg Tyr Lys Ala Ser Gln Asp Pro Phe Pro Ala Ala 130 135 140ata att tta aaa gtt gct ttg aat atg gca aga ggg tta aag tat ctg 661Ile Ile Leu Lys Val Ala Leu Asn Met Ala Arg Gly Leu Lys Tyr Leu 145 150 155cac caa gaa aag aaa ctg ctt cat gga gac ata aag tct tca aat gtt 709His Gln Glu Lys Lys Leu Leu His Gly Asp Ile Lys Ser Ser Asn Val 160 165 170gta att aaa ggc gat ttt gaa aca att aaa atc tgt gat gta gga gtc 757Val Ile Lys Gly Asp Phe Glu Thr Ile Lys Ile Cys Asp Val Gly Val 175 180 185tct cta cca ctg gat gaa aat atg act gtg act gac cct gag gct tgt 805Ser Leu Pro Leu Asp Glu Asn Met Thr Val Thr Asp Pro Glu Ala Cys190 195 200 205tac att ggc aca gag cca tgg aaa ccc aaa gaa gct gtg gag gag aat 853Tyr Ile Gly Thr Glu Pro Trp Lys Pro Lys Glu Ala Val Glu Glu Asn 210 215 220ggt gtt att act gac aag gca gac ata ttt gcc ttt ggc ctt act ttg 901Gly Val Ile Thr Asp Lys Ala Asp Ile Phe Ala Phe Gly Leu Thr Leu 225 230 235tgg gaa atg atg act tta tcg att cca cac att aat ctt tca aat gat 949Trp Glu Met Met Thr Leu Ser Ile Pro His Ile Asn Leu Ser Asn Asp 240 245 250gat gat gat gaa gat aaa act ttt gat gaa agt gat ttt gat gat gaa 997Asp Asp Asp Glu Asp Lys Thr Phe Asp Glu Ser Asp Phe Asp Asp Glu 255 260 265gca tac tat gca gcg ttg gga act agg cca cct att aat atg gaa gaa 1045Ala Tyr Tyr Ala Ala Leu Gly Thr Arg Pro Pro Ile Asn Met Glu Glu270 275 280 285ctg gat gaa tca tac cag aaa gta att gaa ctc ttc tct gta tgc act 1093Leu Asp Glu Ser Tyr Gln Lys Val Ile Glu Leu Phe Ser Val Cys Thr 290 295 300aat gaa gac cct aaa gat cgt cct tct gct gca cac att gtt gaa gct 1141Asn Glu Asp Pro Lys Asp Arg Pro Ser Ala Ala His Ile Val Glu Ala 305 310 315ctg gaa aca gat gtc tagtgatcat ctcagctgaa gtgtggcttg cgtaaataac 1196Leu Glu Thr Asp Val 320tgtttattcc aaaatattta catagttact atcagtagtt attagactct aaaattggca 1256tatttgagga ccatagtttc ttgttaacat atggataact atttctaata tgaaatatgc 1316ttatattggc tataagcact tggaattgta ctgggttttc tgtaaagttt tagaaactag 1376ctacataagt actttgatac tgctcatgct gacttaaaac actagcagta aaacgctgta 1436aactgtaaca ttaaattgaa tgaccattac ttttattaat gatctttctt aaatattcta 1496tattttaatg gatctactga cattagcact ttgtacagta caaaataaag tctacatttg 1556tttaaaaaaa aaaaaaaaaa gggcggccgc 15862322PRTHomo sapiens 2Met Glu Gly Ile Ser Asn Phe Lys Thr Pro Ser Lys Leu Ser Glu Lys1 5 10 15Lys Lys Ser Val Leu Cys Ser Thr Pro Thr Ile Asn Ile Pro Ala Ser 20 25 30Pro Phe Met Gln Lys Leu Gly Phe Gly Thr Gly Val Asn Val Tyr Leu 35 40 45Met Lys Arg Ser Pro Arg Gly Leu Ser His Ser Pro Trp Ala Val Lys 50 55 60Lys Ile Asn Pro Ile Cys Asn Asp His Tyr Arg Ser Val Tyr Gln Lys65 70 75 80Arg Leu Met Asp Glu Ala Lys Ile Leu Lys Ser Leu His His Pro Asn 85 90 95Ile Val Gly Tyr Arg Ala Phe Thr Glu Ala Asn Asp Gly Ser Leu Cys 100 105 110Leu Ala Met Glu Tyr Gly Gly Glu Lys Ser Leu Asn Asp Leu Ile Glu 115 120 125Glu Arg Tyr Lys Ala Ser Gln Asp Pro Phe Pro Ala Ala Ile Ile Leu 130 135 140Lys Val Ala Leu Asn Met Ala Arg Gly Leu Lys Tyr Leu His Gln Glu145 150 155 160Lys Lys Leu Leu His Gly Asp Ile Lys Ser Ser Asn Val Val Ile Lys 165 170 175Gly Asp Phe Glu Thr Ile Lys Ile Cys Asp Val Gly Val Ser Leu Pro 180 185 190Leu Asp Glu Asn Met Thr Val Thr Asp Pro Glu Ala Cys Tyr Ile Gly 195 200 205Thr Glu Pro Trp Lys Pro Lys Glu Ala Val Glu Glu Asn Gly Val Ile 210 215 220Thr Asp Lys Ala Asp Ile Phe Ala Phe Gly Leu Thr Leu Trp Glu Met225 230 235 240Met Thr Leu Ser Ile Pro His Ile Asn Leu Ser Asn Asp Asp Asp Asp 245 250 255Glu Asp Lys Thr Phe Asp Glu Ser Asp Phe Asp Asp Glu Ala Tyr Tyr 260 265 270Ala Ala Leu Gly Thr Arg Pro Pro Ile Asn Met Glu Glu Leu Asp Glu 275 280 285Ser Tyr Gln Lys Val Ile Glu Leu Phe Ser Val Cys Thr Asn Glu Asp 290 295 300Pro Lys Asp Arg Pro Ser Ala Ala His Ile Val Glu Ala Leu Glu Thr305 310 315 320Asp Val3831DNAHomo sapiensCDS(1)...(522) 3tac tat agg gaa ttt ggc cct cga ggc cag aat tcg gca cga gac cga 48Tyr Tyr Arg Glu Phe Gly Pro Arg Gly Gln Asn Ser Ala Arg Asp Arg1 5 10 15act ccg aag agt gtg aga aga ggg gtg gcc ccc gtt gat gat ggg cga 96Thr Pro Lys Ser Val Arg Arg Gly Val Ala Pro Val Asp Asp Gly Arg 20 25 30att cta gga acc cca gac tac ctt gca cct gag ctg tta cta ggc agg 144Ile Leu Gly Thr Pro Asp Tyr Leu Ala Pro Glu Leu Leu Leu Gly Arg 35 40 45gcc cat ggt cct gcg gta gac tgg tgg gca ctt gga gtt tgc ttg ttt 192Ala His Gly Pro Ala Val Asp Trp Trp Ala Leu Gly Val Cys Leu Phe 50 55 60gaa ttt cta aca gga att ccc cct ttc aat gat gaa aca cca caa caa 240Glu Phe Leu Thr Gly Ile Pro Pro Phe Asn Asp Glu Thr Pro Gln Gln65 70 75 80gta ttc cag aat att ctg aaa aga gat atc cct tgg cca gaa ggt gaa 288Val Phe Gln Asn Ile Leu Lys Arg Asp Ile Pro Trp Pro Glu Gly Glu 85 90 95gaa aag tta tct gat aat gct caa agt gca gta gaa ata ctt tta acc 336Glu Lys Leu Ser Asp Asn Ala Gln Ser Ala Val Glu Ile Leu Leu Thr 100 105 110att gat gat aca aag aga gct gga atg aaa gag cta aaa cgt cat cct 384Ile Asp Asp Thr Lys Arg Ala Gly Met Lys Glu Leu Lys Arg His Pro 115 120 125ctc ttc agt gat gtg gac tgg gaa aat ctg cag cat cag act atg cct 432Leu Phe Ser Asp Val Asp Trp Glu Asn Leu Gln His Gln Thr Met Pro 130 135 140ttc atc ccc cag cca gat gat gaa aca gat acc tcc tat ttt gaa gcc 480Phe Ile Pro Gln Pro Asp Asp Glu Thr Asp Thr Ser Tyr Phe Glu Ala145 150 155 160agg aat act gct cag cac ctg acc gta tct gga ttt agt ctg 522Arg Asn Thr Ala Gln His Leu Thr Val Ser Gly Phe Ser Leu 165 170tagcacaaaa attttccttt tagtctagcc tcgtgttata gaatgaactt gcataattat 582atactcctta atactagatt gatctaaggg ggaaagatca ttatttaacc tagttcaatg 642tgcttttaat gtacgttaca gctttcacag agttaaaagg ctgaaaggaa tatagtcagt 702aatttatctt aacctcaaaa ctgtatataa atcttcaaag cttttttcat ctatttattt 762tgtttattgc actttatgaa aactgaagca tcaataaaat tagaggacac tattgagagt 822gagccacta 8314174PRTHomo sapiens 4Tyr Tyr Arg Glu Phe Gly Pro Arg Gly Gln Asn Ser Ala Arg Asp Arg1 5 10 15Thr Pro Lys Ser Val Arg Arg Gly Val Ala Pro Val Asp Asp Gly Arg 20 25 30Ile Leu Gly Thr Pro Asp Tyr Leu Ala Pro Glu Leu Leu Leu Gly Arg 35 40 45Ala His Gly Pro Ala Val Asp Trp Trp Ala Leu Gly Val Cys Leu Phe 50 55 60Glu Phe Leu Thr Gly Ile Pro Pro Phe Asn Asp Glu Thr Pro Gln Gln65 70 75 80Val Phe Gln Asn Ile Leu Lys Arg Asp Ile Pro Trp Pro Glu Gly Glu 85 90 95Glu Lys Leu Ser Asp Asn Ala Gln Ser Ala Val Glu Ile Leu Leu Thr 100 105 110Ile Asp Asp Thr Lys Arg Ala Gly Met Lys Glu Leu Lys Arg His Pro 115 120 125Leu Phe Ser Asp Val Asp Trp Glu Asn Leu Gln His Gln Thr Met Pro 130 135 140Phe Ile Pro Gln Pro Asp Asp Glu Thr Asp Thr Ser Tyr Phe Glu Ala145 150 155 160Arg Asn Thr Ala Gln His Leu Thr Val Ser Gly Phe Ser Leu 165 17052060DNAHomo sapiensCDS(154)...(780)misc_feature(1)...(2060)n = A,T,C or G 5tttttgcctt cattcactcc catgtggggc cttgagaatt aacatcttaa gttgcctcct 60gctccctgcc tcccactcat cgaggatgct ctgactgctc actgcctgga tctttcgtcc 120tctacagaac cagctgggct ccatgaggat gtg atg act atg gat ggt ctt ctc 174 Met Thr Met Asp Gly Leu Leu 1 5tat gat ctc aca gaa aaa caa gta tat cac atc gga aag cag gtc ctt 222Tyr Asp Leu Thr Glu Lys Gln Val Tyr His Ile Gly Lys Gln Val Leu 10 15 20ttg gcg ctg gaa ttc ctg cag gag aag cat ttg ttc cat ggg gat gtg 270Leu Ala Leu Glu Phe Leu Gln Glu Lys His Leu Phe His Gly Asp Val 25 30 35gca gcc agg aat att ctg atg caa agt gat ctc act gct aag ctc tgt 318Ala Ala Arg Asn Ile Leu Met Gln Ser Asp Leu Thr Ala Lys Leu Cys40 45 50 55gga tta ggc ctg gct tat gaa gtt tac acc cga ggg gcc atc tcc tct 366Gly Leu Gly Leu Ala Tyr Glu Val Tyr Thr Arg Gly Ala Ile Ser Ser 60 65 70act caa acc ata cct ctc aag tgg ctt gcc cca gaa cgg ctt ctc ctg 414Thr Gln Thr Ile Pro Leu Lys Trp Leu Ala Pro Glu Arg Leu Leu Leu 75 80 85aga cct gct agc atc aga gca gat gtc tgg tct ttt ggg atc ctg ctc 462Arg Pro Ala Ser Ile Arg Ala Asp Val Trp Ser Phe Gly Ile Leu Leu 90 95 100tat gag atg gtg act cta gga gca cca ccg tat cct gaa gtc cct cct 510Tyr Glu Met Val Thr Leu Gly Ala Pro Pro Tyr Pro Glu Val Pro Pro 105 110 115acc agc atc cta gag cat ctc caa aga agg aaa atc atg aag aga ccc 558Thr Ser Ile Leu Glu His Leu Gln Arg Arg Lys Ile Met Lys Arg Pro120 125 130 135agt agc tgc aca cat acc atg tac agt atc atg aag tcc tgc tgg cgc 606Ser Ser Cys Thr His Thr Met Tyr Ser Ile Met Lys Ser Cys Trp Arg 140 145 150tgg cgt gag gct gac cgc ccc tca cct aga gag ctg cgc ttg cgc cta 654Trp Arg Glu Ala Asp Arg Pro Ser Pro Arg Glu Leu Arg Leu Arg Leu 155 160 165gaa gct gcc att aaa act gca gat gac gag gct gtg tta caa gta cca 702Glu Ala Ala Ile Lys Thr Ala Asp Asp Glu Ala Val Leu Gln Val Pro 170 175 180gag ttg gtg gta cct gaa ctg tat gca gct gtg gcc ggc atc aga gtg 750Glu Leu Val Val Pro Glu Leu Tyr Ala Ala Val Ala Gly Ile Arg Val 185 190 195gag agc ctc ttc tac aac tat agc atg ctt tgaagagtct cgggcaagaa 800Glu Ser Leu Phe Tyr Asn Tyr Ser Met Leu200 205acattcatgc atgagtatat gttcttggaa tcaattcctc taagaacaga gaatggtctt 860tcccagggac acaaagggag aaatgggaca tggattcttg atcttccttt acacatttct 920cgggaaatct gaaatgatgc tggatgggac tctacacatc ctgagctaag acatactgtc 980agtctcactt ctgctgtccc agtcctagaa atcctgggta gaagtggtgg acctgtgcaa 1040aggaggtttt agaactctgc agtatttgtt ggggcatggc acaaataagc tcatccctcc 1100cgtccgaggc tagtttcctc tggaaccaca tttttatcta gatgaaaatt tggaatgaaa 1160tgaaggaata gaaatccaat aaaagagttg aagggaaaga aaatttaagg ttcttcttgc 1220tcaggattac agatatggac caacacctcc ttcaagaaaa ggtggtagga cacaaagttc 1280ttcagtcctg agccctacat gtggggttgg aggagaacta taacggaaaa acctctgagt 1340ttcaccttag gtatagataa aagaaagatg gtcccctttt atctgattct gagacaggta 1400aattctgttt gttactacgt ttaattagaa ggtggaggag tcatttcatg attaagaaca 1460ttcaacatgt attgttcatt aagctagctt cctagttccg attagactaa ggagactaag 1520cctagagagt caatgttaga acagtgaaaa gaattctgtg tgtgtgtgtg tgtgtgtgca 1580caataaatag gaaatgtaga aaccaagcaa gaaggcttag tagctcagtc tttaacaagg 1640gctagaaaag aatgtaatct gatatggaag gatagcagct tctaattttc aatcatctgt 1700tgatatactg tgaaacttat tttattaaat taatatttat taaatggaaa tatgcttttc 1760tggtttataa ctactaaaaa tatcataggg aggataaaag taaataagtg aaagttaatg 1820ccaatagaaa aattcaagag ataatgtaca atgtcagaaa agggattctt tatgtgtaaa 1880tggggataat acctatttca caaggttgtt ctgaggattg atacgttttg agtatgtatt 1940tgtacactat ctggcacata tgcgctcaat aaacgtgttt ctcctttaaa aaaaaaaaaa 2000aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaanaaaa taaaaaaaaa gggcggccgc 20606209PRTHomo sapiens 6Met Thr Met Asp Gly Leu Leu Tyr Asp Leu Thr Glu Lys Gln Val Tyr1 5 10 15His Ile Gly Lys Gln Val Leu Leu Ala Leu Glu Phe Leu Gln Glu Lys 20 25 30His Leu Phe His Gly Asp Val Ala Ala Arg Asn Ile Leu Met Gln Ser 35 40 45Asp Leu Thr Ala Lys Leu Cys Gly Leu Gly Leu Ala Tyr Glu Val Tyr 50 55 60Thr Arg Gly Ala Ile Ser Ser Thr Gln Thr Ile Pro Leu Lys Trp Leu65 70 75 80Ala Pro Glu Arg Leu Leu Leu Arg Pro Ala Ser Ile Arg Ala Asp Val 85 90 95Trp Ser Phe Gly Ile Leu Leu Tyr Glu Met Val Thr Leu Gly Ala Pro 100 105 110Pro Tyr Pro Glu Val Pro Pro Thr Ser Ile Leu Glu His Leu Gln Arg 115 120 125Arg Lys Ile Met Lys Arg Pro Ser Ser Cys Thr His Thr Met Tyr Ser 130 135 140Ile Met Lys Ser Cys Trp Arg Trp Arg Glu Ala Asp Arg Pro Ser Pro145 150 155 160Arg Glu Leu Arg Leu Arg Leu Glu Ala Ala Ile Lys Thr Ala Asp Asp 165 170 175Glu Ala Val Leu Gln Val Pro Glu Leu Val Val Pro Glu Leu Tyr Ala 180 185 190Ala Val Ala Gly Ile Arg Val Glu Ser Leu Phe Tyr Asn Tyr Ser Met 195 200 205Leu 71697DNAHomo sapiensCDS(2)...(1492) 7g gag aac cag gag ctc gtc ggc aaa ggc ggg ttc ggc aca gtg ttc cgg 49 Glu Asn Gln Glu Leu Val Gly Lys Gly Gly Phe Gly Thr Val Phe Arg 1 5 10 15gcg caa cat agg aag tgg ggc tac gat gtg gcg gtc aag atc gta aac 97Ala Gln His Arg Lys Trp Gly Tyr Asp Val Ala Val Lys Ile Val Asn 20 25 30tcg aag gcg ata tcc agg gag gtc aag gcc atg gca agt ctg gat aac 145Ser Lys Ala Ile Ser Arg Glu Val Lys Ala Met Ala Ser Leu Asp Asn 35 40 45gaa ttc gtg ctg cgc cta gaa ggg gtt atc gag aag gtg aac tgg gac 193Glu Phe Val Leu Arg Leu Glu Gly Val Ile Glu Lys Val Asn Trp Asp 50 55 60caa gat ccc aag ccg gct ctg gtg act aaa ttc atg gag aac ggc tcc 241Gln Asp Pro Lys Pro Ala Leu Val Thr Lys Phe Met Glu Asn Gly Ser65 70 75 80ttg tcg ggg ctg ctg cag tcc cag tgc cct cgg ccc tgg ccg ctc ctt 289Leu Ser Gly Leu Leu Gln Ser Gln Cys Pro Arg Pro Trp Pro Leu Leu 85 90 95tgc cgc ctg ctg aaa gaa gtg gtg ctt ggg atg ttt tac ctg cac gac 337Cys Arg Leu Leu Lys Glu Val Val Leu Gly Met Phe Tyr Leu His Asp 100 105 110cag aac ccg gtg ctc ctg cac cgg gac ctc aag cca tcc aac gtc ctg 385Gln Asn

Pro Val Leu Leu His Arg Asp Leu Lys Pro Ser Asn Val Leu 115 120 125ctg gac cca gag ctg cac gtc aag ctg gca gat ttt ggc ctg tcc aca 433Leu Asp Pro Glu Leu His Val Lys Leu Ala Asp Phe Gly Leu Ser Thr 130 135 140ttt cag gga ggc tca cag tca ggg aca ggg tcc ggg gag cca ggg ggc 481Phe Gln Gly Gly Ser Gln Ser Gly Thr Gly Ser Gly Glu Pro Gly Gly145 150 155 160acc ctg ggc tac ttg gcc cca gaa ctg ttt gtt aac gta aac cgg aag 529Thr Leu Gly Tyr Leu Ala Pro Glu Leu Phe Val Asn Val Asn Arg Lys 165 170 175gcc tcc aca gcc agt gac gtc tac agc ttc ggg atc cta atg tgg gca 577Ala Ser Thr Ala Ser Asp Val Tyr Ser Phe Gly Ile Leu Met Trp Ala 180 185 190gtg ctt gct gga aga gaa gtt gag ttg cca acc gaa cca tca ctc gtg 625Val Leu Ala Gly Arg Glu Val Glu Leu Pro Thr Glu Pro Ser Leu Val 195 200 205tac gaa gca gtg tgc aac agg cag aac cgg cct tca ttg gct gag ctg 673Tyr Glu Ala Val Cys Asn Arg Gln Asn Arg Pro Ser Leu Ala Glu Leu 210 215 220ccc caa gcc ggg cct gag act ccc ggc tta gaa gga ctg aag gag cta 721Pro Gln Ala Gly Pro Glu Thr Pro Gly Leu Glu Gly Leu Lys Glu Leu225 230 235 240atg cag ctc tgc tgg agc agt gag ccc aag gac aga ccc tcc ttc cag 769Met Gln Leu Cys Trp Ser Ser Glu Pro Lys Asp Arg Pro Ser Phe Gln 245 250 255gaa tgc cta cca aaa act gat gaa gtc ttc cag atg gtg gag aac aat 817Glu Cys Leu Pro Lys Thr Asp Glu Val Phe Gln Met Val Glu Asn Asn 260 265 270atg aat gct gct gtc tcc acg gta aag gat ttc ctg tct cag ctc agg 865Met Asn Ala Ala Val Ser Thr Val Lys Asp Phe Leu Ser Gln Leu Arg 275 280 285agc agc aat agg aga ttt tct atc cca gag tca ggc caa gga ggg aca 913Ser Ser Asn Arg Arg Phe Ser Ile Pro Glu Ser Gly Gln Gly Gly Thr 290 295 300gaa atg gat ggc ttt agg aga acc ata gaa aac cag cac tct cgt aat 961Glu Met Asp Gly Phe Arg Arg Thr Ile Glu Asn Gln His Ser Arg Asn305 310 315 320gat gtc atg gtt tct gag tgg cta aac aaa ctg aat cta gag gag cct 1009Asp Val Met Val Ser Glu Trp Leu Asn Lys Leu Asn Leu Glu Glu Pro 325 330 335ccc agc tct gtt cct aaa aaa tgc ccg agc ctt acc aag agg agc agg 1057Pro Ser Ser Val Pro Lys Lys Cys Pro Ser Leu Thr Lys Arg Ser Arg 340 345 350gca caa gag gag cag gtt cca caa gcc tgg aca gca ggc aca tct tca 1105Ala Gln Glu Glu Gln Val Pro Gln Ala Trp Thr Ala Gly Thr Ser Ser 355 360 365gat tcg atg gcc caa cct ccc cag act cca gag acc tca act ttc aga 1153Asp Ser Met Ala Gln Pro Pro Gln Thr Pro Glu Thr Ser Thr Phe Arg 370 375 380aac cag atg ccc agc cct acc tca act gga aca cca agt cct gga ccc 1201Asn Gln Met Pro Ser Pro Thr Ser Thr Gly Thr Pro Ser Pro Gly Pro385 390 395 400cga ggg aat cag ggg gct gag aga caa ggc atg aac tgg tcc tgc agg 1249Arg Gly Asn Gln Gly Ala Glu Arg Gln Gly Met Asn Trp Ser Cys Arg 405 410 415acc ccg gag cca aat cca gta aca ggg cga ccg ctc gtt aac ata tac 1297Thr Pro Glu Pro Asn Pro Val Thr Gly Arg Pro Leu Val Asn Ile Tyr 420 425 430aac tgc tct ggg gtg caa gtt gga gac aac aac tac ttg act atg caa 1345Asn Cys Ser Gly Val Gln Val Gly Asp Asn Asn Tyr Leu Thr Met Gln 435 440 445cag aca act gcc ttg ccc aca tgg ggc ttg gca cct tcg ggc aag ggg 1393Gln Thr Thr Ala Leu Pro Thr Trp Gly Leu Ala Pro Ser Gly Lys Gly 450 455 460agg ggc ttg cag cac ccc cca cca gta ggt tcg caa gaa ggc cct aaa 1441Arg Gly Leu Gln His Pro Pro Pro Val Gly Ser Gln Glu Gly Pro Lys465 470 475 480gat cct gaa gcc tgg agc agg cca cag ggt tgg tat aat cat agc ggg 1489Asp Pro Glu Ala Trp Ser Arg Pro Gln Gly Trp Tyr Asn His Ser Gly 485 490 495aaa taaagcacct tccaagcttg cctccaagag ttacgagtta aggaagagtg 1542Lysccaccccttg aggcccctga cttccttcta gggcagtctg gcctgcccac aaactgactt 1602tgtgacctgt cccccaggag tcaataaaca tgatggaatg ctaaaaaaaa aaaaaaaaaa 1662aaaaaaaaaa aaaaaaaaaa aaaaggggcg gccgc 16978497PRTHomo sapiens 8Glu Asn Gln Glu Leu Val Gly Lys Gly Gly Phe Gly Thr Val Phe Arg1 5 10 15Ala Gln His Arg Lys Trp Gly Tyr Asp Val Ala Val Lys Ile Val Asn 20 25 30Ser Lys Ala Ile Ser Arg Glu Val Lys Ala Met Ala Ser Leu Asp Asn 35 40 45Glu Phe Val Leu Arg Leu Glu Gly Val Ile Glu Lys Val Asn Trp Asp 50 55 60Gln Asp Pro Lys Pro Ala Leu Val Thr Lys Phe Met Glu Asn Gly Ser65 70 75 80Leu Ser Gly Leu Leu Gln Ser Gln Cys Pro Arg Pro Trp Pro Leu Leu 85 90 95Cys Arg Leu Leu Lys Glu Val Val Leu Gly Met Phe Tyr Leu His Asp 100 105 110Gln Asn Pro Val Leu Leu His Arg Asp Leu Lys Pro Ser Asn Val Leu 115 120 125Leu Asp Pro Glu Leu His Val Lys Leu Ala Asp Phe Gly Leu Ser Thr 130 135 140Phe Gln Gly Gly Ser Gln Ser Gly Thr Gly Ser Gly Glu Pro Gly Gly145 150 155 160Thr Leu Gly Tyr Leu Ala Pro Glu Leu Phe Val Asn Val Asn Arg Lys 165 170 175Ala Ser Thr Ala Ser Asp Val Tyr Ser Phe Gly Ile Leu Met Trp Ala 180 185 190Val Leu Ala Gly Arg Glu Val Glu Leu Pro Thr Glu Pro Ser Leu Val 195 200 205Tyr Glu Ala Val Cys Asn Arg Gln Asn Arg Pro Ser Leu Ala Glu Leu 210 215 220Pro Gln Ala Gly Pro Glu Thr Pro Gly Leu Glu Gly Leu Lys Glu Leu225 230 235 240Met Gln Leu Cys Trp Ser Ser Glu Pro Lys Asp Arg Pro Ser Phe Gln 245 250 255Glu Cys Leu Pro Lys Thr Asp Glu Val Phe Gln Met Val Glu Asn Asn 260 265 270Met Asn Ala Ala Val Ser Thr Val Lys Asp Phe Leu Ser Gln Leu Arg 275 280 285Ser Ser Asn Arg Arg Phe Ser Ile Pro Glu Ser Gly Gln Gly Gly Thr 290 295 300Glu Met Asp Gly Phe Arg Arg Thr Ile Glu Asn Gln His Ser Arg Asn305 310 315 320Asp Val Met Val Ser Glu Trp Leu Asn Lys Leu Asn Leu Glu Glu Pro 325 330 335Pro Ser Ser Val Pro Lys Lys Cys Pro Ser Leu Thr Lys Arg Ser Arg 340 345 350Ala Gln Glu Glu Gln Val Pro Gln Ala Trp Thr Ala Gly Thr Ser Ser 355 360 365Asp Ser Met Ala Gln Pro Pro Gln Thr Pro Glu Thr Ser Thr Phe Arg 370 375 380Asn Gln Met Pro Ser Pro Thr Ser Thr Gly Thr Pro Ser Pro Gly Pro385 390 395 400Arg Gly Asn Gln Gly Ala Glu Arg Gln Gly Met Asn Trp Ser Cys Arg 405 410 415Thr Pro Glu Pro Asn Pro Val Thr Gly Arg Pro Leu Val Asn Ile Tyr 420 425 430Asn Cys Ser Gly Val Gln Val Gly Asp Asn Asn Tyr Leu Thr Met Gln 435 440 445Gln Thr Thr Ala Leu Pro Thr Trp Gly Leu Ala Pro Ser Gly Lys Gly 450 455 460Arg Gly Leu Gln His Pro Pro Pro Val Gly Ser Gln Glu Gly Pro Lys465 470 475 480Asp Pro Glu Ala Trp Ser Arg Pro Gln Gly Trp Tyr Asn His Ser Gly 485 490 495Lys9981DNAHomo sapiensmisc_feature(1)...(981)n=A,T,C or G 9cgcgcagagg gcggtggcct gggctggccg aaccatggcg gccccggagc cggcgccgag 60gcgggcccgg gaacgggagc gggagcggga ggacgagagc gaggacgaga gcgacatcct 120ggaggaaagc ccgtgtggtc gctggcaaaa gcgacgggag caggtaaacc aagggaacat 180gccagggctt cagagcacct tcctagccat ggacacggag gagggggtag aggtggtgtg 240gaacgagctc cacttcggag acaggaaggc cttcgcggcg cacgaggaga agatccagac 300cgtgttcgag cagctggtgc tggtggacca cccgaacatc gtgaagttgc acaagtactg 360gctggatacc tctgaggcct gcgcgagggt catcttcatc acagagtacg tgtcatcagg 420cagcctcaag caattcctca aaaagaccaa gaagaaccac aaggccatga acgcccgggc 480ctggaagcgc tggtgcacgc agatcctgtc tgcgctcagc ttcctgcacg cctgcagccc 540cccaatcatc cacgggaacc tgaccagcga caccatcttc attcagcaca acggcctcat 600caagatcggc tccgtgtggc accgaatctt ctccaatgca cttccagatg atctccgaag 660ccccatccgc gctgagcgag aggaacttcg gaacctgcac ttcttccccc cagagtatgg 720agaggtggcc gatgggaccg ctgtggacat cttcttcttt gggatgtgtg cgctggagat 780ggctgtactg gaaatccaga ccaatgggga cacccgggtc acagaggagg ccattgctcg 840cgccaggcac tcgctgagtg accccaacat gcgggagttc atcctttgct gcctggcccg 900ggaccctgcc cgncggccct ctgtccacag cctcctcttc cacncgcgtg ctcttngagg 960tgcactcgct gaagctcctg g 98110326PRTHomo sapiensVARIANT(1)...(326)Xaa = Any Amino Acid 10Ala Gln Arg Ala Val Ala Trp Ala Gly Arg Thr Met Ala Ala Pro Glu1 5 10 15Pro Ala Pro Arg Arg Ala Arg Glu Arg Glu Arg Glu Arg Glu Asp Glu 20 25 30Ser Glu Asp Glu Ser Asp Ile Leu Glu Glu Ser Pro Cys Gly Arg Trp 35 40 45Gln Lys Arg Arg Glu Gln Val Asn Gln Gly Asn Met Pro Gly Leu Gln 50 55 60Ser Thr Phe Leu Ala Met Asp Thr Glu Glu Gly Val Glu Val Val Trp65 70 75 80Asn Glu Leu His Phe Gly Asp Arg Lys Ala Phe Ala Ala His Glu Glu 85 90 95Lys Ile Gln Thr Val Phe Glu Gln Leu Val Leu Val Asp His Pro Asn 100 105 110Ile Val Lys Leu His Lys Tyr Trp Leu Asp Thr Ser Glu Ala Cys Ala 115 120 125Arg Val Ile Phe Ile Thr Glu Tyr Val Ser Ser Gly Ser Leu Lys Gln 130 135 140Phe Leu Lys Lys Thr Lys Lys Asn His Lys Ala Met Asn Ala Arg Ala145 150 155 160Trp Lys Arg Trp Cys Thr Gln Ile Leu Ser Ala Leu Ser Phe Leu His 165 170 175Ala Cys Ser Pro Pro Ile Ile His Gly Asn Leu Thr Ser Asp Thr Ile 180 185 190Phe Ile Gln His Asn Gly Leu Ile Lys Ile Gly Ser Val Trp His Arg 195 200 205Ile Phe Ser Asn Ala Leu Pro Asp Asp Leu Arg Ser Pro Ile Arg Ala 210 215 220Glu Arg Glu Glu Leu Arg Asn Leu His Phe Phe Pro Pro Glu Tyr Gly225 230 235 240Glu Val Ala Asp Gly Thr Ala Val Asp Ile Phe Phe Phe Gly Met Cys 245 250 255Ala Leu Glu Met Ala Val Leu Glu Ile Gln Thr Asn Gly Asp Thr Arg 260 265 270Val Thr Glu Glu Ala Ile Ala Arg Ala Arg His Ser Leu Ser Asp Pro 275 280 285Asn Met Arg Glu Phe Ile Leu Cys Cys Leu Ala Arg Asp Pro Ala Arg 290 295 300Arg Pro Ser Val His Ser Leu Leu Phe His Xaa Arg Ala Leu Xaa Gly305 310 315 320Ala Leu Ala Glu Ala Pro 32511518DNAHomo sapiensmisc_feature(1)...(518)n=A,T,C or G 11aaacggaatt caattgcagg atttcctcca cgtgtggagc cgtcttgaag agtttgangg 60aggtggtgga ggagaaggaa atgtgagcca ggtgggaaga gtttggccat cttcgtatcg 120agctcttata agtgcctttt ccagactgac gcgtttggat gatttcacct gtgaaaaaat 180agggtctggc ttcttttctg aagtgttcaa ggtacgacac cgagcttctg gtcaggtgat 240ggctcttaag atgaacacat tgagcagtaa ccgggcaaac atgctgaaag aagtacagct 300catgaataga ctctcccatc ccaacatcct taggttcatg ggtgtatgtg ttcatcaagg 360acaattgcat gcacttacag agtatatcaa ctccgggaac ctggaacagt tgctagacag 420taacctgcat ttgccttgga ctgtgagggt aaaactggcc tatgacatag cagtgggcct 480cagctacctt cacttcaaag gcatttttca tcgggacc 51812172PRTHomo sapiensVARIANT(1)...(172)Xaa = Any Amino Acid 12Asn Gly Ile Gln Leu Gln Asp Phe Leu His Val Trp Ser Arg Leu Glu1 5 10 15Glu Phe Xaa Gly Gly Gly Gly Gly Glu Gly Asn Val Ser Gln Val Gly 20 25 30Arg Val Trp Pro Ser Ser Tyr Arg Ala Leu Ile Ser Ala Phe Ser Arg 35 40 45Leu Thr Arg Leu Asp Asp Phe Thr Cys Glu Lys Ile Gly Ser Gly Phe 50 55 60Phe Ser Glu Val Phe Lys Val Arg His Arg Ala Ser Gly Gln Val Met65 70 75 80Ala Leu Lys Met Asn Thr Leu Ser Ser Asn Arg Ala Asn Met Leu Lys 85 90 95Glu Val Gln Leu Met Asn Arg Leu Ser His Pro Asn Ile Leu Arg Phe 100 105 110Met Gly Val Cys Val His Gln Gly Gln Leu His Ala Leu Thr Glu Tyr 115 120 125Ile Asn Ser Gly Asn Leu Glu Gln Leu Leu Asp Ser Asn Leu His Leu 130 135 140Pro Trp Thr Val Arg Val Lys Leu Ala Tyr Asp Ile Ala Val Gly Leu145 150 155 160Ser Tyr Leu His Phe Lys Gly Ile Phe His Arg Asp 165 170131737DNAHomo sapiensCDS(275)...(1522) 13accctactaa agggaacaaa agctggagct ccaccgcggt ggcggccgct ctagaactag 60tggatccccc gggctgcagg aattcggcac gagtaacagc ccacctccta gccccgggct 120acgcgccgcc agcccagtaa ccccactttt gtgtgtcctc ccaggccccg atcgaaaagc 180ctgggagggc cgccgaacta cccccggagg gaggagccag tccgaaccca aggcgccacc 240gccgcagaag cggagcgagg cagcattcgc ctcc atg gcc cac tcg ccg gtg gct 295 Met Ala His Ser Pro Val Ala 1 5gtc caa gtg cct ggg atg cag aat aac ata gct gat cca gaa gaa ctg 343Val Gln Val Pro Gly Met Gln Asn Asn Ile Ala Asp Pro Glu Glu Leu 10 15 20ttc aca aaa tta gag cgc att ggg aaa ggc tca ttt ggg gaa gtt ttc 391Phe Thr Lys Leu Glu Arg Ile Gly Lys Gly Ser Phe Gly Glu Val Phe 25 30 35aaa gga att gat aac cgt acc cag caa gtc gtt gct att aaa atc ata 439Lys Gly Ile Asp Asn Arg Thr Gln Gln Val Val Ala Ile Lys Ile Ile40 45 50 55gac ctt gag gaa gcc gaa gat gaa ata gaa gac att cag caa gaa ata 487Asp Leu Glu Glu Ala Glu Asp Glu Ile Glu Asp Ile Gln Gln Glu Ile 60 65 70act gtc ttg agt caa tgt gac agc tca tat gta aca aaa tac tat ggg 535Thr Val Leu Ser Gln Cys Asp Ser Ser Tyr Val Thr Lys Tyr Tyr Gly 75 80 85tca tat tta aag ggg tct aaa tta tgg ata ata atg gaa tac ctg ggc 583Ser Tyr Leu Lys Gly Ser Lys Leu Trp Ile Ile Met Glu Tyr Leu Gly 90 95 100ggt ggt tca gca ctg gat ctt ctt cga gct ggt cca ttt gat gag ttc 631Gly Gly Ser Ala Leu Asp Leu Leu Arg Ala Gly Pro Phe Asp Glu Phe 105 110 115cag att gct acc atg cta aag gaa att tta aaa ggt ctg gac tat ctg 679Gln Ile Ala Thr Met Leu Lys Glu Ile Leu Lys Gly Leu Asp Tyr Leu120 125 130 135cat tca gaa aag aaa att cac cga gac ata aaa gct gcc aat gtc ttg 727His Ser Glu Lys Lys Ile His Arg Asp Ile Lys Ala Ala Asn Val Leu 140 145 150ctc tca gaa caa gga gat gtt aaa ctt gct gat ttt gga gtt gct ggt 775Leu Ser Glu Gln Gly Asp Val Lys Leu Ala Asp Phe Gly Val Ala Gly 155 160 165cag ctg aca gat aca cag att aaa aga aat acc ttt gtg gga act cca 823Gln Leu Thr Asp Thr Gln Ile Lys Arg Asn Thr Phe Val Gly Thr Pro 170 175 180ttt tgg atg gct cct gaa gtt att caa cag tca gct tat gac tca aaa 871Phe Trp Met Ala Pro Glu Val Ile Gln Gln Ser Ala Tyr Asp Ser Lys 185 190 195gct gac att tgg tca ttg gga att act gct att gaa cta gcc aag gga 919Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu Ala Lys Gly200 205 210 215gag cca cct aac tcc gat atg cat cca atg aga gtt ctg ttt ctt att 967Glu Pro Pro Asn Ser Asp Met His Pro Met Arg Val Leu Phe Leu Ile 220 225 230ccc aaa aac aat cct cca act ctt gtt gga gac ttt act aag tct ttt 1015Pro Lys Asn Asn Pro Pro Thr Leu Val Gly Asp Phe Thr Lys Ser Phe 235 240 245aag gag ttt att gat gct tgc ctg aac aaa gat cca tca ttt cgt cct 1063Lys Glu Phe Ile Asp Ala Cys Leu Asn Lys Asp Pro Ser Phe Arg Pro 250 255 260aca gca aaa gaa ctt ctg aaa cac aaa ttc att gta aaa aat tca aag 1111Thr Ala Lys Glu Leu Leu Lys His Lys Phe Ile Val Lys Asn Ser Lys 265 270 275aag act tct tat ctg act gaa ctg ata gat cgt ttt aag aga tgg aag 1159Lys Thr Ser Tyr Leu Thr Glu Leu Ile Asp Arg Phe Lys Arg Trp Lys280 285 290 295gca gaa gga cac agt gat gat gaa tct gat tcc gag ggc tct gat tcg

1207Ala Glu Gly His Ser Asp Asp Glu Ser Asp Ser Glu Gly Ser Asp Ser 300 305 310gaa tct acc agc agg gaa aac aat act cat cct gaa tgg agc ttt acc 1255Glu Ser Thr Ser Arg Glu Asn Asn Thr His Pro Glu Trp Ser Phe Thr 315 320 325acc gta cga aag aag cct gat cca aag aaa gta cag aat ggg gca gag 1303Thr Val Arg Lys Lys Pro Asp Pro Lys Lys Val Gln Asn Gly Ala Glu 330 335 340caa gat ctt gtg caa acc ctg agt tgt ttg tct atg ata atc aca cct 1351Gln Asp Leu Val Gln Thr Leu Ser Cys Leu Ser Met Ile Ile Thr Pro 345 350 355gca ttt gct gaa ctt aaa cag cag gac gag aat aac gct agc agg aat 1399Ala Phe Ala Glu Leu Lys Gln Gln Asp Glu Asn Asn Ala Ser Arg Asn360 365 370 375cag gcg att gaa gaa ctc gag aaa agt att gct gtg gct gaa gcc gcc 1447Gln Ala Ile Glu Glu Leu Glu Lys Ser Ile Ala Val Ala Glu Ala Ala 380 385 390tgt ccc ggc atc aca gat aaa atg gtg aag aaa cta att gaa aaa ttt 1495Cys Pro Gly Ile Thr Asp Lys Met Val Lys Lys Leu Ile Glu Lys Phe 395 400 405caa aag tgt tca gca gac gaa tcc ccc taagaaactt attattggct 1542Gln Lys Cys Ser Ala Asp Glu Ser Pro 410 415tctgkttcat atggacccag agagccccac caaacctacg tcaagataac aatgcttaac 1602ccatgagctc catgtgcctt ttggatcttt gcaacacttg aagatttgga agaagctatt 1662aaactatttt ggggatggcg gttatcattt tatattttgg aaggattatt tgtaagggat 1722aacttttaat actat 173714416PRTHomo sapiens 14Met Ala His Ser Pro Val Ala Val Gln Val Pro Gly Met Gln Asn Asn1 5 10 15Ile Ala Asp Pro Glu Glu Leu Phe Thr Lys Leu Glu Arg Ile Gly Lys 20 25 30Gly Ser Phe Gly Glu Val Phe Lys Gly Ile Asp Asn Arg Thr Gln Gln 35 40 45Val Val Ala Ile Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile 50 55 60Glu Asp Ile Gln Gln Glu Ile Thr Val Leu Ser Gln Cys Asp Ser Ser65 70 75 80Tyr Val Thr Lys Tyr Tyr Gly Ser Tyr Leu Lys Gly Ser Lys Leu Trp 85 90 95Ile Ile Met Glu Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Arg 100 105 110Ala Gly Pro Phe Asp Glu Phe Gln Ile Ala Thr Met Leu Lys Glu Ile 115 120 125Leu Lys Gly Leu Asp Tyr Leu His Ser Glu Lys Lys Ile His Arg Asp 130 135 140Ile Lys Ala Ala Asn Val Leu Leu Ser Glu Gln Gly Asp Val Lys Leu145 150 155 160Ala Asp Phe Gly Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg 165 170 175Asn Thr Phe Val Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Gln 180 185 190Gln Ser Ala Tyr Asp Ser Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr 195 200 205Ala Ile Glu Leu Ala Lys Gly Glu Pro Pro Asn Ser Asp Met His Pro 210 215 220Met Arg Val Leu Phe Leu Ile Pro Lys Asn Asn Pro Pro Thr Leu Val225 230 235 240Gly Asp Phe Thr Lys Ser Phe Lys Glu Phe Ile Asp Ala Cys Leu Asn 245 250 255Lys Asp Pro Ser Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys 260 265 270Phe Ile Val Lys Asn Ser Lys Lys Thr Ser Tyr Leu Thr Glu Leu Ile 275 280 285Asp Arg Phe Lys Arg Trp Lys Ala Glu Gly His Ser Asp Asp Glu Ser 290 295 300Asp Ser Glu Gly Ser Asp Ser Glu Ser Thr Ser Arg Glu Asn Asn Thr305 310 315 320His Pro Glu Trp Ser Phe Thr Thr Val Arg Lys Lys Pro Asp Pro Lys 325 330 335Lys Val Gln Asn Gly Ala Glu Gln Asp Leu Val Gln Thr Leu Ser Cys 340 345 350Leu Ser Met Ile Ile Thr Pro Ala Phe Ala Glu Leu Lys Gln Gln Asp 355 360 365Glu Asn Asn Ala Ser Arg Asn Gln Ala Ile Glu Glu Leu Glu Lys Ser 370 375 380Ile Ala Val Ala Glu Ala Ala Cys Pro Gly Ile Thr Asp Lys Met Val385 390 395 400Lys Lys Leu Ile Glu Lys Phe Gln Lys Cys Ser Ala Asp Glu Ser Pro 405 410 41515645PRTArabidopsis thaliana 15Met Phe Phe Leu Val Phe Ala Phe Phe Leu Ile Ser Pro Val Arg Ser1 5 10 15Ser Asp Val Glu Ala Leu Leu Ser Leu Lys Ser Ser Ile Asp Pro Ser 20 25 30Asn Ser Ile Pro Trp Arg Gly Thr Asp Pro Cys Asn Trp Glu Gly Val 35 40 45Lys Lys Cys Met Lys Gly Arg Val Ser Lys Leu Val Leu Glu Asn Leu 50 55 60Asn Leu Ser Gly Ser Leu Asn Gly Lys Ser Leu Asn Gln Leu Asp Gln65 70 75 80Leu Arg Val Leu Ser Phe Lys Gly Asn Ser Leu Ser Gly Ser Ile Pro 85 90 95Asn Leu Ser Gly Leu Val Asn Leu Lys Ser Leu Tyr Leu Asn Asp Asn 100 105 110Asn Phe Ser Gly Glu Phe Pro Glu Ser Leu Thr Ser Leu His Arg Leu 115 120 125Lys Thr Val Val Leu Ser Arg Asn Arg Phe Ser Gly Lys Ile Pro Ser 130 135 140Ser Leu Leu Arg Leu Ser Arg Leu Tyr Thr Phe Tyr Val Gln Asp Asn145 150 155 160Leu Phe Ser Gly Ser Ile Pro Pro Leu Asn Gln Ala Thr Leu Arg Phe 165 170 175Phe Asn Val Ser Asn Asn Gln Leu Ser Gly His Ile Pro Pro Thr Gln 180 185 190Ala Leu Asn Arg Phe Asn Glu Ser Ser Phe Thr Asp Asn Ile Ala Leu 195 200 205Cys Gly Asp Gln Ile Gln Asn Ser Cys Asn Asp Thr Thr Gly Ile Thr 210 215 220Ser Thr Pro Ser Ala Lys Pro Ala Ile Pro Val Ala Lys Thr Arg Ser225 230 235 240Arg Thr Lys Leu Ile Gly Ile Ile Ser Gly Ser Ile Cys Gly Gly Ile 245 250 255Leu Ile Leu Leu Leu Thr Phe Leu Leu Ile Cys Leu Leu Trp Arg Arg 260 265 270Lys Arg Ser Lys Ser Lys Arg Glu Glu Arg Arg Ser Lys Arg Val Ala 275 280 285Glu Ser Lys Glu Ala Lys Thr Ala Glu Thr Glu Glu Gly Thr Ser Asp 290 295 300Gln Lys Asn Lys Arg Phe Ser Trp Glu Lys Glu Ser Glu Glu Gly Ser305 310 315 320Val Gly Thr Leu Val Phe Leu Gly Arg Asp Ile Thr Val Val Arg Tyr 325 330 335Thr Met Asp Asp Leu Leu Lys Ala Ser Ala Glu Thr Leu Gly Arg Gly 340 345 350Thr Leu Gly Ser Thr Tyr Lys Ala Val Met Glu Ser Gly Phe Ile Ile 355 360 365Thr Val Lys Arg Leu Lys Asp Ala Gly Phe Pro Arg Met Asp Glu Phe 370 375 380Lys Arg His Ile Glu Ile Leu Gly Arg Leu Lys His Pro Asn Leu Val385 390 395 400Pro Leu Arg Ala Tyr Phe Gln Ala Lys Glu Glu Cys Leu Leu Val Tyr 405 410 415Asp Tyr Phe Pro Asn Gly Ser Leu Phe Ser Leu Ile His Gly Ser Lys 420 425 430Val Ser Gly Ser Gly Lys Pro Leu His Trp Thr Ser Cys Leu Lys Ile 435 440 445Ala Glu Asp Leu Ala Met Gly Leu Val Tyr Ile His Gln Asn Pro Gly 450 455 460Leu Thr His Gly Asn Leu Lys Ser Ser Asn Val Leu Leu Gly Pro Asp465 470 475 480Phe Glu Ser Cys Leu Thr Asp Tyr Gly Leu Ser Asp Leu His Asp Pro 485 490 495Tyr Ser Ile Glu Asp Thr Ser Ala Ala Ser Leu Phe Tyr Lys Ala Pro 500 505 510Glu Cys Arg Asp Leu Arg Lys Ala Ser Thr Gln Pro Ala Asp Val Tyr 515 520 525Ser Phe Gly Val Leu Leu Leu Glu Leu Leu Thr Gly Arg Thr Ser Phe 530 535 540Lys Asp Leu Val His Lys Tyr Gly Ser Asp Ile Ser Thr Trp Val Arg545 550 555 560Ala Val Arg Glu Glu Glu Thr Glu Val Ser Glu Glu Leu Asn Ala Ser 565 570 575Glu Glu Lys Leu Gln Ala Leu Leu Thr Ile Ala Thr Ala Cys Val Ala 580 585 590Val Lys Pro Glu Asn Arg Pro Ala Met Arg Glu Val Leu Lys Met Val 595 600 605Lys Asp Ala Arg Ala Glu Ala Ala Leu Phe Ser Phe Asn Ser Ser Asp 610 615 620His Ser Pro Gly Arg Trp Ser Asp Thr Ile Gln Ser Leu Pro Arg Glu625 630 635 640Asp His Met Ser Ile 64516645PRTArabidopsis thaliana 16Met Phe Phe Leu Val Phe Ala Phe Phe Leu Ile Ser Pro Val Arg Ser1 5 10 15Ser Asp Val Glu Ala Leu Leu Ser Leu Lys Ser Ser Ile Asp Pro Ser 20 25 30Asn Ser Ile Pro Trp Arg Gly Thr Asp Pro Cys Asn Trp Glu Gly Val 35 40 45Lys Lys Cys Met Lys Gly Arg Val Ser Lys Leu Val Leu Glu Asn Leu 50 55 60Asn Leu Ser Gly Ser Leu Asn Gly Lys Ser Leu Asn Gln Leu Asp Gln65 70 75 80Leu Arg Val Leu Ser Phe Lys Gly Asn Ser Leu Ser Gly Ser Ile Pro 85 90 95Asn Leu Ser Gly Leu Val Asn Leu Lys Ser Leu Tyr Leu Asn Asp Asn 100 105 110Asn Phe Ser Gly Glu Phe Pro Glu Ser Leu Thr Ser Leu His Arg Leu 115 120 125Lys Thr Val Val Leu Ser Arg Asn Arg Phe Ser Gly Lys Ile Pro Ser 130 135 140Ser Leu Leu Arg Leu Ser Arg Leu Tyr Thr Phe Tyr Val Gln Asp Asn145 150 155 160Leu Phe Ser Gly Ser Ile Pro Pro Leu Asn Gln Ala Thr Leu Arg Phe 165 170 175Phe Asn Val Ser Asn Asn Gln Leu Ser Gly His Ile Pro Pro Thr Gln 180 185 190Ala Leu Asn Arg Phe Asn Glu Ser Ser Phe Thr Asp Asn Ile Ala Leu 195 200 205Cys Gly Asp Gln Ile Gln Asn Ser Cys Asn Asp Thr Thr Gly Ile Thr 210 215 220Ser Thr Pro Ser Ala Lys Pro Ala Ile Pro Val Ala Lys Thr Arg Ser225 230 235 240Arg Thr Lys Leu Ile Gly Ile Ile Ser Gly Ser Ile Cys Gly Gly Ile 245 250 255Leu Ile Leu Leu Leu Thr Phe Leu Leu Ile Cys Leu Leu Trp Arg Arg 260 265 270Lys Arg Ser Lys Ser Lys Arg Glu Glu Arg Arg Ser Lys Arg Val Ala 275 280 285Glu Ser Lys Glu Ala Lys Thr Ala Glu Thr Glu Glu Gly Thr Ser Asp 290 295 300Gln Lys Asn Lys Arg Phe Ser Trp Glu Lys Glu Ser Glu Glu Gly Ser305 310 315 320Val Gly Thr Leu Val Phe Leu Gly Arg Asp Ile Thr Val Val Arg Tyr 325 330 335Thr Met Asp Asp Leu Leu Lys Ala Ser Ala Glu Thr Leu Gly Arg Gly 340 345 350Thr Leu Gly Ser Thr Tyr Lys Ala Val Met Glu Ser Gly Phe Ile Ile 355 360 365Thr Val Lys Arg Leu Lys Asp Ala Gly Phe Pro Arg Met Asp Glu Phe 370 375 380Lys Arg His Ile Glu Ile Leu Gly Arg Leu Lys His Pro Asn Leu Val385 390 395 400Pro Leu Arg Ala Tyr Phe Gln Ala Lys Glu Glu Cys Leu Leu Val Tyr 405 410 415Asp Tyr Phe Pro Asn Gly Ser Leu Phe Ser Leu Ile His Gly Ser Lys 420 425 430Val Ser Gly Ser Gly Lys Pro Leu His Trp Thr Ser Cys Leu Lys Ile 435 440 445Ala Glu Asp Leu Ala Met Gly Leu Val Tyr Ile His Gln Asn Pro Gly 450 455 460Leu Thr His Gly Asn Leu Lys Ser Ser Asn Val Leu Leu Gly Pro Asp465 470 475 480Phe Glu Ser Cys Leu Thr Asp Tyr Gly Leu Ser Asp Leu His Asp Pro 485 490 495Tyr Ser Ile Glu Asp Thr Ser Ala Ala Ser Leu Phe Tyr Lys Ala Pro 500 505 510Glu Cys Arg Asp Leu Arg Lys Ala Ser Thr Gln Pro Ala Asp Val Tyr 515 520 525Ser Phe Gly Val Leu Leu Leu Glu Leu Leu Thr Gly Arg Thr Ser Phe 530 535 540Lys Asp Leu Val His Lys Tyr Gly Ser Asp Ile Ser Thr Trp Val Arg545 550 555 560Ala Val Arg Glu Glu Glu Thr Glu Val Ser Glu Glu Leu Asn Ala Ser 565 570 575Glu Glu Lys Leu Gln Ala Leu Leu Thr Ile Ala Thr Ala Cys Val Ala 580 585 590Val Lys Pro Glu Asn Arg Pro Ala Met Arg Glu Val Leu Lys Met Val 595 600 605Lys Asp Ala Arg Ala Glu Ala Ala Leu Phe Ser Phe Asn Ser Ser Asp 610 615 620His Ser Pro Gly Arg Trp Ser Asp Thr Ile Gln Ser Leu Pro Arg Glu625 630 635 640Asp His Met Ser Ile 64517604PRTArabidopsis thaliana 17Ser Leu Lys Ser Ser Ile Asp Pro Ser Asn Ser Ile Ser Trp Arg Gly1 5 10 15Thr Asp Leu Cys Asn Trp Gln Gly Val Arg Glu Cys Met Asn Gly Arg 20 25 30Val Ser Lys Leu Val Leu Glu Tyr Leu Asn Leu Thr Gly Ser Leu Asn 35 40 45Glu Lys Ser Leu Asn Gln Leu Asp Gln Leu Arg Val Leu Ser Phe Lys 50 55 60Ala Asn Ser Leu Ser Gly Ser Ile Pro Asn Leu Ser Gly Leu Val Asn65 70 75 80Leu Lys Ser Val Tyr Leu Asn Asp Asn Asn Phe Ser Gly Asp Phe Pro 85 90 95Glu Ser Leu Thr Ser Leu His Arg Leu Lys Thr Ile Phe Leu Ser Gly 100 105 110Asn Arg Leu Ser Gly Arg Ile Pro Ser Ser Leu Leu Arg Leu Ser Arg 115 120 125Leu Tyr Thr Leu Asn Val Glu Asp Asn Leu Phe Thr Gly Ser Ile Pro 130 135 140Pro Leu Asn Gln Thr Ser Leu Arg Tyr Phe Asn Val Ser Asn Asn Lys145 150 155 160Leu Ser Gly Gln Ile Pro Leu Thr Arg Ala Leu Lys Gln Phe Asp Glu 165 170 175Ser Ser Phe Thr Gly Asn Val Ala Leu Cys Gly Asp Gln Ile Gly Lys 180 185 190Glu Gln Ser Glu Leu Ile Gly Ile Ile Ala Gly Ser Val Ala Gly Gly 195 200 205Val Leu Val Leu Ile Leu Leu Leu Thr Leu Leu Ile Val Cys Trp Arg 210 215 220Arg Lys Arg Arg Asn Gln Ala Pro Arg Glu Asp Arg Lys Gly Lys Gly225 230 235 240Ile Ala Glu Ala Glu Gly Ala Thr Thr Ala Glu Thr Glu Arg Asp Ile 245 250 255Glu Arg Lys Asp Arg Gly Phe Ser Trp Glu Arg Gly Glu Glu Gly Ala 260 265 270Val Gly Thr Leu Val Phe Leu Gly Thr Ser Asp Ser Gly Glu Thr Val 275 280 285Val Arg Tyr Thr Met Glu Asp Leu Leu Lys Ala Ser Ala Glu Thr Leu 290 295 300Gly Arg Gly Thr Leu Gly Ser Thr Tyr Lys Ala Val Met Glu Ser Gly305 310 315 320Phe Ile Val Thr Val Lys Arg Leu Lys Asn Ala Arg Tyr Pro Arg Met 325 330 335Glu Glu Phe Lys Arg His Val Glu Ile Leu Gly Gln Leu Lys His Pro 340 345 350Asn Leu Val Pro Leu Arg Ala Tyr Phe Gln Ala Lys Glu Glu Arg Leu 355 360 365Leu Val Tyr Asp Tyr Phe Pro Asn Gly Ser Leu Phe Thr Leu Ile His 370 375 380Gly Thr Arg Ala Ser Gly Ser Gly Lys Pro Leu His Trp Thr Ser Cys385 390 395 400Leu Lys Ile Ala Glu Asp Leu Ala Ser Ala Leu Leu Tyr Ile His Gln 405 410 415Asn Pro Gly Leu Thr His Gly Asn Leu Lys Ser Ser Asn Val Leu Leu 420 425 430Gly Pro Asp Phe Glu Ser Cys Leu Thr Asp Tyr Gly Leu Ser Thr Leu 435 440 445His Asp Pro Asp Ser Val Glu Glu Thr Ser Ala Val Ser Leu Phe Tyr 450 455 460Lys Ala Pro Glu Cys Arg Asp Pro Arg Lys Ala Ser Thr Gln Pro Ala465 470 475 480Asp Val Tyr Ser Phe Gly Val Leu Leu Leu Glu Leu Leu Thr Gly Arg 485 490 495Thr Pro Phe Gln Asp Leu Val Gln Glu Tyr Gly Ser Asp Ile Ser Arg 500 505 510Trp Val Arg Ala Val Arg Glu Glu Glu Thr Glu Ser Gly Glu

Glu Pro 515 520 525Thr Ser Ser Gly Asn Glu Ala Ser Glu Glu Lys Leu Gln Ala Leu Leu 530 535 540Ser Ile Ala Thr Val Cys Val Thr Ile Gln Pro Asp Asn Arg Pro Val545 550 555 560Met Arg Glu Val Leu Lys Met Val Arg Asp Ala Arg Ala Glu Ala Pro 565 570 575Phe Ser Ser Asn Ser Ser Glu His Ser Pro Gly Arg Trp Ser Asp Thr 580 585 590Val Gln Ser Leu Pro Arg Asp Asp Gln Val Ser Ile 595 60018328PRTC. elegans 18Met Ser Arg Asn His Glu Glu Asn Lys Arg Lys Thr Lys Asn Lys Glu1 5 10 15Tyr Lys Cys Met Lys Met Ser Thr Pro Thr Ser Asn Glu Ser Thr Ser 20 25 30Ser Ser Ser Asn Asn Ser Asp Gln Arg Val Leu Phe Pro Asp Ile Gln 35 40 45Arg Asp Asp Ile Gln Val Gly Asp His Ile Gly Val Gly Thr Phe Gly 50 55 60Ala Val Phe Ser Gly Asn Trp Thr Leu Pro Asp Gly Ser Gln Arg Thr65 70 75 80Ile Ala Leu Lys Lys Val Phe Val Leu Glu Lys Glu Ala Glu Ile Leu 85 90 95Ser Lys Ile Arg His Lys Asn Ile Ile Gln Phe Tyr Gly Ile Cys Lys 100 105 110Ala Thr Gly Asn Asp Phe Phe Ile Val Thr Glu Tyr Ala Glu Lys Gly 115 120 125Ser Leu Tyr Asp Phe Ile His Ser Glu Glu Ser Gln Ser Phe Ala Ser 130 135 140Ser Ser Gly Gly Asn Ser Phe Asp Val Val Val Lys Trp Ala Ser Gln145 150 155 160Ile Ala Ser Gly Ile Gln Tyr Leu His Tyr Asp Ala Val Asp Thr Ile 165 170 175Ile His Arg Asp Leu Lys Ser Lys Asn Val Val Leu Asp Lys Asn Leu 180 185 190Val Cys Lys Ile Cys Asp Phe Gly Thr Ser Lys Asp Leu Thr His Ser 195 200 205Cys Thr Ala Pro Ser Trp Gly Gly Thr Ala Ala Trp Met Ser Pro Glu 210 215 220Met Ile Leu Gln Ser Glu Gly Leu Thr Thr Ala Thr Asp Val Trp Ser225 230 235 240Tyr Gly Val Val Leu Trp Glu Ile Leu Ser Lys Glu Val Pro Tyr Lys 245 250 255Asp Tyr Ser Glu Phe Arg Ile Phe Thr Met Ile Thr Gln Ser Gly Ile 260 265 270Thr Leu Ala Ile Pro Pro Ser Cys Pro Ala Pro Leu Lys Gln Leu Met 275 280 285Ser Asn Cys Trp Lys Met Thr Pro Lys Asp Arg Ala Asn Met Arg Gln 290 295 300Ile Gln Gly Glu Leu Asn Arg Leu Ala Gly Asn Gln Lys Val Arg Val305 310 315 320Ser Lys Leu Ser Leu Ser Ser Val 32519394PRTHomo sapiens 19Ala Glu Leu Thr Leu Glu Glu Ile Ile Gly Ile Gly Gly Phe Gly Lys1 5 10 15Val Tyr Arg Ala Phe Trp Ile Gly Asp Glu Val Ala Val Lys Ala Ala 20 25 30Arg His Asp Pro Asp Glu Asp Ile Ser Gln Thr Ile Glu Asn Val Arg 35 40 45Gln Glu Ala Lys Leu Phe Ala Met Leu Lys His Pro Asn Ile Ile Ala 50 55 60Leu Arg Gly Val Cys Leu Lys Glu Pro Asn Leu Cys Leu Val Met Glu65 70 75 80Phe Ala Arg Gly Gly Pro Leu Asn Arg Val Leu Ser Gly Lys Arg Ile 85 90 95Pro Pro Asp Ile Leu Val Asn Trp Ala Val Gln Ile Ala Arg Gly Met 100 105 110Asn Tyr Leu His Asp Glu Ala Ile Val Pro Ile Ile His Arg Asp Leu 115 120 125Lys Ser Ser Asn Ile Leu Ile Leu Gln Lys Val Glu Asn Gly Asp Leu 130 135 140Ser Asn Lys Ile Leu Lys Ile Thr Asp Phe Gly Leu Ala Arg Glu Trp145 150 155 160His Arg Thr Thr Lys Met Ser Ala Ala Gly Thr Tyr Ala Trp Met Ala 165 170 175Pro Glu Val Ile Arg Ala Ser Met Phe Ser Lys Gly Ser Asp Val Trp 180 185 190Ser Tyr Gly Val Leu Leu Trp Glu Leu Leu Thr Gly Glu Val Pro Phe 195 200 205Arg Gly Ile Asp Gly Leu Arg Val Ala Tyr Gly Val Ala Met Asn Lys 210 215 220Leu Ala Leu Pro Ile Pro Ser Thr Cys Pro Glu Pro Phe Ala Lys Leu225 230 235 240Met Glu Asp Cys Trp Asn Pro Asp Pro His Ser Arg Pro Ser Phe Thr 245 250 255Asn Ile Leu Asp Gln Leu Thr Thr Ile Glu Glu Ser Gly Phe Phe Glu 260 265 270Met Pro Lys Asp Ser Phe His Cys Leu Gln Asp Asn Trp Lys His Glu 275 280 285Ile Gln Glu Met Phe Asp Gln Leu Arg Ala Lys Glu Lys Glu Leu Arg 290 295 300Thr Trp Glu Glu Glu Leu Thr Arg Ala Ala Leu Gln Gln Lys Asn Gln305 310 315 320Glu Glu Leu Leu Arg Arg Arg Glu Gln Glu Leu Ala Glu Arg Glu Ile 325 330 335Asp Ile Leu Glu Arg Glu Leu Asn Ile Ile Ile His Gln Leu Cys Gln 340 345 350Glu Lys Pro Arg Val Lys Lys Arg Lys Gly Lys Phe Arg Lys Ser Arg 355 360 365Leu Ala Gln Pro Val Leu Pro Phe Pro His Gly His Ser Arg Cys Pro 370 375 380Gly Gly Thr Gly Ser Ser Trp Gly Gly Gln385 39020370PRTavian 20Ala Asp Ser Pro Gly Leu Ala Arg Pro His Ala His Phe Ala Ser Ala1 5 10 15Gly Ala Asp Ala Ala Gly Gly Gly Ser Pro Val Leu Leu Leu Arg Thr 20 25 30Thr Ser Cys Cys Leu Glu Asp Leu Arg Pro Glu Leu Leu Glu Glu Val 35 40 45Lys Asp Ile Leu Ile Pro Glu Glu Arg Leu Ile Thr His Arg Ser Arg 50 55 60Val Ile Gly Arg Gly His Phe Gly Ser Val Tyr His Gly Thr Tyr Met65 70 75 80Asp Pro Leu Leu Gly Asn Leu His Cys Ala Val Lys Ser Leu His Arg 85 90 95Ile Thr Tyr Leu Glu Glu Val Glu Glu Phe Leu Arg Glu Gly Ile Leu 100 105 110Met Lys Gly Phe His His Pro Gln Val Leu Ser Leu Leu Gly Val Cys 115 120 125Leu Pro Arg His Gly Leu Pro Leu Val Val Leu Pro Tyr Met Arg His 130 135 140Gly Asp Leu Arg His Phe Val Arg Ala Gln Glu Arg Ser Pro Thr Val145 150 155 160Lys Glu Leu Ile Gly Phe Gly Leu Gln Val Ala Leu Gly Met Glu Tyr 165 170 175Leu Ala Gln Lys Lys Phe Val His Arg Asp Leu Ala Ala Arg Asn Cys 180 185 190Met Leu Asp Glu Thr Leu Thr Val Lys Val Ala Asp Phe Gly Leu Ala 195 200 205Arg Asp Val Phe Gly Lys Glu Tyr Tyr Ser Ile Arg Gln His Arg His 210 215 220Ala Lys Leu Pro Val Arg Trp Met Ala Leu Glu Ser Leu Gln Thr Gln225 230 235 240Lys Phe Thr Thr Lys Ser Asp Val Trp Ser Phe Gly Val Leu Met Trp 245 250 255Glu Leu Leu Thr Arg Gly Ala Ser Pro Tyr Pro Glu Val Asp Pro Tyr 260 265 270Asp Met Ala Arg Tyr Leu Leu Arg Gly Arg Arg Leu Pro Gln Pro Gln 275 280 285Pro Cys Pro Asp Thr Leu Tyr Gly Val Met Leu Ser Cys Trp Ala Pro 290 295 300Thr Pro Glu Glu Arg Pro Ser Phe Ser Gly Leu Val Cys Glu Leu Glu305 310 315 320Arg Val Leu Ala Ser Leu Glu Gly Glu His Tyr Ile Asn Met Ala Val 325 330 335Thr Tyr Val Asn Leu Glu Ser Gly Pro Pro Phe Pro Pro Ala Pro Arg 340 345 350Gly Gln Leu Pro Asp Ser Glu Asp Glu Glu Asp Glu Glu Glu Glu Val 355 360 365Ala Glu 37021596PRTavian 21Lys Leu Thr Met Leu Ala Pro Asn His Thr Asp Ile Leu Lys Val Leu1 5 10 15Ala Asn Ser Ser Arg Thr Gly Ile Arg Arg Lys Arg Asn Thr Ser His 20 25 30Leu Asp Asp Thr Cys Ser Asp Glu Val Gln Leu Trp Gly Pro Thr Ala 35 40 45Arg Ile Phe Ala Ser Ile Leu Ala Pro Gly Val Ala Ala Thr Gln Ala 50 55 60Leu Arg Glu Ile Glu Arg Leu Ala Cys Trp Ser Val Lys Gln Ala Asn65 70 75 80Leu Thr Thr Ser Leu Leu Gly Asp Leu Leu Asp Asp Val Thr Ser Ile 85 90 95Arg His Ala Val Leu Gln Asn Arg Ala Ala Ile Asp Phe Leu Leu Leu 100 105 110Ala His Gly His Gly Cys Glu Asp Ile Ala Gly Met Cys Cys Phe Asn 115 120 125Leu Ser Asp His Ser Glu Ser Ile Gln Lys Lys Phe Gln Leu Met Lys 130 135 140Lys His Val Asn Lys Ile Gly Val Asp Ser Asp Pro Ile Gly Ser Trp145 150 155 160Leu Arg Gly Leu Phe Gly Gly Ile Gly Glu Trp Ala Val His Leu Leu 165 170 175Lys Gly Leu Leu Leu Gly Leu Val Val Ile Leu Leu Leu Val Val Cys 180 185 190Leu Pro Cys Leu Leu Gln Phe Val Ser Ser Ser Ile Arg Lys Met Ile 195 200 205Asp Asn Ser Leu Gly Tyr Arg Glu Glu Cys Arg Lys Leu Gln Glu Ala 210 215 220Asn Arg Ala Asp Ser Pro Gly Leu Ala Arg Pro His Ala His Phe Ala225 230 235 240Ser Ala Gly Ala Asp Ala Ala Gly Gly Gly Ser Pro Val Leu Leu Leu 245 250 255Arg Thr Thr Ser Cys Cys Leu Glu Asp Leu Arg Pro Glu Leu Leu Glu 260 265 270Glu Val Lys Asp Ile Leu Ile Pro Glu Glu Arg Leu Ile Thr His Arg 275 280 285Ser Arg Val Ile Gly Arg Gly His Phe Gly Ser Val Tyr His Gly Thr 290 295 300Tyr Met Asp Pro Leu Leu Gly Asn Leu His Cys Ala Val Lys Ser Leu305 310 315 320His Arg Ile Thr Asp Leu Glu Glu Val Glu Glu Phe Leu Arg Glu Gly 325 330 335Ile Leu Met Lys Gly Phe His His Pro Gln Val Leu Ser Leu Leu Gly 340 345 350Val Cys Leu Pro Arg His Gly Leu Pro Leu Val Val Leu Pro Tyr Met 355 360 365Arg His Gly Asp Leu Arg His Phe Val Arg Ala Gln Glu Arg Ser Pro 370 375 380Thr Val Lys Glu Leu Ile Gly Phe Gly Leu Gln Val Ala Leu Gly Met385 390 395 400Glu Tyr Leu Ala Gln Lys Lys Phe Val His Arg Asp Leu Ala Ala Arg 405 410 415Asn Cys Met Leu Asp Glu Thr Leu Thr Val Lys Val Ala Asp Phe Gly 420 425 430Leu Ala Arg Asp Val Phe Gly Lys Glu Tyr Tyr Ser Ile Arg Gln His 435 440 445Arg His Ala Lys Leu Pro Val Arg Trp Met Ala Leu Glu Ser Leu Gln 450 455 460Thr Gln Lys Phe Thr Thr Lys Ser Asp Val Trp Ser Phe Gly Val Leu465 470 475 480Met Trp Glu Leu Leu Thr Arg Gly Ala Ser Pro Tyr Pro Glu Val Asp 485 490 495Pro Tyr Asp Met Ala Arg Tyr Leu Leu Arg Gly Arg Arg Leu Pro Gln 500 505 510Pro Gln Pro Cys Pro Asp Thr Leu Tyr Gly Val Met Leu Ser Cys Trp 515 520 525Ala Pro Thr Pro Glu Glu Arg Pro Ser Phe Ser Gly Leu Val Cys Glu 530 535 540Leu Glu Arg Val Leu Ala Ser Leu Glu Gly Glu His Tyr Ile Asn Met545 550 555 560Ala Val Thr Tyr Val Asn Leu Glu Ser Gly Pro Pro Phe Pro Pro Ala 565 570 575Pro Arg Gly Gln Leu Pro Asp Ser Glu Asp Glu Glu Asp Glu Glu Glu 580 585 590Glu Val Ala Glu 59522430PRTC. elegans 22Met Ile Ile Gly Ile Val Ile Gly Ser Leu Val Val Ile Leu Val Ala1 5 10 15Ile Val Val Ile Trp Phe Tyr Phe Arg Lys Lys Ser Glu Asn Met Lys 20 25 30Phe Lys Phe Gln Met Glu Gln Val Gly Lys Asn Asn Met Asn Arg Tyr 35 40 45Ile Asp Phe Pro Ile Met Ala Ala Lys Asn Asp Ile Trp Glu Ile Glu 50 55 60Arg Arg Asn Leu Ile Ile His Asn Asp Lys Lys Leu Gly Ser Gly Ala65 70 75 80Phe Gly Ala Val Tyr Leu Gly Lys Leu Ile Gly Lys Ser Leu Ala His 85 90 95Lys Asp Ala Asn Ser Pro Leu Gly Ile Asn Leu Met Arg Ala Glu Asn 100 105 110Cys Gln Val Ala Val Lys Met Leu Pro Glu Tyr Ala Asp Glu Met Ser 115 120 125Lys His Glu Phe Leu Arg Glu Ile Ala Leu Met Lys Thr Leu Gly Tyr 130 135 140His Glu Arg Leu Val Asn Met Leu Ala Cys Val Thr Glu Ser Glu Pro145 150 155 160Leu Cys Leu Val Val Glu Tyr Cys Asp Asn Gly Asp Leu Leu Lys Phe 165 170 175Leu Arg Glu Arg Cys Lys Tyr Met Met Lys Leu Asp Asp Leu Gly Ile 180 185 190Asn Tyr His Asp Pro Pro Glu Asn Glu Asn Tyr Asp Thr Asn Met Ile 195 200 205Val Thr Leu Lys Gln Leu Leu Gln Phe Ala Val Gln Ile Ser Tyr Gly 210 215 220Leu Glu Tyr Leu Ser Gln Lys Gly Phe Val His Arg Asp Val Ala Ala225 230 235 240Arg Asn Val Leu Val His Glu Gly Thr Ala Cys Lys Ile Gly Asp Phe 245 250 255Gly Leu Cys Arg Tyr Ile Tyr Ala Asp Gln Ser Gln Tyr Lys Ser Lys 260 265 270Gly Gly Lys Leu Pro Leu Lys Trp Met Ser Pro Glu Ala Ile Arg His 275 280 285Tyr Glu Phe Ser Ile Lys Ser Asp Ile Trp Ser Phe Gly Ile Leu Leu 290 295 300Phe Glu Val Ile Thr Leu Gly Gly Ser Pro Tyr Pro Gly Met Pro Pro305 310 315 320Glu Asp Val Leu Pro Phe Leu Glu Gly Gly Gly Arg Ile Glu Lys Pro 325 330 335Asp Asn Cys Pro Glu Asn Phe Tyr Asp Val Met Met Gln Cys Trp Asn 340 345 350Ala Asp Pro Asp Asp Arg Ile Glu Phe Ser Asp Val Arg Met Gln Leu 355 360 365Ala Thr Gln Leu Glu Asp Ile Thr Glu Asp Tyr Ser Tyr Leu Lys Leu 370 375 380Asp Ala Ala Lys Asp Tyr Tyr Asn Val Gln Tyr Gly Asp Glu Lys Lys385 390 395 400Thr Asp Val Val Ile Ile Pro Asp Glu Ile Ile Lys Pro Ser Lys Leu 405 410 415Ile Met Asp Asp Ile Ser Glu Lys Asn Leu Val Ile Glu Gln 420 425 43023923PRTDrosophila melanogaster 23Met Leu Ile Phe Tyr Ala Lys Tyr Ala Phe Ile Phe Trp Phe Phe Val1 5 10 15Gly Ser Asn Gln Gly Glu Met Leu Leu Met Asp Lys Ile Ser His Asp 20 25 30Lys Thr Leu Leu Asn Val Thr Ala Cys Thr Gln Asn Cys Leu Glu Lys 35 40 45Gly Gln Met Asp Phe Arg Ser Cys Leu Lys Asp Cys Arg Ile Asn Gly 50 55 60Thr Phe Pro Gly Ala Leu Arg Lys Val Gln Glu Asn Tyr Gln Met Asn65 70 75 80Met Ile Cys Arg Thr Glu Ser Glu Ile Val Phe Gln Ile Asp Trp Val 85 90 95Gln His Ser Arg Gly Thr Glu Pro Ala Pro Asn Ala Thr Tyr Ile Ile 100 105 110Arg Val Asp Ala Val Lys Asp Asp Asn Lys Glu Thr Thr Leu Tyr Leu 115 120 125Ser Asp Asp Asn Phe Leu Ile Leu Pro Gly Leu Glu Ser Asn Ser Thr 130 135 140His Asn Ile Thr Ala Leu Ala Met His Gly Asp Gly Ser Tyr Ser Leu145 150 155 160Ile Ala Lys Asp Gln Thr Phe Ala Thr Leu Ile Arg Gly Tyr Gln Pro 165 170 175Ser Lys Met Gly Ala Val Asn Leu Leu Arg Phe Val Pro Gln Pro Asp 180 185 190Asp Leu His His Ile Ala Ala Glu Ile Glu Trp Lys Pro Ser Ala Glu 195 200 205Ser Asn Cys Tyr Phe Asp Met Val Ser Tyr Ser Thr Asn Ser Val Asn 210 215 220Met Asp Glu Pro Leu Glu Val Gln Phe Arg Asp Arg Lys Lys Leu Tyr225 230 235 240Arg His Thr Val Asp Asn Leu Glu Phe Asp Lys Gln Tyr His Val Gly 245 250 255Val Arg Thr Val Asn

Ile Met Asn Arg Leu Glu Ser Asp Leu Gln Trp 260 265 270Leu Pro Ile Ala Val Pro Ser Cys Leu Asp Trp Tyr Pro Tyr Asn Tyr 275 280 285Thr Leu Cys Pro Pro His Lys Pro Glu Asn Leu Thr Val Thr Gln Lys 290 295 300Gln Tyr Leu Pro Asn Ile Leu Ala Leu Asn Ile Thr Trp Ala Arg Pro305 310 315 320Arg Tyr Leu Pro Asp Asn Tyr Thr Leu His Ile Phe Asp Leu Phe Lys 325 330 335Gly Gly Thr Glu Leu Asn Tyr Thr Leu Asp Gln Asn Arg Ser His Phe 340 345 350Tyr Val Pro Lys Ile Thr Val Leu Gly Ser His Phe Glu Val His Leu 355 360 365Val Ala Gln Ser Ala Gly Gly Lys Asn Val Ser Gly Leu Thr Leu Asp 370 375 380Lys Val Pro Arg Gly Val Leu Leu Ser Glu Gly Asn Met Val Lys Leu385 390 395 400Val Leu Phe Ile Ile Val Pro Ile Cys Cys Ile Leu Met Leu Cys Ser 405 410 415Leu Thr Phe Cys Arg Arg Asn Arg Ser Glu Val Gln Ala Leu Gln Met 420 425 430Asp Ala Lys Asp Ala Lys Ala Ser Glu Phe His Leu Ser Leu Met Asp 435 440 445Ser Ser Gly Leu Leu Val Thr Leu Ser Ala Asn Glu Ser Leu Glu Val 450 455 460Met Asp Glu Leu Glu Val Glu Pro His Ser Val Leu Leu Gln Asp Val465 470 475 480Leu Gly Glu Gly Ala Phe Gly Leu Val Arg Arg Gly Val Tyr Lys Lys 485 490 495Arg Gln Val Ala Val Lys Leu Leu Lys Asp Glu Pro Asn Asp Glu Asp 500 505 510Val Tyr Ala Phe Lys Cys Glu Ile Gln Met Leu Lys Ala Val Gly Lys 515 520 525His Pro Asn Ile Val Gly Ile Val Gly Tyr Ser Thr Arg Phe Ser Asn 530 535 540Gln Met Met Leu Leu Ile Glu Tyr Cys Ser Leu Gly Ser Leu Gln Asn545 550 555 560Phe Leu Arg Glu Glu Trp Lys Phe Arg Gln Glu Gln Asn Ala Ile Gly 565 570 575Leu Lys Lys Asn Leu Glu Gln Asn Val Asp Asn Arg Arg Phe Asn Arg 580 585 590Leu Pro Arg Asn Ser Ile His Asp Arg Ile Glu Asp Ile Asn Asn Ser 595 600 605Met Leu Ser Thr Val Glu Glu Glu Ser Glu Ser Asp Gln Thr His Ser 610 615 620Ser Arg Cys Glu Thr Tyr Thr Leu Thr Arg Ile Thr Asn Ala Ala Asp625 630 635 640Asn Lys Gly Tyr Gly Leu Glu Asp Ile Glu Asn Ile Gly Gly Ser Tyr 645 650 655Ile Pro Lys Thr Ala Glu Ala Pro Lys Asp Gln Pro Lys Arg Lys Leu 660 665 670Lys Pro Gln Pro Lys Lys Asp Ser Lys Gln Asp Phe Lys Ser Asp Asn 675 680 685Lys Lys Arg Ile Phe Glu Asn Lys Glu Tyr Phe Asp Cys Leu Asp Ser 690 695 700Ser Asp Thr Lys Pro Arg Ile Pro Leu Lys Tyr Ala Asp Leu Leu Asp705 710 715 720Ile Ala Gln Gln Val Ala Val Gly Met Glu Phe Leu Ala Gln Asn Lys 725 730 735Val Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Ile Ser Val Asp 740 745 750Arg Ser Ile Lys Ile Ala Asp Phe Gly Leu Ser Arg Asp Val Tyr His 755 760 765Glu Asn Val Tyr Arg Lys Ser Gly Gly Ser Gly Lys Leu Pro Ile Lys 770 775 780Trp Leu Ala Leu Glu Ser Leu Thr His Gln Val Tyr Thr Ser Gln Ser785 790 795 800Asp Val Trp Ser Phe Gly Val Leu Leu Tyr Glu Ile Thr Thr Leu Gly 805 810 815Gly Met Pro Tyr Pro Ser Val Ser Pro Ser Asp Leu Leu Gln Leu Leu 820 825 830Arg Gln Gly His Arg Met Lys Arg Pro Glu Gly Cys Thr Gln Glu Met 835 840 845Phe Ser Leu Met Glu Ser Cys Trp Ser Ser Val Pro Ser His Arg Pro 850 855 860Thr Phe Ser Ala Leu Lys His Arg Leu Gly Gly Met Ile Leu Ala Thr865 870 875 880Asn Asp Val Pro Glu Arg Leu Lys Gln Leu Gln Ala Ala Thr Glu Ser 885 890 895Lys Leu Lys Ser Cys Asp Gly Leu Asn Ser Lys Val Glu Gln Val Pro 900 905 910Cys Glu Glu Glu Leu Tyr Leu Glu Pro Leu Asn 915 920241404PRTGallus gallus 24Met Gly Pro Arg Cys Leu Val Cys Leu Leu Leu Leu Leu Ala Pro Ser1 5 10 15Leu Leu Gln Ala Gly Ala Trp Gln Cys Arg Arg Ile Pro Phe Ser Ser 20 25 30Thr Arg Asn Phe Ser Val Pro Tyr Thr Leu Pro Ser Leu Asp Ala Gly 35 40 45Ser Pro Val Gln Asn Ile Ala Val Phe Pro Asp Pro Pro Thr Val Phe 50 55 60Val Ala Val Arg Asn Arg Ile Leu Val Val Asp Pro Glu Leu Arg Leu65 70 75 80Arg Ser Val Leu Val Thr Gly Pro Thr Gly Ser Ala Pro Cys Glu Ile 85 90 95Cys Arg Leu Cys Pro Ala Ala Val Asp Ala Pro Gly Pro Glu Asp Val 100 105 110Asp Asn Val Leu Leu Leu Leu Asp Pro Val Glu Pro Trp Leu Tyr Ser 115 120 125Cys Gly Thr Ala Arg Arg Gly Leu Cys Tyr Leu His Gln Leu Asp Val 130 135 140Arg Gly Ser Glu Val Thr Ile Ala Ser Thr Arg Cys Leu Tyr Ser Ala145 150 155 160Ala Ala Asn Ser Pro Val Asn Cys Pro Asp Cys Val Ala Ser Pro Leu 165 170 175Gly Ser Thr Ala Thr Val Val Ala Asp Arg Tyr Thr Ala Ser Phe Tyr 180 185 190Leu Gly Ser Thr Val Asn Ser Ser Val Ala Ala Arg Tyr Ser Pro Arg 195 200 205Ser Val Ser Val Arg Arg Leu Lys Gly Thr Arg Asp Gly Phe Ala Asp 210 215 220Pro Phe His Ser Leu Thr Val Leu Pro His Tyr Gln Asp Val Tyr Pro225 230 235 240Ile His Tyr Val His Ser Phe Thr Asp Gly Asp His Val Tyr Leu Val 245 250 255Thr Val Gln Pro Glu Phe Pro Gly Ser Ser Thr Phe His Thr Arg Leu 260 265 270Val Arg Leu Ser Ala His Glu Pro Glu Leu Arg Arg Tyr Arg Glu Ile 275 280 285Val Leu Asp Cys Arg Tyr Glu Ser Lys Arg Arg Arg Arg Arg Arg Gly 290 295 300Ala Glu Glu Glu Thr Glu Arg Asp Val Ala Tyr Asn Val Leu Gln Ala305 310 315 320Ala His Ala Ala Arg Pro Gly Ala Arg Leu Ala Arg Asp Leu Gly Ile 325 330 335Asp Gly Thr Glu Thr Val Leu Phe Gly Ala Phe Ala Glu Ser His Pro 340 345 350Glu Ser Arg Ala Pro Gln His Asn Ser Ala Val Cys Ala Phe Pro Leu 355 360 365Arg Leu Leu Asn Gln Ala Ile Arg Glu Gly Met Asp Lys Cys Cys Gly 370 375 380Thr Gly Thr Gln Thr Leu Lys Arg Gly Leu Ala Phe Phe Gln Pro Gln385 390 395 400Gln Tyr Cys Pro His Ser Val Asn Leu Ser Ala Pro Val Thr Asn Thr 405 410 415Ser Cys Trp Asp Gln Pro Thr Leu Val Pro Ala Ala Ser His Lys Val 420 425 430Asp Leu Phe Asn Gly Arg Leu Ser Gly Thr Leu Leu Thr Ser Ile Phe 435 440 445Val Thr Val Leu Gln Asn Val Thr Val Ala His Leu Gly Thr Ala Gln 450 455 460Gly Arg Val Leu Gln Met Val Leu Gln Arg Ser Ser Ser Tyr Val Val465 470 475 480Ala Leu Thr Asn Phe Ser Leu Gly Glu Pro Gly Leu Val Gln His Ala 485 490 495Thr Gly Leu Gln Gly His Ser Leu Leu Phe Ala Ala Gly Thr Lys Val 500 505 510Trp Arg Val Asn Val Thr Gly Pro Gly Cys Arg His Phe Ser Thr Cys 515 520 525Asp Arg Cys Leu Arg Ala Glu Arg Phe Met Gly Cys Gly Trp Cys Gly 530 535 540Asn Gly Cys Thr Arg His His Glu Cys Ala Gly Pro Trp Val Gln Asp545 550 555 560Ser Cys Pro Pro Val Leu Thr Asp Phe His Pro Arg Ser Ala Pro Leu 565 570 575Arg Gly Gln Thr Arg Val Thr Leu Cys Gly Met Thr Phe His Ser Pro 580 585 590Pro Asp Pro Thr Ala His His Ser Leu Pro Gly Pro Tyr Arg Val Ala 595 600 605Val Gly Gly Arg Ser Cys Thr Val Leu Leu Asp Glu Ser Glu Ser Tyr 610 615 620Arg Pro Leu Pro Thr Phe Arg Arg Lys Asp Phe Val Asp Val Leu Val625 630 635 640Cys Val Leu Glu Pro Gly Glu Pro Ala Val Ala Ala Gly Pro Ala Asp 645 650 655Val Val Leu Asn Val Thr Glu Ser Ala Gly Thr Ser Arg Phe Arg Val 660 665 670Gln Gly Ser Ser Thr Leu Ser Gly Phe Val Phe Val Glu Pro His Ile 675 680 685Ser Thr Leu His Pro Ser Phe Gly Pro Gln Gly Gly Gly Thr Leu Met 690 695 700Ser Leu Tyr Gly Thr His Leu Ser Ala Gly Ser Ser Trp Arg Val Thr705 710 715 720Ile Asn Gly Ser Glu Cys Leu Leu Asp Gly Gln Pro Ser Glu Gly Asp 725 730 735Gly Glu Ile Arg Cys Thr Ala Pro Ala Ala Thr Ser Leu Gly Ala Ala 740 745 750Pro Val Ala Leu Trp Ile Asp Gly Glu Glu Phe Leu Ala Pro Leu Pro 755 760 765Phe Glu Tyr Arg Pro Asp Pro Ser Val Leu Thr Val Val Pro Asn Cys 770 775 780Ser Tyr Gly Gly Ser Thr Leu Thr Leu Ile Gly Thr His Leu Asp Ser785 790 795 800Val Tyr Arg Ala Lys Ile Gln Phe Gln Gly Gly Gly Gly Gly Lys Thr 805 810 815Glu Ala Thr Glu Cys Glu Gly Pro Gln Ser Pro Asn Trp Leu Leu Cys 820 825 830Arg Ser Pro Ala Phe Pro Ile Glu Ile Lys Pro Val Pro Gly Asn Leu 835 840 845Ser Val Leu Leu Asp Gly Ala Ala Asp Arg Trp Leu Phe Arg Leu Arg 850 855 860Tyr Phe Pro Gln Pro Gln Met Phe Ser Phe Gly Gln Gln Gly Glu Arg865 870 875 880Tyr Gln Leu Lys Pro Gly Asp Asn Glu Ile Lys Val Asn Gln Leu Gly 885 890 895Leu Asp Ser Val Ala Gly Cys Met Asn Ile Thr Met Thr Val Gly Gly 900 905 910Arg Asp Cys His Pro Asn Val Leu Lys Asn Glu Val Thr Cys Arg Val 915 920 925Pro Arg Asp Val Asp Leu Thr Pro Ala Gly Ala Pro Val Gln Ile Cys 930 935 940Val Asn Gly Asp Cys Gln Ala Leu Gly Leu Val Leu Pro Ala Ser Ser945 950 955 960Leu Asp Met Ala Ala Ser Leu Ala Leu Gly Thr Gly Val Thr Phe Leu 965 970 975Val Cys Cys Val Leu Ala Ala Val Leu Leu Arg Trp Arg Trp Arg Lys 980 985 990Arg Arg Gly Leu Glu Asn Leu Glu Leu Leu Val His Pro Pro Arg Ile 995 1000 1005Glu His Pro Ile Thr Ile Gln Arg Pro Asn Val Asp Tyr Arg Glu Val 1010 1015 1020Gln Val Leu Pro Val Ala Asp Ser Pro Gly Leu Ala Arg Pro His Ala1025 1030 1035 1040His Phe Ala Ser Ala Gly Ala Asp Ala Ala Gly Gly Gly Ser Pro Val 1045 1050 1055Pro Leu Leu Arg Thr Thr Ser Cys Cys Leu Glu Asp Leu Arg Pro Glu 1060 1065 1070Leu Leu Glu Glu Val Lys Asp Ile Leu Ile Pro Glu Glu Arg Leu Ile 1075 1080 1085Thr His Arg Ser Arg Val Ile Gly Arg Gly His Phe Gly Ser Val Tyr 1090 1095 1100His Gly Thr Tyr Met Asp Pro Leu Leu Gly Asn Leu His Cys Ala Val1105 1110 1115 1120Lys Ser Leu His Arg Ile Thr Asp Leu Glu Glu Val Glu Glu Phe Leu 1125 1130 1135Arg Glu Gly Ile Leu Met Lys Ser Phe His His Pro Gln Val Leu Ser 1140 1145 1150Leu Leu Gly Val Cys Leu Pro Arg His Gly Leu Pro Leu Val Val Leu 1155 1160 1165Pro Tyr Met Arg His Gly Asp Leu Arg His Phe Ile Arg Ala Gln Glu 1170 1175 1180Arg Ser Pro Thr Val Lys Glu Leu Ile Gly Phe Gly Leu Gln Val Ala1185 1190 1195 1200Leu Gly Met Glu Tyr Leu Ala Gln Lys Lys Phe Val His Arg Asp Leu 1205 1210 1215Ala Ala Arg Asn Cys Met Leu Asp Glu Thr Leu Thr Val Lys Val Ala 1220 1225 1230Asp Phe Gly Leu Ala Arg Asp Val Phe Gly Lys Glu Tyr Tyr Ser Ile 1235 1240 1245Arg Gln His Arg His Ala Lys Leu Pro Val Lys Trp Met Ala Leu Glu 1250 1255 1260Ser Leu Gln Thr Gln Lys Phe Thr Thr Lys Ser Asp Val Trp Ser Phe1265 1270 1275 1280Gly Val Leu Met Trp Glu Leu Leu Thr Arg Gly Ala Ser Pro Tyr Pro 1285 1290 1295Glu Val Asp Pro Tyr Asp Met Ala Arg Tyr Leu Leu Arg Gly Arg Arg 1300 1305 1310Leu Pro Gln Pro Gln Pro Cys Pro Asp Thr Leu Tyr Gly Val Met Leu 1315 1320 1325Ser Cys Trp Ala Pro Thr Pro Glu Glu Arg Pro Ser Phe Ser Gly Leu 1330 1335 1340Val Cys Glu Leu Glu Arg Val Leu Ala Ser Leu Glu Gly Glu Arg Tyr1345 1350 1355 1360Val Asn Leu Ala Val Thr Tyr Val Asn Leu Glu Ser Gly Pro Pro Phe 1365 1370 1375Pro Pro Ala Pro Arg Gly Gln Leu Pro Asp Ser Glu Asp Glu Glu Asp 1380 1385 1390Glu Glu Asp Glu Glu Asp Glu Asp Ala Ala Val Arg 1395 140025891PRTHydra vulgaris 25Met Leu Phe Met Lys Ile Ile Leu Leu Asn Phe Val Leu Leu Asn Val1 5 10 15Ser Asn Ile Ala Glu Ala Leu Gln Phe Ile Ala Lys Pro Phe Ser Gly 20 25 30Gly Ile Trp His Val Asn Lys Asp Asp Asn Ile Thr Ile Ser Cys Leu 35 40 45Thr Asp Asp Ser Ser Ala Asn Val Thr Leu Leu Val Gly Glu Lys Thr 50 55 60Ile Gln Asp Gln Phe Ile Lys Arg Lys Gly Leu Leu Lys Ile Asp Gly65 70 75 80Gln Ile Phe Lys Leu His Leu Ile Thr Ser Ser Asp Trp Asn Thr Tyr 85 90 95Gln Cys Met Ala Arg Ala Glu Asp Lys Asn Leu Val Leu Lys Leu Gly 100 105 110Thr Leu Ile Val Asn Pro Ala Pro Cys Asn Lys Ala Pro Asp Leu Gln 115 120 125Arg Phe Gly Lys Thr Leu Asn Tyr Ser Val Asp Val Glu Tyr Glu Leu 130 135 140Phe Asp Glu Ile Ile Ile Val Cys Ser Thr Pro Gly Ile Asp Gly Ile145 150 155 160Lys Asn Ile Leu Thr Trp Val Asn Lys Asn Ile Ser Ser Asp Leu Lys 165 170 175Gln Thr Val Leu Pro Asp Glu Arg Asp Gln Val Thr Tyr Ile Asp Arg 180 185 190Leu Gln Leu Lys Ile Ser Tyr Ala Asn Leu Met Asn Glu Gly Glu Tyr 195 200 205Ile Cys Lys Arg Ser Leu Cys Asn Ile Thr Ser Ser Arg Ser Ile Lys 210 215 220Leu Lys Tyr Lys Asn Pro Tyr Lys Pro Ile Ile Ser Leu Ser Tyr Ser225 230 235 240Gly Lys Pro Gln Lys Gly Arg Ser Ile Lys Ile Gln Cys Leu Val Asp 245 250 255Ser Ser Pro Ser Ser Thr Ile Glu Trp Tyr Ser Gly Asp Ser Leu Leu 260 265 270Leu Val Cys Lys Ser Ser Lys Lys Pro Tyr Thr Asp Leu Gln Ile Pro 275 280 285Cys Glu Tyr Thr Ile Gln Asp Phe Asn Arg Asn Thr Asn Phe Thr Cys 290 295 300Ile Ala Lys Asn Ala Ala Gly Asn Ser Ser Gln Ser Leu Ile Ile Tyr305 310 315 320Val Leu Val Pro Pro Leu Ile Ser Pro Ser Lys Ala Glu Ser Gln Arg 325 330 335Phe Glu Cys Thr Val Thr Gln Gly Asn Pro Leu Pro Phe Ile Tyr Trp 340 345 350Glu Arg Lys Val Leu Ser Cys Lys Asn Cys Glu Ser Gln Trp Val Asn 355 360 365Phe Ser Ser Glu Asn Val Lys Val Val Pro Pro Thr Tyr Glu Pro Ser 370 375 380Ser Gln Ser Ala Leu Ile Phe Gln Asn Ser Phe Lys Asp Ile Gly Ser385 390 395

400Ile Arg Cys His Ala Tyr Asn Ser Glu Gly Asn Ser Ser Ala Val Ile 405 410 415Ser Leu Asn Tyr Ser Ala Gly Lys Glu Pro Arg Phe Pro Thr Val Gly 420 425 430Ile Ile Cys Gly Phe Leu Val Ile Ile Phe Ile Phe Leu Ile Ile Ile 435 440 445Phe Phe Tyr Lys Arg Tyr Thr Asn Lys Lys Phe Ala Leu Phe Met Glu 450 455 460Pro Asn Pro Lys Phe Lys Leu Asp Pro Ser Arg Thr Ile Phe Glu Gln465 470 475 480Ser Ile Glu Leu Pro Tyr Asp Leu Ser Trp Glu Phe Pro Arg His Arg 485 490 495Leu Asp Phe Val Arg Val Ile Gly Ser Gly Ala Phe Gly Gln Val Trp 500 505 510Phe Ala His Ala Arg Gly Ile Leu Ala Leu Cys Pro Arg Asp Lys Ser 515 520 525Ala Ser Ala Ala Arg Gln Arg Ala Lys Leu Tyr Phe Asn Thr Lys Val 530 535 540Pro Lys Ser Leu Thr Lys Leu Phe Thr Asn Gly Ser Met Cys Asp His545 550 555 560Asp Thr Phe Val Ala Val Lys Thr Leu Lys Ser Ser Ala Ser Asp Val 565 570 575Glu Tyr Arg Asp Leu Ser Ser Glu Ile Lys Val Leu Ile His Leu Gly 580 585 590Glu His Pro Asn Ile Val Asn Leu Leu Gly Ser Cys Thr Lys Asp Gly 595 600 605Arg Leu Cys Ala Ile Met Glu Tyr Cys Pro His Gly Asn Leu Val Gly 610 615 620Phe Leu Arg Pro Arg Arg His Val Phe Ser Leu Gln Trp Glu Lys Gln625 630 635 640Ala Leu Asn Tyr Asp Glu Asp Phe Cys Trp Leu Asp Ala Ala Thr Ala 645 650 655Ala Phe Gln Ile Ala Ser Gly Met Leu Phe Leu Ser Glu Lys Lys Leu 660 665 670Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Gly Pro Asp Tyr 675 680 685Ile Met Lys Leu Ala Asp Phe Gly Leu Ala Arg Asp Ile Tyr Leu Ser 690 695 700Gly Val Tyr Ile Lys Glu Ser Cys Gly Ile Leu Pro Val Lys Trp Met705 710 715 720Ala Pro Glu Ser Leu Phe Asp Lys Val Tyr Thr Ile Lys Ser Asp Val 725 730 735Trp Ser Phe Gly Ile Val Leu Trp Glu Ile Cys Thr Met Gly Gly Ser 740 745 750Pro Tyr Pro Gly Leu Pro Thr Glu Asp Leu Phe Glu Tyr Leu Thr Ala 755 760 765Gly Lys Arg Met Cys Gln Pro Val Thr Cys Pro Asp Glu Leu Tyr Glu 770 775 780Ile Met Leu Gln Cys Trp Gln Glu Arg Pro Glu Glu Arg Pro Trp Phe785 790 795 800His Glu Ile Val Ser Gln Leu Gln Arg Ile Ile Glu Ser Lys Asn Glu 805 810 815Pro Pro Asn Asn Leu Ser Ala Phe Asp Arg Ile Gln Ser Val Ser Asp 820 825 830Glu Thr Asp Cys Leu Val Pro Leu Ser Pro Leu Lys Lys Lys Lys Ser 835 840 845Ser Asp Val Ile Phe Thr Lys Lys Asp Ser Leu Lys Thr Lys Ile Asp 850 855 860Cys Val Phe Asn Phe Pro Pro Ile Glu Asp Asn Ser Asp Lys Asn Gly865 870 875 880Asn Ser Val Asn Lys Glu Gln Leu Asn Thr Thr 885 89026355PRTArabidopsis thaliana 26Met Ala Asn Ala Lys Glu Thr Thr Phe Tyr Ile Thr Ile Ser Val Val1 5 10 15Ala Phe Val Ile Gly Lys Ile Val Ile Ala Leu Leu Phe Tyr Lys Arg 20 25 30Trp Lys Arg Lys His Thr Ile His Glu Asn Gly Phe Pro Val Lys Gly 35 40 45Gly Gly Lys Met Val Met Phe Arg Ser Gln Leu Leu Asn Ser Val Ser 50 55 60Ser Asp Met Phe Met Lys Lys Thr His Lys Leu Ser Asn Lys Asp Ile65 70 75 80Leu Gly Ser Gly Gly Phe Gly Thr Val Tyr Arg Leu Val Ile Asp Asp 85 90 95Ser Thr Thr Phe Ala Val Lys Arg Leu Asn Arg Gly Thr Ser Glu Arg 100 105 110Asp Arg Gly Phe His Arg Glu Leu Glu Ala Met Ala Asp Ile Lys His 115 120 125Arg Asn Ile Val Thr Leu His Gly Tyr Phe Thr Ser Pro His Tyr Asn 130 135 140Leu Leu Ile Tyr Glu Leu Met Pro Asn Gly Ser Leu Asp Ser Phe Leu145 150 155 160His Gly Arg Lys Ala Leu Asp Trp Ala Ser Arg Tyr Arg Ile Ala Val 165 170 175Gly Ala Ala Arg Gly Ile Ser Tyr Leu His His Asp Cys Ile Pro His 180 185 190Ile Ile His Arg Asp Ile Lys Ser Ser Asn Ile Leu Leu Asp His Asn 195 200 205Met Glu Ala Arg Val Ser Asp Phe Gly Leu Ala Thr Leu Met Glu Pro 210 215 220Asp Lys Thr His Val Ser Thr Phe Val Ala Gly Thr Phe Gly Tyr Leu225 230 235 240Ala Pro Glu Tyr Phe Asp Thr Gly Lys Ala Thr Met Lys Gly Asp Val 245 250 255Tyr Ser Phe Gly Val Val Leu Leu Glu Leu Leu Thr Gly Arg Lys Pro 260 265 270Thr Asp Asp Glu Phe Phe Glu Glu Gly Thr Lys Leu Val Thr Trp Val 275 280 285Lys Gly Val Val Arg Asp Gln Arg Glu Glu Val Val Ile Asp Asn Arg 290 295 300Leu Arg Gly Ser Ser Val Gln Glu Asn Glu Glu Met Asn Asp Val Phe305 310 315 320Gly Ile Ala Met Met Cys Leu Glu Pro Glu Pro Ala Ile Arg Pro Ala 325 330 335Met Thr Glu Val Val Lys Leu Leu Glu Tyr Ile Lys Leu Ser Thr Arg 340 345 350Ser Ser Phe 35527669PRTArabidopsis thaliana 27Met Lys Phe Phe Val Leu Val Leu Leu Leu Val Leu Gln Phe Phe Ser1 5 10 15Asn Lys Ala Leu Ser Gln Ser Glu Glu Gly Glu Phe Gly Phe Asn Gly 20 25 30Tyr Leu Tyr Asp Asn Ser Gly Ile Ala Ile Thr Asn Ser Lys Gly Leu 35 40 45Met Lys Leu Thr Asn Ser Ser Glu Phe Ser Tyr Gly His Val Phe Tyr 50 55 60Asn Ser Pro Val Arg Phe Lys Asn Ser Pro Asn Gly Thr Val Ser Ser65 70 75 80Phe Ser Thr Thr Phe Val Phe Ala Ile Val Ser Asn Val Asn Ala Leu 85 90 95Asp Gly His Gly Leu Ala Phe Val Ile Ser Pro Thr Lys Gly Leu Pro 100 105 110Tyr Ser Ser Ser Ser Gln Tyr Leu Gly Leu Phe Asn Leu Thr Asn Asn 115 120 125Gly Asp Pro Ser Asn His Ile Val Ala Val Glu Phe Asp Thr Phe Gln 130 135 140Asn Gln Glu Phe Asp Asp Met Asp Asn Asn His Val Gly Ile Asp Ile145 150 155 160Asn Ser Leu Ser Ser Glu Lys Ala Ser Thr Ala Gly Tyr Tyr Glu Asp 165 170 175Asp Asp Gly Thr Phe Lys Asn Ile Arg Leu Ile Asn Gln Lys Pro Ile 180 185 190Gln Ala Trp Ile Glu Tyr Asp Ser Ser Arg Arg Gln Leu Asn Val Thr 195 200 205Ile His Pro Ile His Leu Pro Lys Pro Lys Ile Pro Leu Leu Ser Leu 210 215 220Thr Lys Asp Leu Ser Pro Tyr Leu Phe Asp Ser Met Tyr Val Gly Phe225 230 235 240Thr Ser Ala Thr Gly Arg Leu Arg Ser Ser His Tyr Ile Leu Gly Trp 245 250 255Thr Phe Lys Leu Asn Gly Thr Ala Ser Asn Ile Asp Ile Ser Arg Leu 260 265 270Pro Lys Leu Pro Arg Asp Ser Arg Ser Thr Ser Val Lys Lys Ile Leu 275 280 285Ala Ile Ser Leu Ser Leu Thr Ser Leu Ala Ile Leu Val Phe Leu Thr 290 295 300Ile Ser Tyr Met Leu Phe Leu Lys Arg Lys Lys Leu Met Glu Val Leu305 310 315 320Glu Asp Trp Glu Val Gln Phe Gly Pro His Arg Phe Ala Tyr Lys Asp 325 330 335Leu Tyr Ile Ala Thr Lys Gly Phe Arg Asn Ser Glu Leu Leu Gly Lys 340 345 350Gly Gly Phe Gly Lys Val Tyr Lys Gly Thr Leu Ser Thr Ser Asn Met 355 360 365Asp Ile Ala Val Lys Lys Val Ser His Asp Ser Arg Gln Gly Met Arg 370 375 380Glu Phe Val Ala Glu Ile Ala Thr Ile Gly Arg Leu Arg His Pro Asn385 390 395 400Leu Val Arg Leu Leu Gly Tyr Cys Arg Arg Lys Gly Glu Leu Tyr Leu 405 410 415Val Tyr Asp Cys Met Pro Lys Gly Ser Leu Asp Lys Phe Leu Tyr His 420 425 430Gln Pro Glu Gln Ser Leu Asp Trp Ser Gln Arg Phe Lys Ile Ile Lys 435 440 445Asp Val Ala Ser Gly Leu Cys Tyr Leu His His Gln Trp Val Gln Val 450 455 460Ile Ile His Arg Asp Ile Lys Pro Ala Asn Val Leu Leu Asp Asp Ser465 470 475 480Met Asn Gly Lys Leu Gly Asp Phe Gly Leu Ala Lys Leu Cys Glu His 485 490 495Gly Phe Asp Pro Gln Thr Ser Asn Val Ala Gly Thr Phe Gly Tyr Ile 500 505 510Ser Pro Glu Leu Ser Arg Thr Gly Lys Ala Ser Thr Ser Ser Asp Val 515 520 525Phe Ala Phe Gly Ile Leu Met Leu Glu Ile Thr Cys Gly Arg Arg Pro 530 535 540Val Leu Pro Arg Ala Ser Ser Pro Ser Glu Met Val Leu Thr Asp Trp545 550 555 560Val Leu Asp Cys Trp Glu Asp Asp Ile Leu Gln Val Val Asp Glu Arg 565 570 575Val Lys Gln Asp Asp Lys Tyr Leu Glu Glu Gln Val Ala Leu Val Leu 580 585 590Lys Leu Gly Leu Phe Cys Ser His Pro Val Ala Ala Val Arg Pro Ser 595 600 605Met Ser Ser Val Ile Gln Phe Leu Asp Gly Val Ala Gln Leu Pro Asn 610 615 620Asn Leu Phe Asp Ile Val Lys Ala Arg Glu Asn Val Gly Ala Ile Glu625 630 635 640Gly Phe Gly Glu Ala Ala Glu Ser Leu Ala Glu Pro Cys Ser Val Ala 645 650 655Thr Leu Thr Phe Thr Glu Pro Phe Val Ser His Gly Arg 660 66528540PRTHomo sapiens 28Met Asn Gly Glu Ala Ile Cys Ser Ala Leu Pro Thr Ile Pro Tyr His1 5 10 15Lys Leu Ala Asp Leu Arg Tyr Leu Ser Arg Gly Ala Ser Gly Thr Val 20 25 30Ser Ser Ala Arg His Ala Asp Trp Arg Val Gln Val Ala Val Lys His 35 40 45Leu His Ile His Thr Pro Leu Leu Asp Ser Glu Arg Lys Asp Val Leu 50 55 60Arg Glu Ala Glu Ile Leu His Lys Ala Arg Phe Ser Tyr Ile Leu Pro65 70 75 80Ile Leu Gly Ile Cys Asn Glu Pro Glu Phe Leu Gly Ile Val Thr Glu 85 90 95Tyr Met Pro Asn Gly Ser Leu Asn Glu Leu Leu His Arg Lys Thr Glu 100 105 110Tyr Pro Asp Val Ala Trp Pro Leu Arg Phe Arg Ile Leu His Glu Ile 115 120 125Ala Leu Gly Val Asn Tyr Leu His Asn Met Thr Pro Pro Leu Leu His 130 135 140His Asp Leu Lys Thr Gln Asn Ile Leu Leu Asp Asn Glu Phe His Val145 150 155 160Lys Ile Ala Asp Phe Gly Leu Ser Lys Trp Arg Met Met Ser Leu Ser 165 170 175Gln Ser Arg Ser Ser Lys Ser Ala Pro Glu Gly Gly Thr Ile Ile Tyr 180 185 190Met Pro Pro Glu Asn Tyr Glu Pro Gly Gln Lys Ser Arg Ala Ser Ile 195 200 205Lys His Asp Ile Tyr Ser Tyr Ala Val Ile Thr Trp Glu Val Leu Ser 210 215 220Arg Lys Gln Pro Phe Glu Asp Val Thr Asn Pro Leu Gln Ile Met Tyr225 230 235 240Ser Val Ser Gln Gly His Arg Pro Val Ile Asn Glu Glu Ser Leu Pro 245 250 255Tyr Asp Ile Pro His Arg Ala Arg Met Ile Ser Leu Ile Glu Ser Gly 260 265 270Trp Ala Gln Asn Pro Asp Glu Arg Pro Ser Phe Leu Lys Cys Leu Ile 275 280 285Glu Leu Glu Pro Val Leu Arg Thr Phe Glu Glu Ile Thr Phe Leu Glu 290 295 300Ala Val Ile Gln Leu Lys Lys Thr Lys Leu Gln Ser Val Ser Ser Ala305 310 315 320Ile His Leu Cys Asp Lys Lys Lys Met Glu Leu Ser Leu Asn Ile Pro 325 330 335Val Asn His Gly Pro Gln Glu Glu Ser Cys Gly Ser Ser Gln Leu His 340 345 350Glu Asn Ser Gly Ser Pro Glu Thr Ser Arg Ser Leu Pro Ala Pro Gln 355 360 365Asp Asn Asp Phe Leu Ser Arg Lys Ala Gln Asp Cys Tyr Phe Met Lys 370 375 380Leu His His Cys Pro Gly Asn His Ser Trp Asp Ser Thr Ile Ser Gly385 390 395 400Ser Gln Arg Ala Ala Phe Cys Asp His Lys Thr Thr Pro Cys Ser Ser 405 410 415Ala Ile Ile Asn Pro Leu Ser Thr Ala Gly Asn Ser Glu Arg Leu Gln 420 425 430Pro Gly Ile Ala Gln Gln Trp Ile Gln Ser Lys Arg Glu Asp Ile Val 435 440 445Asn Gln Met Thr Glu Ala Cys Leu Asn Gln Ser Leu Asp Ala Leu Leu 450 455 460Ser Arg Asp Leu Ile Met Lys Glu Asp Tyr Glu Leu Val Ser Thr Lys465 470 475 480Pro Thr Arg Thr Ser Lys Val Arg Gln Leu Leu Asp Thr Thr Asp Ile 485 490 495Gln Gly Glu Glu Phe Ala Lys Val Ile Val Gln Lys Leu Lys Asp Asn 500 505 510Lys Gln Met Gly Leu Gln Pro Tyr Pro Glu Ile Leu Val Val Ser Arg 515 520 525Ser Pro Ser Leu Asn Leu Leu Gln Asn Lys Ser Met 530 535 54029671PRTHomo sapiens 29Met Gln Pro Asp Met Ser Leu Asn Val Ile Lys Met Lys Ser Ser Asp1 5 10 15Phe Leu Glu Ser Ala Glu Leu Asp Ser Gly Gly Phe Gly Lys Val Ser 20 25 30Leu Cys Phe His Arg Thr Gln Gly Leu Met Ile Met Lys Thr Val Tyr 35 40 45Lys Gly Pro Asn Cys Ile Glu His Asn Glu Ala Leu Leu Glu Glu Ala 50 55 60Lys Met Met Asn Arg Leu Arg His Ser Arg Val Val Lys Leu Leu Gly65 70 75 80Val Ile Ile Glu Glu Gly Lys Tyr Ser Leu Val Met Glu Tyr Met Glu 85 90 95Lys Gly Asn Leu Met His Val Leu Lys Ala Glu Met Ser Thr Pro Leu 100 105 110Ser Val Lys Gly Arg Ile Ile Leu Glu Ile Ile Glu Gly Met Cys Tyr 115 120 125Leu His Gly Lys Gly Val Ile His Lys Asp Leu Lys Pro Glu Asn Ile 130 135 140Leu Val Asp Asn Asp Phe His Ile Lys Ile Ala Asp Leu Gly Leu Ala145 150 155 160Ser Phe Lys Met Trp Ser Lys Leu Asn Asn Glu Glu His Asn Glu Leu 165 170 175Arg Glu Val Asp Gly Thr Ala Lys Lys Asn Gly Gly Thr Leu Tyr Tyr 180 185 190Met Ala Pro Glu His Leu Asn Asp Val Asn Ala Lys Pro Thr Glu Lys 195 200 205Ser Asp Val Tyr Ser Phe Ala Val Val Leu Trp Ala Ile Phe Ala Asn 210 215 220Lys Glu Pro Tyr Glu Asn Ala Ile Cys Glu Gln Gln Leu Ile Met Cys225 230 235 240Ile Lys Ser Gly Asn Arg Pro Asp Val Asp Asp Ile Thr Glu Tyr Cys 245 250 255Pro Arg Glu Ile Ile Ser Leu Met Lys Leu Cys Trp Glu Ala Asn Pro 260 265 270Glu Ala Arg Pro Thr Phe Pro Gly Ile Glu Glu Lys Phe Arg Pro Phe 275 280 285Tyr Leu Ser Gln Leu Glu Glu Ser Val Glu Glu Asp Val Lys Ser Leu 290 295 300Lys Lys Glu Tyr Ser Asn Glu Asn Ala Val Val Lys Arg Met Gln Ser305 310 315 320Leu Gln Leu Asp Cys Val Ala Val Pro Ser Ser Arg Ser Asn Ser Ala 325 330 335Thr Glu Gln Pro Gly Ser Leu His Ser Ser Gln Gly Leu Gly Met Gly 340 345 350Pro Val Glu Glu Ser Trp Phe Ala Pro Ser Leu Glu His Pro Gln Glu 355 360 365Glu Asn Glu Pro Ser Leu Gln Ser Lys Leu Gln Asp Glu Ala Asn Tyr 370 375 380His Leu Tyr Gly Ser Arg Met Asp Arg Gln Thr Lys Gln Gln Pro Arg385 390 395

400Gln Asn Val Ala Tyr Asn Arg Glu Glu Glu Arg Arg Arg Arg Val Ser 405 410 415His Asp Pro Phe Ala Gln Gln Arg Pro Tyr Glu Asn Phe Gln Asn Thr 420 425 430Glu Gly Lys Gly Thr Val Tyr Ser Ser Ala Ala Ser His Gly Asn Ala 435 440 445Val His Gln Pro Ser Gly Leu Thr Ser Gln Pro Gln Val Leu Tyr Gln 450 455 460Asn Asn Gly Leu Tyr Ser Ser His Gly Phe Gly Thr Arg Pro Leu Asp465 470 475 480Pro Gly Thr Ala Gly Pro Arg Val Trp Tyr Arg Pro Ile Pro Ser His 485 490 495Met Pro Ser Leu His Asn Ile Pro Val Pro Glu Thr Asn Tyr Leu Gly 500 505 510Asn Thr Pro Thr Met Pro Phe Ser Ser Leu Pro Pro Thr Asp Glu Ser 515 520 525Ile Lys Tyr Thr Ile Tyr Asn Ser Thr Gly Ile Gln Ile Gly Ala Tyr 530 535 540Asn Tyr Met Glu Ile Gly Gly Thr Ser Ser Ser Leu Leu Asp Ser Thr545 550 555 560Asn Thr Asn Phe Lys Glu Glu Pro Ala Ala Lys Tyr Gln Ala Ile Phe 565 570 575Asp Asn Thr Thr Ser Leu Thr Asp Lys His Leu Asp Pro Ile Arg Glu 580 585 590Asn Leu Gly Lys His Trp Lys Asn Cys Ala Arg Lys Leu Gly Phe Thr 595 600 605Gln Ser Gln Ile Asp Glu Ile Asp His Asp Tyr Glu Arg Asp Gly Leu 610 615 620Lys Glu Lys Val Tyr Gln Met Leu Gln Lys Trp Val Met Arg Glu Gly625 630 635 640Ile Lys Gly Ala Thr Val Gly Lys Leu Ala Gln Ala Leu His Gln Cys 645 650 655Ser Arg Ile Asp Leu Leu Ser Ser Leu Ile Tyr Val Ser Gln Asn 660 665 67030656PRTMus musculus 30Met Gln Pro Asp Met Ser Leu Asp Asn Ile Lys Met Ala Ser Ser Asp1 5 10 15Leu Leu Glu Lys Thr Asp Leu Asp Ser Gly Gly Phe Gly Lys Val Ser 20 25 30Leu Cys Tyr His Arg Ser His Gly Phe Val Ile Leu Lys Lys Val Tyr 35 40 45Thr Gly Pro Asn Arg Ala Glu Tyr Asn Glu Val Leu Leu Glu Glu Gly 50 55 60Lys Met Met His Arg Leu Arg His Ser Arg Val Val Lys Leu Leu Gly65 70 75 80Ile Ile Ile Glu Glu Gly Asn Tyr Ser Leu Val Met Glu Tyr Met Glu 85 90 95Lys Gly Asn Leu Met His Val Leu Lys Thr Gln Ile Asp Val Pro Leu 100 105 110Ser Leu Lys Gly Arg Ile Ile Val Glu Ala Ile Glu Gly Met Cys Tyr 115 120 125Leu His Asp Lys Gly Val Ile His Lys Asp Leu Lys Pro Glu Asn Ile 130 135 140Leu Val Asp Arg Asp Phe His Ile Lys Ile Ala Asp Leu Gly Val Ala145 150 155 160Ser Phe Lys Thr Trp Ser Lys Leu Thr Lys Glu Lys Asp Asn Lys Gln 165 170 175Lys Glu Val Ser Ser Thr Thr Lys Lys Asn Asn Gly Gly Thr Leu Tyr 180 185 190Tyr Met Ala Pro Glu His Leu Asn Asp Ile Asn Ala Lys Pro Thr Glu 195 200 205Lys Ser Asp Val Tyr Ser Phe Gly Ile Val Leu Trp Ala Ile Phe Ala 210 215 220Lys Lys Glu Pro Tyr Glu Asn Val Ile Cys Thr Glu Gln Phe Val Ile225 230 235 240Cys Ile Lys Ser Gly Asn Arg Pro Asn Val Glu Glu Ile Leu Glu Tyr 245 250 255Cys Pro Arg Glu Ile Ile Ser Leu Met Glu Arg Cys Trp Gln Ala Ile 260 265 270Pro Glu Asp Arg Pro Thr Phe Leu Gly Ile Glu Glu Glu Phe Arg Pro 275 280 285Phe Tyr Leu Ser His Phe Glu Glu Tyr Val Glu Glu Asp Val Ala Ser 290 295 300Leu Lys Lys Glu Tyr Pro Asp Gln Ser Pro Val Leu Gln Arg Met Phe305 310 315 320Ser Leu Gln His Asp Cys Val Pro Leu Pro Pro Ser Arg Ser Asn Ser 325 330 335Glu Gln Pro Gly Ser Leu His Ser Ser Gln Gly Leu Gln Met Gly Pro 340 345 350Val Glu Glu Ser Trp Phe Ser Ser Ser Pro Glu Tyr Pro Gln Asp Glu 355 360 365Asn Asp Arg Ser Val Gln Ala Lys Leu Gln Glu Glu Ala Ser Tyr His 370 375 380Ala Phe Gly Ile Phe Ala Glu Lys Gln Thr Lys Pro Gln Pro Arg Gln385 390 395 400Asn Glu Ala Tyr Asn Arg Glu Glu Glu Arg Lys Arg Arg Val Ser His 405 410 415Asp Pro Phe Ala Gln Gln Arg Ala Arg Glu Asn Ile Lys Ser Ala Gly 420 425 430Ala Arg Gly His Ser Asp Pro Ser Thr Thr Ser Arg Gly Ile Ala Val 435 440 445Gln Gln Leu Ser Trp Pro Ala Thr Gln Thr Val Trp Asn Asn Gly Leu 450 455 460Tyr Asn Gln His Gly Phe Gly Thr Thr Gly Thr Gly Val Trp Tyr Pro465 470 475 480Pro Asn Leu Ser Gln Met Tyr Ser Thr Tyr Lys Thr Pro Val Pro Glu 485 490 495Thr Asn Ile Pro Gly Ser Thr Pro Thr Met Pro Tyr Phe Ser Gly Pro 500 505 510Val Ala Asp Asp Leu Ile Lys Tyr Thr Ile Phe Asn Ser Ser Gly Ile 515 520 525Gln Ile Gly Asn His Asn Tyr Met Asp Val Gly Leu Asn Ser Gln Pro 530 535 540Pro Asn Asn Thr Cys Lys Glu Glu Ser Thr Ser Arg His Gln Ala Ile545 550 555 560Phe Asp Asn Thr Thr Ser Leu Thr Asp Glu His Leu Asn Pro Ile Arg 565 570 575Glu Asn Leu Gly Arg Gln Trp Lys Asn Cys Ala Arg Lys Leu Gly Phe 580 585 590Thr Glu Ser Gln Ile Asp Glu Ile Asp His Asp Tyr Glu Arg Asp Gly 595 600 605Leu Lys Glu Lys Val Tyr Gln Met Leu Gln Lys Trp Leu Met Arg Glu 610 615 620Gly Thr Lys Gly Ala Thr Val Gly Lys Leu Ala Gln Ala Leu His Gln625 630 635 640Cys Cys Arg Ile Asp Leu Leu Asn His Leu Ile Arg Ala Ser Gln Ser 645 650 65531142PRTRattus norvegicus 31Met Cys Tyr Leu His Ser Leu Asn Pro Ser Leu Leu His Arg Asp Leu1 5 10 15Lys Pro Ser Asn Val Leu Leu Asp Leu Glu Leu His Ala Lys Leu Ala 20 25 30Asp Phe Gly Leu Ser Thr Phe Gln Gly Gly Ser Gln Ser Gly Ser Gly 35 40 45Ser Gly Ser Arg Asp Ser Gly Gly Thr Leu Ala Tyr Leu Ala Pro Glu 50 55 60Leu Leu Asp Asn Asp Gly Lys Ala Ser Lys Ala Ser Asp Val Tyr Ser65 70 75 80Phe Gly Val Leu Val Trp Thr Val Leu Ala Gly Arg Glu Ala Glu Val 85 90 95Val Asp Lys Thr Ser Leu Ile Arg Gly Ala Val Cys Asn Arg Gln Arg 100 105 110Arg Pro Pro Leu Thr Glu Leu Pro Pro Asp Ser Pro Glu Thr Pro Gly 115 120 125Leu Glu Gly Leu Lys Glu Leu Met Thr His Cys Trp Ser Tyr 130 135 14032549PRTArabidopsis thaliana 32Met Tyr Met Glu Ile Ser Ser Ala Ser Asp Asp Ser Ile Ala Tyr Val1 5 10 15Glu Thr Asp Pro Ser Gly Arg Tyr Gly Arg Phe Arg Glu Val Leu Gly 20 25 30Lys Gly Ala Met Lys Thr Val Tyr Lys Ala Phe Asp Gln Val Leu Gly 35 40 45Met Glu Val Ala Trp Asn Gln Val Lys Leu Asn Glu Val Phe Arg Ser 50 55 60Pro Glu Pro Leu Gln Arg Leu Tyr Ser Glu Val His Leu Leu Lys Asn65 70 75 80Leu Asn His Glu Ser Ile Ile Arg Tyr Cys Thr Ser Trp Ile Asp Val 85 90 95Asn Arg Arg Thr Phe Asn Phe Ile Thr Glu Leu Phe Thr Ser Gly Thr 100 105 110Leu Arg Glu Tyr Arg Arg Lys Tyr Gln Lys Val Asp Ile Arg Ala Ile 115 120 125Lys Ser Trp Ala Arg Gln Ile Leu Asn Gly Leu Ala Tyr Leu His Gly 130 135 140His Asp Pro Pro Val Ile His Arg Asp Leu Lys Cys Asp Asn Ile Phe145 150 155 160Val Asn Gly His Leu Gly Gln Val Lys Ile Gly Asp Leu Gly Leu Ala 165 170 175Ala Ile Leu Arg Gly Ser Gln Asn Ala His Ser Val Ile Gly Thr Pro 180 185 190Glu Phe Met Ala Pro Glu Leu Tyr Glu Glu Asp Tyr Asn Glu Leu Val 195 200 205Asp Ile Tyr Ser Phe Gly Met Cys Val Leu Glu Met Leu Thr Gly Glu 210 215 220Tyr Pro Tyr Ser Glu Cys Thr Asn Pro Ala Gln Ile Tyr Lys Lys Val225 230 235 240Thr Ser Gly Lys Leu Pro Asp Ser Phe His Leu Ile Gln His Thr Glu 245 250 255Ala Gln Arg Phe Val Gly Lys Cys Leu Glu Thr Val Ser Arg Arg Leu 260 265 270Pro Ala Lys Glu Leu Leu Ala Asp Pro Phe Leu Ala Ala Thr Asp Glu 275 280 285Arg Asp Leu Ala Pro Leu Phe Arg Leu Pro Gln Gln Leu Ala Ile Gln 290 295 300Asn Leu Ala Ala Asn Gly Thr Val Val Glu His Leu Pro Ser Thr Thr305 310 315 320Asp Pro Thr Arg Thr Thr Asp Met Ser Ile Thr Gly Lys Met Asn Ser 325 330 335Glu Asp His Thr Ile Phe Leu Gln Val Gln Ile Leu Asp Gly Asp Gly 340 345 350His Met Arg Asn Ile Gln Phe Pro Phe Asn Ile Leu Ser Asp Thr Pro 355 360 365Leu Glu Val Ala Leu Glu Met Val Lys Glu Leu Glu Ile Thr Asp Trp 370 375 380Asp Pro Leu Glu Ile Ala Ala Met Ile Glu Asn Glu Ile Ser Leu Leu385 390 395 400Val Pro Asn Trp Arg Ala Asn Asp Ser Ser Ile Arg His Glu Ser Phe 405 410 415Gly His Glu Asp Asp Glu Asp Asn Gly Asp Thr Glu Gly Arg Thr Arg 420 425 430Leu Phe Ser Ser Ala Ser Ser Ser His Asp Ser Pro Val Ala Val Arg 435 440 445Glu Asn Asn Asp Asp Ser Ser Asn Asp Val Ile Pro Asp Met Asp Asp 450 455 460Gly Asn Arg Ser Ser Asn Arg Leu Leu Asn Ser Ser Thr Tyr His Tyr465 470 475 480Ser Pro Ala Ile Asp Asp Asp Gln Asn Gln Gln Gln Arg Arg Arg Val 485 490 495Arg Leu Gln Gln Lys Met Arg Ser Leu Val Asp Thr Arg Thr Gln Val 500 505 510Leu His Arg Ser Leu Met Glu Leu Ile Asn Lys Arg Arg Gly Arg Gly 515 520 525Phe Asp Pro Asn Thr Asn Glu Leu Gln Pro Gln Pro Ser Ser Thr Asp 530 535 540Phe Ile Arg Arg Cys54533553PRTArabidopsis thaliana 33Met Ala Gly Ser Ser Thr Lys Arg Phe Pro Leu Tyr Ala Lys Asp Tyr1 5 10 15Glu Leu Phe Glu Glu Val Gly Glu Gly Val Ser Ala Thr Val Tyr Arg 20 25 30Ala Arg Cys Ile Ala Leu Asn Glu Ile Val Ala Val Lys Ile Leu Asp 35 40 45Leu Glu Lys Cys Arg Asn Asp Leu Glu Thr Ile Arg Lys Glu Val His 50 55 60Ile Met Ser Leu Ile Asp His Pro Asn Leu Leu Lys Ala His Cys Ser65 70 75 80Phe Ile Asp Ser Ser Ser Leu Trp Ile Val Met Pro Tyr Met Ser Gly 85 90 95Gly Ser Cys Phe His Leu Met Lys Ser Val Tyr Pro Glu Gly Leu Glu 100 105 110Gln Pro Ile Ile Ala Thr Leu Leu Arg Glu Val Leu Lys Ala Leu Val 115 120 125Tyr Leu His Arg Gln Gly His Ile His Arg Asp Val Lys Ala Gly Asn 130 135 140Ile Leu Ile His Ser Lys Gly Val Val Lys Leu Gly Asp Phe Gly Val145 150 155 160Ser Ala Cys Met Phe Asp Ser Gly Glu Arg Met Gln Thr Arg Asn Thr 165 170 175Phe Val Gly Thr Pro Cys Trp Met Ala Pro Glu Val Met Gln Gln Leu 180 185 190Asp Gly Tyr Asp Phe Lys Leu Trp Ser Phe Gly Ile Thr Ala Leu Glu 195 200 205Leu Ala His Gly His Ala Pro Phe Ser Lys Tyr Pro Pro Met Lys Val 210 215 220Leu Leu Met Thr Leu Gln Asn Ala Pro Pro Arg Leu Asp Tyr Asp Arg225 230 235 240Asp Lys Lys Phe Ser Lys Ser Phe Arg Glu Leu Ile Ala Ala Cys Leu 245 250 255Val Lys Asp Pro Lys Lys Arg Pro Thr Ala Ala Lys Leu Leu Lys His 260 265 270Pro Phe Phe Lys His Ala Arg Ser Thr Asp Tyr Leu Ser Arg Lys Ile 275 280 285Leu His Gly Leu Ser Pro Leu Gly Glu Arg Phe Lys Lys Leu Lys Glu 290 295 300Ala Glu Ala Glu Leu Phe Lys Gly Ile Asn Gly Asp Lys Glu Gln Leu305 310 315 320Ser Gln His Glu Tyr Met Arg Gly Ile Ser Ala Trp Asn Phe Asp Leu 325 330 335Glu Ala Leu Arg Arg Gln Ala Ser Leu Val Ile Val Ser Lys Glu Leu 340 345 350Asn Arg Asn Gly Asp Val Pro Lys Gly Lys Pro Val Ile Gln Arg Ser 355 360 365Gln Thr Met Pro Leu Glu Tyr Phe Ser Glu Lys Asp Met Val Ser Glu 370 375 380Ser Ser Ser Gln Leu Thr Gly Ser Leu Leu Pro Ser Phe His Arg Lys385 390 395 400Phe Leu Pro Ala Leu Gly Tyr Gln Val Gly Ile Ile Ser Asn Glu Ser 405 410 415Asn Ala Cys Asn Ser Ser Asp Arg Ala Ala Glu Lys Leu Ala Phe Glu 420 425 430Glu Pro Arg Gln Val Leu His Pro Leu Ala Asp Thr Lys Lys Ile Arg 435 440 445Lys Ala Gly Ser Asp Gln Gln Glu Lys Pro Lys Asn Gly Tyr Ala Asp 450 455 460Ser Pro Val Asn Arg Glu Ser Ser Thr Leu Ser Lys Glu Pro Leu Ala465 470 475 480Asp Thr Lys Gln Val Arg Lys Pro Gly Asn Glu Gln Glu Lys Pro Lys 485 490 495Asn Gly Tyr Ile Val Ser His Val Asn Arg Glu Ser Ser Thr Ser Glu 500 505 510Glu Ile Leu Pro Leu Leu Gln Ser Leu Leu Val Gln Asn Asp Ile Gln 515 520 525Arg Val Cys Val Leu Ser Val Ser Thr Ala Ser Cys Gly Tyr Thr Ser 530 535 540Pro Lys Trp Leu Leu Arg Phe Gly Phe545 55034516PRTArabidopsis thaliana 34Met Arg Gln Asp Glu Asn Asn Ser Glu Glu Glu Phe Val Glu Ile Asp1 5 10 15Pro Thr Gly Arg Tyr Gly Arg Tyr Lys Glu Val Leu Gly Lys Gly Ala 20 25 30Phe Lys Glu Val Tyr Arg Ala Phe Asp Gln Leu Glu Gly Ile Glu Val 35 40 45Ala Trp Asn Gln Val Lys Leu Asp Asp Lys Phe Cys Ser Ser Glu Asp 50 55 60Leu Asp Arg Leu Tyr Ser Glu Val His Leu Leu Lys Thr Leu Lys His65 70 75 80Lys Ser Ile Ile Lys Phe Tyr Thr Ser Trp Ile Asp His Gln His Met 85 90 95Thr Ile Asn Leu Ile Thr Glu Val Phe Thr Ser Gly Asn Leu Arg Gln 100 105 110Tyr Arg Lys Lys His Lys Cys Val Asp Leu Arg Ala Leu Lys Lys Trp 115 120 125Ser Arg Gln Ile Leu Glu Gly Leu Val Tyr Leu His Ser His Asp Pro 130 135 140Pro Val Ile His Arg Asp Leu Lys Cys Asp Asn Ile Phe Ile Asn Gly145 150 155 160Asn Gln Gly Glu Val Lys Ile Gly Asp Leu Gly Leu Ala Ala Ile Leu 165 170 175His Arg Ala Arg Ser Ala His Ser Val Ile Gly Thr Pro Glu Phe Met 180 185 190Ala Pro Glu Leu Tyr Glu Glu Asp Tyr Asn Val Leu Val Asp Ile Tyr 195 200 205Ala Phe Gly Met Cys Leu Leu Glu Leu Val Thr Phe Glu Tyr Pro Tyr 210 215 220Ser Glu Cys Thr Asn Ala Ala Gln Ile Tyr Arg Lys Val Thr Ser Gly225 230 235 240Ile Lys Pro Ala Ala Leu Leu Asn Val Thr Asp Pro Gln Val Arg Ala 245 250 255Phe Ile Glu Lys Cys Ile Ala Lys Val Ser Gln Arg Leu Ser Ala Lys 260 265 270Glu Leu Leu Asp Asp Pro Phe Leu Lys Cys Tyr Lys Glu Asn Thr Glu 275 280 285Asn Val Ser Ser His Lys Glu

Asn Gly Tyr Asn Gly Asn Gly Ile Val 290 295 300Asp Lys Leu Ser Asp Ser Glu Val Gly Leu Leu Thr Val Glu Gly Gln305 310 315 320Arg Lys Asp Leu Asn Thr Ile Phe Leu Lys Leu Arg Ile Thr Asp Ser 325 330 335Lys Gly Gln Ile Arg Asn Ile His Phe Pro Phe Asn Ile Glu Thr Asp 340 345 350Thr Ser Phe Ser Val Ala Ile Glu Met Val Glu Glu Leu Asp Leu Thr 355 360 365Asp Asp Gln Asp Ile Ser Thr Ile Ala Lys Met Ile Asp Thr Glu Ile 370 375 380His Ser His Ile Pro Asp Trp Thr Pro Ser Arg Leu Ile Gly Asp Asp385 390 395 400Ser Ala Val Gln Lys Cys Leu Ser Ser Pro Glu Thr Leu His Leu Asp 405 410 415Arg Phe Pro Ser Gly Arg Lys Phe Trp Ser Ser Pro Lys Ala Gly Ala 420 425 430Gly Asp Ser Arg Ser Pro Phe Ala Pro Arg Ser Asn Ser Lys Leu Ser 435 440 445Ser Ala Gln Gly Pro Ile Asn Gln Glu Val Gly Val Ile Val Glu Lys 450 455 460Leu Glu Ser Leu Leu Arg Lys Gln Arg Glu Glu Ile Glu Glu Met Gln465 470 475 480Arg Asp Gln Glu Arg Ile Val Thr Glu Phe Leu Lys Glu Phe Pro Pro 485 490 495Glu Ile Cys Glu Glu Ala Leu Val Arg Leu Gln Val Lys Asp Ser Asp 500 505 510Asn Leu Leu Cys 51535461PRTC. elegans 35Met Cys Lys Asp Val Ser Gly Gln Asn Leu Leu Val Ala Pro Asp Ala1 5 10 15Ile Asn His His Val Lys Thr Cys Arg Glu Asn Met Arg Tyr Met His 20 25 30Tyr Ile Ala Pro Glu Tyr Glu Asn Asn Thr Glu Leu Thr Ser Ala Ala 35 40 45Asp Ile Tyr Ser Phe Gly Ile Cys Ser Leu Glu Ile Ala Val Ile Gly 50 55 60Gly Leu Ser Gly Cys Gln Asn Gly Ser Ser Glu Gly Pro Val Thr Glu65 70 75 80Asp Val Ile Glu Lys Ala Ile Arg Ser Leu Glu Asp Pro Met Gln Gln 85 90 95Asp Phe Ile Arg Gln Cys Leu Arg Lys Asp Pro Ala Glu Arg Pro Ser 100 105 110Ala Arg Glu Leu Leu Phe His Gln Ile Leu Phe Glu Val His Ser Leu 115 120 125Lys Leu Leu Ser Ala His Ala Ile Val Asp Ser Lys Lys Tyr Glu Asp 130 135 140Val Ser Glu Ser Ala Phe Arg Ile Lys Asp Asn Glu Thr Ile Ala Ala145 150 155 160Thr Ser Lys Leu Arg Glu Met Ala Tyr Cys Gln Val Ala Ala Phe Gln 165 170 175Val Asp Leu Glu Lys Phe Leu Asp Asp Val Arg Asn Gly Ile Tyr Pro 180 185 190Leu Thr Ala Phe Ala Pro Leu Ala His Gln Pro Ser Thr Thr Leu Arg 195 200 205Ala Tyr Ser Asn Thr Asn Pro Ser Thr Leu Ile Thr Thr Asp Ile Ser 210 215 220Ala Pro Ser Ser Thr His Pro Ser Ala Asn Ser Thr Ile Thr Ala Glu225 230 235 240Thr Ser Val Asn Thr Ser Leu Pro Gly Gln Ser Ser Gln Pro Ser Gly 245 250 255Thr Thr Thr Asn Thr Asn Gly Pro Ser Ser Ile Gly Lys Ser Ala Ser 260 265 270Pro Glu Ala Val Asp Lys Lys Ile Gly Glu Val Thr Ser Thr Glu Ser 275 280 285Thr Ser Lys Val Glu Val Glu Val Asn Gly Ala Asn Val Thr Ile Gly 290 295 300Ser Ser Asn Gly Arg Asp Ala Gly Ser Pro Thr Pro Glu Glu Glu Gly305 310 315 320Glu Pro Asn Gly Glu Arg Asp Met Arg Leu Glu Asn Arg His Ile Leu 325 330 335Glu Ile Asn Val His Ile Glu Asn Glu Glu Met Ser Ile Val Leu Leu 340 345 350Leu Glu Asp Gln Met His Arg Gln Leu Thr Thr Ser Ile Asn Lys Gly 355 360 365Asp Asn Pro Glu Thr Leu Thr Glu Asn Leu Ile Thr His Gly Phe Met 370 375 380Cys Gln Leu Asp Ser Glu Gly Val Glu Lys Ala Ile Ala Val Ala Phe385 390 395 400Asp Ile Arg Ala Ala Arg Ile Ala Glu Gly Val Gln Glu Glu Glu Asn 405 410 415Glu Thr Ser Thr Arg Glu Ser Asn Ser Glu Ala Pro Ile Glu His Gly 420 425 430Thr Ser Ser Ser Ile Thr Asn Ser Val Lys Pro Ile Val Asp Ser Val 435 440 445Ala Pro Ser Ser Gln Thr Pro Thr Thr Thr Thr Ser Ser 450 455 46036231PRTC. elegans 36Met Val Ser Ser Gly Glu Glu Arg Thr Ala Ala Gly Lys Thr Pro Ile1 5 10 15Gly Asp Asp Ala Ala Ser Asp Ser Asp Ala Asp Gly Ala Glu Glu Ile 20 25 30Leu Glu Glu Ser Pro Asp Lys Arg Trp Ser Lys Arg Arg Glu Gln Val 35 40 45Lys Gln Arg Asp Val Pro Gly Ile Asp Val Ala Tyr Leu Ala Met Asp 50 55 60Asn Glu Thr Gly Asn Glu Val Val Trp Asn Glu Val Gln Phe Ser Glu65 70 75 80Arg Lys Asn Phe Arg Ala Gln Glu Glu Lys Ile Asn Ala Val Phe Asp 85 90 95Asn Leu Thr Gln Leu Val His Thr Asn Leu Val Lys Phe His Lys Tyr 100 105 110Trp Thr Asp Ser Lys Ser Glu Lys Pro Arg Ile Ile Phe Ile Thr Glu 115 120 125Tyr Met Ser Ser Gly Ser Met Ser Ala Phe Leu Gln Arg Thr Arg Lys 130 135 140Ala Gly Ser Ser Leu Ser Ile Lys Ala Trp Lys Lys Trp Thr Thr Gln145 150 155 160Ile Leu Ser Ala Leu Asn Tyr Leu His Ser Ser Asp Pro Pro Ile Ile 165 170 175His Gly Asn Leu Thr Cys Asn Thr Val Phe Ile Gln Gln Asn Gly Leu 180 185 190Ile Lys Ile Gly Cys Gly Glu Phe Gln Phe Phe Ala Val Ile Phe Ile 195 200 205Leu Ile Asp Gln Phe Glu Lys Phe Thr Gly Tyr Cys Arg Lys Tyr Ser 210 215 220Asp Lys Met Val Lys Asn His225 23037309PRTHomo sapiens 37Asp Arg Lys Leu Thr Lys Leu Glu Arg Gln Arg Phe Lys Glu Glu Ala1 5 10 15Glu Met Leu Lys Gly Leu Gln His Pro Asn Ile Val Arg Phe Tyr Asp 20 25 30Phe Trp Glu Ser Ser Ala Lys Gly Lys Arg Cys Ile Val Leu Val Thr 35 40 45Glu Leu Met Thr Ser Gly Thr Leu Lys Thr Tyr Leu Lys Arg Phe Lys 50 55 60Val Met Lys Pro Lys Val Leu Arg Ser Trp Cys Arg Gln Ile Leu Lys65 70 75 80Gly Leu Leu Phe Leu His Thr Arg Thr Pro Pro Ile Ile His Arg Asp 85 90 95Leu Lys Cys Asp Asn Ile Phe Ile Thr Gly Pro Thr Gly Ser Val Lys 100 105 110Ile Gly Asp Leu Gly Leu Ala Thr Leu Lys Arg Ala Ser Phe Ala Lys 115 120 125Ser Val Ile Gly Thr Pro Glu Phe Met Val Pro Glu Met Tyr Glu Glu 130 135 140His Tyr Asp Glu Ser Val Asp Val Tyr Ala Phe Gly Met Cys Met Leu145 150 155 160Glu Met Ala Thr Ser Glu Tyr Pro Tyr Ser Glu Cys Gln Asn Ala Ala 165 170 175Gln Ile Tyr Arg Lys Val Thr Cys Gly Ile Lys Pro Ala Ser Phe Glu 180 185 190Lys Val His Asp Pro Glu Ile Lys Glu Ile Ile Gly Glu Cys Ile Cys 195 200 205Lys Asn Arg Glu Glu Arg Tyr Glu Ile Lys Asp Leu Leu Ser His Ala 210 215 220Phe Phe Ala Glu Asp Thr Gly Val Arg Val Glu Leu Ala Glu Glu Asp225 230 235 240His Gly Arg Lys Ser Thr Ile Ala Leu Arg Leu Trp Val Glu Asp Pro 245 250 255Lys Lys Leu Lys Gly Lys Pro Lys Asp Asn Gly Ala Thr Glu Phe Thr 260 265 270Phe Asp Leu Glu Lys Glu Thr Pro Asp Glu Val Ala Gln Glu Met Ile 275 280 285Glu Ser Gly Phe Phe His Glu Ser Asp Val Lys Ile Val Ala Lys Ser 290 295 300Ile Arg Asp Arg Val30538677PRTOryza sativa 38Met Gly Pro Lys Ala Asn Ala Ala Ala Ala Gly Asp Leu Pro Glu Tyr1 5 10 15Ala Glu Val Asp Pro Thr Gly Arg Tyr Gly Arg Tyr Asn Asp Val Leu 20 25 30Gly Lys Gly Ala Ser Lys Thr Val Tyr Arg Ala Phe Asp Glu Tyr Gln 35 40 45Gly Met Glu Val Ala Trp Asn Gln Val Lys Leu His Asp Phe Leu Gln 50 55 60Ser Pro Glu Asp Leu Glu Arg Leu Tyr Cys Glu Ile His Leu Leu Lys65 70 75 80Thr Leu Lys His Arg Asn Ile Met Lys Phe Tyr Thr Ser Trp Val Asp 85 90 95Val Ser Arg Arg Asn Ile Asn Phe Ile Thr Glu Met Phe Thr Ser Gly 100 105 110Thr Leu Arg Gln Tyr Arg Gln Lys His Met Arg Val Asn Ile Trp Ala 115 120 125Val Lys His Trp Cys Arg Gln Ile Leu Ser Gly Leu Leu Tyr Leu His 130 135 140Ser His Asp Pro Pro Ile Ile His Arg Asp Leu Lys Cys Asp Asn Ile145 150 155 160Phe Val Asn Gly Asn Gln Gly Glu Val Lys Ile Gly Asp Leu Gly Leu 165 170 175Ala Ala Ile Leu Arg Lys Ser His Ala Val His Cys Val Gly Thr Pro 180 185 190Glu Phe Met Ala Pro Glu Val Tyr Glu Glu Glu Tyr Asn Glu Leu Val 195 200 205Asp Ile Tyr Ser Phe Gly Met Cys Val Leu Glu Met Val Thr Phe Glu 210 215 220Tyr Pro Tyr Ser Glu Cys Thr His Pro Val Gln Ile Tyr Lys Lys Val225 230 235 240Ile Ser Gly Thr Lys Pro Glu Ala Leu Tyr Lys Val Lys Asp Pro Met 245 250 255Val Arg Gln Phe Val Glu Lys Cys Leu Ala Thr Ala Ser Arg Arg Leu 260 265 270Ser Ala Arg Glu Val Leu Lys Asp Pro Phe Leu Gln Val Asp Asp Leu 275 280 285Val Phe Cys Pro Gly Asp Gly Asn Tyr Ser Leu Met Asn Tyr Leu Arg 290 295 300Gln Pro Tyr Leu Gln His Ala Tyr Ser Thr Val Ser Met Met Ser Asn305 310 315 320Gly Leu Ser Glu Ser Ile Asp Glu Asp Ser Pro Thr Glu Asp Arg Trp 325 330 335Asp Cys Glu Asp Asp Asp Ile Lys Ala Asp Gly Ile Asp Leu Phe Asn 340 345 350Gly His Glu Asp Glu Pro Leu Gly Asn Val Asp Ile Thr Ile Lys Gly 355 360 365Arg Lys Ser Glu Asp Gly Ser Ile Phe Leu Arg Leu Arg Ile Ala Asp 370 375 380Asn Asp Gly His Val Arg Asn Ile Tyr Phe Pro Phe Asp Ile Glu Ala385 390 395 400Asp Thr Ala Leu Ser Val Ala Thr Glu Met Val Ala Glu Leu Asp Ile 405 410 415Thr Asp His Glu Val Thr Arg Ile Ala Glu Met Ile Asp Gly Glu Val 420 425 430Ser Ala Leu Val Pro Asp Trp Arg Pro Gly Pro Gly Ile Glu Glu Ser 435 440 445Gln Asp Thr Thr Tyr Cys His Asn Cys Gly Ser Asn Val Ser Ser Cys 450 455 460Gly Ser Leu Tyr Ala Tyr Met Ser Cys Ala Ala Arg Gly Cys His Cys465 470 475 480Ala Asp Leu His Gly Arg Phe Glu Asp Ile Thr Phe Gln Ala Asn Gly 485 490 495Glu Gln Thr Asp Leu Gln Asp Ser Gly Gly Ser Ser Asp Asp Gly Gly 500 505 510Gly Gln Thr Gln His Val Lys Asp Gln Glu Ala Val His Ser Asn Gly 515 520 525Phe Val Gln Met Gly Thr Thr Arg Pro Arg Asp Gln Phe Cys Phe Ser 530 535 540Ser Phe Gln Glu Gln Ser Cys Ser Pro Arg His Tyr Glu Tyr Asp Thr545 550 555 560Ser Leu Gln Ala Lys Gly Phe Asp Met Lys His Glu Val Lys Met Ala 565 570 575Lys Tyr Lys Ala Arg Lys Met Ala His Leu Arg Arg Gly Ile His Pro 580 585 590Ser Leu Asp Phe Asp Asn Leu Asn Gly Glu Arg Arg Met Lys Ser Ser 595 600 605Leu Asn Lys Leu Gln Ser Phe His Ile Gly Lys Asn His Asn Phe Arg 610 615 620Ile Pro Thr Cys Glu Arg Ser Pro Gly Ala Arg Asp Ala Glu Glu Asp625 630 635 640Pro Asp Ile Phe Asn Leu Ala Tyr His Ser Arg His Pro Asp Pro Gly 645 650 655Ala Gln Arg Ala Arg His Cys Glu Val Asp Ala Gln Ser Ser Pro Asp 660 665 670Gly His Val Tyr Ser 67539613PRTPhycomyces blakesleeanus 39Met Pro Asp Tyr Glu Lys Val Ile Glu Ala Ser Gly Asn Gly Arg Tyr1 5 10 15Ser Lys Leu Asn Thr Val Leu Gly Lys Gly Ala Tyr Lys Val Val Tyr 20 25 30Lys Ala Ile Asp Arg Glu Glu Ala Ile Asn Asp Asn Glu Ile Thr Asn 35 40 45Val Lys Val Thr Arg Gln Glu Phe Lys Asp Leu Gly His Glu Ile Asp 50 55 60Ile Leu Lys Ser Val Arg His Pro Asn Ile Ile Thr Phe His Asp Ala65 70 75 80Trp Tyr Asn Glu Thr Glu Phe Val Phe Ile Thr Glu Leu Met Thr Ser 85 90 95Gly Thr Leu Arg Glu Tyr Ile Arg Lys Leu Thr Pro Leu Pro Asn Ile 100 105 110Lys Ile Val Lys Arg Trp Cys Arg Gln Ile Leu Lys Gly Leu Ala Tyr 115 120 125Leu His Gly His Glu Pro Pro Ile Ile His Arg Asp Ile Lys Cys Asp 130 135 140Asn Ile Phe Ile Asn Gly Ala His Gly Glu Ile Lys Ile Gly Asp Met145 150 155 160Gly Thr Ala Glu Met Lys Asn Gly Lys Lys Tyr Thr Val Ile Gly Thr 165 170 175Pro Glu Phe Met Ala Pro Glu Met Tyr Glu Glu Gln Gly Tyr Asn Glu 180 185 190Lys Val Asp Ile Tyr Ala Phe Gly Met Cys Leu Leu Glu Met Ala Thr 195 200 205Gly Glu Tyr Pro Tyr Gly Glu Cys Thr Asn Ala Val Gln Val Phe Lys 210 215 220Lys Val Thr Gln Thr Ile Lys Pro Glu Cys Leu Ser Arg Val Gln Asp225 230 235 240Pro Glu Leu Leu Thr Leu Val Asn Ile Cys Leu Thr Pro Glu Asp Glu 245 250 255Arg Met Thr Ala Gln Glu Ile Leu Glu His Arg Phe Leu Ala Val Glu 260 265 270Pro Glu Val Val Leu Val Ser Lys Asp Met Thr Met Lys Leu Leu Thr 275 280 285Leu Gln Val Val Phe Lys Gly Met Asp Lys Leu Ser Val Lys Phe Glu 290 295 300Phe Asn Ala Asp Thr Asp Thr Ala Ala Asp Val Val Ala Glu Met Ile305 310 315 320Glu Glu Gln Val Leu Gln Asn Cys Tyr Gln Gln Leu Ile Thr Cys Glu 325 330 335Ile Asn Arg Ile Leu Arg Asp Ile Ala Arg Asn Gln Gly Pro Pro Asp 340 345 350Lys Gly Glu Asp Glu Lys Ile Val Trp Arg Arg Glu Asn Asp Ile Arg 355 360 365Ser Glu Leu Glu Arg Ala Lys Lys Asp Leu Ala Leu Ala Val Glu Arg 370 375 380Val Phe Glu Ala Glu Lys Lys Cys Glu Leu Leu Glu Gln His Asn Ile385 390 395 400Ile Ala Glu Glu Arg Cys Lys Glu Thr Ile Phe Ala Leu Glu Gln Ala 405 410 415Lys Phe Gln Ile Pro Asp Leu Leu Gln Pro Gln Pro Gln Pro Gln Pro 420 425 430Gln Pro Gln Pro Gln Pro Gln Pro Gln Pro Gln Phe Gln Leu Gln Pro 435 440 445Gln Leu Gln Tyr Leu Ser Pro Gln Ser Thr Thr Ser Pro Gly Pro Thr 450 455 460Ser Asp Asp Asn Ser Thr Asn Ser Thr Met Leu Ser Ser Leu Glu Ser465 470 475 480Glu Leu Ser Lys Leu Cys Val Ser Gly Asp Glu Gln Val Glu Thr Thr 485 490 495Thr His Ser Ala Leu Met Glu Asn Val Leu Ala Gly Lys Ala Lys Tyr 500 505 510Tyr Glu Tyr Ser Asn Asp Thr Ser Ile Asp Lys Phe Val Met Asp Thr 515 520 525Ala Gly Ala Thr Asn Arg Ser Lys Asp Lys Gln Lys Gln Trp Ala Ala 530 535 540Lys Leu Gln Asp Gln Asp Ile Met Thr Val Gly Asp Leu Arg Asp Leu545 550 555 560His Asp Glu Asp Trp Ser Gly Ile Gly Leu

Thr Val Phe Ala Leu Arg 565 570 575Ala Leu Lys Asn Met Leu Ala Gly Lys Lys Ala Ala Val Thr Gln Arg 580 585 590Gly Leu Gln Gly Thr Arg Ser Gly Ala Ser Thr Pro Val Glu Glu Gln 595 600 605Glu Gln Glu Leu Met 610401601PRTC. elegans 40Ser Ser Ser Ser Pro Ser Asp Ala Ala Asn Asn Asp Lys Pro Ile Gln1 5 10 15Gln Arg His Ser Ile Leu Ser Asn Val Arg Thr Leu Thr Gln Ala Met 20 25 30Val Asn Asp Gly Pro Arg Thr Leu Thr Gly Asp Asp Met Asp Lys Met 35 40 45Val Ser Glu Glu Glu Arg Ala Arg Lys Glu Gln Glu Lys Arg Glu Glu 50 55 60Glu Glu Lys Ala Ala Arg Arg Ile Asp Val Glu Asp Asp Phe Asp Ala65 70 75 80Gln Glu Lys Pro Ile Asp Lys Ser Lys Asn Gly Arg Phe Leu Lys Phe 85 90 95Asp Glu Glu Leu Gly Arg Gly Ser Phe Lys Thr Val Phe Arg Gly Leu 100 105 110Asp Thr Glu Thr Gly Val Ala Val Ala Trp Cys Glu Leu Gln Glu Ser 115 120 125Lys Leu Asn Lys Thr Glu Arg Gln Arg Phe Arg Glu Glu Ala Glu Met 130 135 140Leu Lys Asp Leu Gln His Pro Asn Ile Val Arg Phe Tyr Asp Tyr Trp145 150 155 160Glu Ser Ala Asp Leu Cys Gly Lys Arg Lys Tyr Ile Val Leu Val Thr 165 170 175Glu Leu Met Thr Ser Gly Thr Leu Lys Met Tyr Leu Lys Arg Phe Lys 180 185 190Arg Ile Asn Ile Lys Val Val Leu Lys Ser Trp Cys Arg Gln Ile Leu 195 200 205Lys Gly Leu Ser Phe Leu His Thr Arg Asn Pro Pro Val Ile His Arg 210 215 220Asp Leu Lys Cys Asp Asn Ile Phe Ile Thr Gly Thr Thr Gly Ser Val225 230 235 240Lys Ile Gly Asp Leu Gly Leu Ala Thr Leu Lys Asn Lys Ser Phe Ala 245 250 255Lys Ser Val Ile Gly Thr Pro Glu Phe Met Ala Pro Glu Met Tyr Glu 260 265 270Glu Met Tyr Asp Glu Ser Val Asp Val Tyr Ala Phe Gly Met Cys Leu 275 280 285Leu Glu Met Val Thr Gly Glu Tyr Pro Tyr Ser Glu Cys Met Asn Pro 290 295 300Ala Thr Ile Tyr Arg Lys Val Ile Ser Gly Val Lys Pro Glu Cys Phe305 310 315 320Ser Arg Ile Pro Ala Gln Tyr Pro Glu Ile Arg Glu Ile Ile Asp Arg 325 330 335Cys Ile Arg Val Arg Arg Glu Glu Arg Ser Thr Val Lys Gln Leu Leu 340 345 350Val Asp Asp Phe Phe Thr Pro Glu Asp Leu Ile Gly Ile Arg Val Glu 355 360 365Ile Lys Asn Arg Asp Ala Asp Leu Asn Asp Leu Asn Val Glu Ile Gln 370 375 380Met Gln Leu Arg Val Tyr Asp Glu Lys Lys Arg Lys Gln Tyr Arg Phe385 390 395 400Lys Glu Asn Glu Gly Leu Gln Phe Ala Phe Asp Ile Glu Asn Asp Ser 405 410 415Pro Asp Glu Val Val Gln Gln Met Ile Glu Gln Gln His Ile Pro Asp 420 425 430Glu Asp Thr Arg Met Ile Thr Lys Leu Ile Lys Asp Lys Val Asp Ala 435 440 445Phe Arg Arg Asp Arg Asp His Arg Leu Leu Glu Ile Lys Arg Ala Lys 450 455 460Glu Glu Glu Glu Arg Ile Arg Glu Glu Ala Glu Ile Lys Glu Glu Leu465 470 475 480Arg Leu Arg Ala Glu Ala Lys Glu Lys Glu Lys Glu Arg Leu Glu Lys 485 490 495Glu Arg Leu Glu Lys Lys Ala Ala Ala Ala Ala Ala Ala Asn Pro Asn 500 505 510Pro Thr Pro Ile Pro Pro Thr Pro Ala Thr Pro His Ser Ser Ala Gln 515 520 525Gln Gln Pro Ile Pro Pro Pro Leu Ser Thr Gln Thr Ser Ala Glu Ile 530 535 540Gln Gln Ser Ala Gln Gln Pro Ser Val Pro Val Thr Met Ile Ala Asn545 550 555 560Ile Pro Ala Met Ser Pro Thr Ser Ala Gln Pro Gln Pro Val Leu Ser 565 570 575Pro Thr Ser Ala Ala Val Pro Val Pro Thr Thr Met Ile His Val Pro 580 585 590Lys Pro Ser Glu Ile Pro Val Gln Asn Val Ala Thr Thr Ala Ala Pro 595 600 605Val Ala Ala Asn Asn Val Pro Pro Ser Pro Ala Pro Phe Lys Thr Glu 610 615 620Asp Ile Gln Thr Pro Thr Leu Ala Gln Asn Thr Val Pro Arg Thr Ile625 630 635 640Ser Thr Asp Ala Ser Gly Leu Val Ile Asn Thr Pro Ala Ser Ile Ala 645 650 655Ser Pro Ser Pro Ala Pro Ser Ala Thr Asp Val Ala Ser Thr Thr Ala 660 665 670Pro Val Thr Pro Ala Pro Thr Pro Thr Thr Thr Thr Asp Gly Gly Ala 675 680 685Ala Ala Ala Ser Thr Thr Thr Glu Asn Lys Glu Glu Lys Arg Lys Ser 690 695 700Asn Lys Arg Lys Val Val Met Glu Ile Leu Gly Cys Asp Glu Ser Arg705 710 715 720Asn Phe Ala Leu Val Ser Cys Arg Leu Asp Thr Ser His Lys Ser Val 725 730 735Thr Phe Gln Phe Ala Pro Gly Thr Asp Lys Pro Cys Thr Ile Ala Thr 740 745 750Lys Leu Leu Ala Glu Asp Cys Leu Leu Lys Val His Val His Ile Val 755 760 765Glu Ala Gln Leu Gly Glu Val Ile Gln Leu Ile Asn Ser Asp Gly Lys 770 775 780Lys Gly Val Gly Thr Lys Leu Ala Thr Val Leu Asp Pro Asn Ser Thr785 790 795 800Glu Pro Pro Thr Ile Thr Ala Val Met Pro Lys Asp Ser Ser Ala Ala 805 810 815Thr Ala Ser Asn Thr Lys Pro Lys Ile Glu Ile Glu Lys Thr Pro Pro 820 825 830Thr Arg Asp Ala Ser Gln Glu Pro Asn Asn Val Gln Val Thr Asn Val 835 840 845Arg Lys Val Ser Gln Glu Ser Asn Ala Glu Ser Val Gln Ser Ile Pro 850 855 860Arg Pro Gly Gly Ile Ile Val Met Ser Pro Thr Asn Gln Thr Asp Ser865 870 875 880Ala Pro Pro Pro Thr Gly Ala Ala Ala Lys Pro Ser Arg Phe Gln Val 885 890 895Thr Lys Ser Ala Asp Pro Ile Ala Thr Pro Ile Ser Ser Ser Ile Ser 900 905 910Thr Ala Thr Val Ile Pro Ile Val Ala Ala Thr Pro Thr Asn Ile Thr 915 920 925Ser Glu Pro Val Ile Val Gln Pro Ile Thr Ala Gln Val Ile Thr His 930 935 940Leu Ala Thr Pro Ser Pro Val Ser His Ser Leu Ser Ser Asn Ser Ser945 950 955 960Pro Ser Ala Thr Thr His Ser Asn Met Ser Ser Ile Gln Ser Thr Thr 965 970 975Ser Val Pro Gly Arg Arg Phe Thr Val Gln Pro Val Ser Gln Ala Glu 980 985 990Ser Gly Ile Ser Ser Ser Ile Ser Thr Pro His Pro Glu Pro Thr Pro 995 1000 1005Ala Ile Thr Ser Cys Pro Pro Pro Val Pro Ser Val Pro Pro Val Val 1010 1015 1020Ser Asn Gly Thr Leu Asn Leu Glu Val Ala Pro Lys Gln Thr Pro Ser1025 1030 1035 1040Ala Thr Asn Gln Asn Val Asp Thr Gln His Ser Ser Ser Thr Ala Ser 1045 1050 1055Thr Ala Thr Leu Val Ser Glu Thr Pro Ala Thr Val His Val Thr Pro 1060 1065 1070Ile Ser Val Pro Ala Pro Val Gln Glu Pro Leu Val Ile Asp His His 1075 1080 1085Ser Asp Val Leu Thr Gln Leu Asp Ser Glu Leu Arg Lys Val Ser Gly 1090 1095 1100Val Ser His Ser Ala Ser Pro Ser Thr Val Val Glu Ser Leu Thr Ser1105 1110 1115 1120Met Thr Pro Gln Thr Ile Pro Leu Ala Cys Gln Thr Val Pro Ala Ser 1125 1130 1135Ile Gly Gln Ala Pro Ala Val Ile Ala Ala Ala His Ala Ala Ser Leu 1140 1145 1150Ile Pro Asn Ala Ser Val Pro Gln Ser Pro Ser Arg Leu Asp Ala Glu 1155 1160 1165Thr Gly Leu Ala Gly Leu His Glu Lys Leu Glu Ala Leu Lys Met Glu 1170 1175 1180Gln Asp Arg Arg Glu Asp Met Gly Asp Asp Ala Ile Gly Thr Thr Thr1185 1190 1195 1200Thr Asp Gly Lys Asp Glu Ile Pro Ile Asp Thr Leu Lys Gly Leu Ala 1205 1210 1215Glu Ala Leu Gly Lys Val Ile His Ala Asp Gly Arg Glu Thr Thr Pro 1220 1225 1230Met Pro Pro Asp His Pro Asp Leu Thr Asp Ala Ser Thr Gln Gln Leu 1235 1240 1245Ile Ser Pro Ser Asn Pro Asp Val Leu Thr Thr Met Ser Ser Ala Val 1250 1255 1260Glu Gly Ser Ala Ser Ser Thr Met Ile Glu Asp Ile Asp Ala Ser Thr1265 1270 1275 1280Ser Ala Val Asp Ala Ser Met Met Asn Ser Met Pro Pro Gly Ala Gln 1285 1290 1295Asn Ser Thr Asp Gln Ile Pro Ala Ala Met Thr Leu Ser Met Asp Gln 1300 1305 1310Glu Cys Ala Gln Ser Met Thr Ser Ser Ile Thr Arg Asn Thr Thr Gly 1315 1320 1325Thr Lys Leu Ala Thr Phe Glu Asn Leu Glu Thr Ala Leu Ser Ser Thr 1330 1335 1340Leu Gly Thr His Ile Arg Gln Pro Asn Ala Pro Ser Ser Arg Asp Glu1345 1350 1355 1360Thr Thr Ala Pro Met Thr Pro Ser Phe Thr Asn Glu Arg Ile Gly Gly 1365 1370 1375Gly Gly Gly Gly Gly Ala Thr Ser Phe Ser Ile Gly Thr Pro Pro Ser 1380 1385 1390His Ser Pro Phe Pro Val Ser Glu Cys Asp Tyr Asp Leu Lys Gly Gln 1395 1400 1405Met Asp Leu Glu Ser Glu Asp Pro Glu Val Ile Gln Met Ile Val Arg 1410 1415 1420His Arg Met Glu Gln His Lys Leu Leu Glu Lys Gln Arg Val Glu Ile1425 1430 1435 1440Glu Arg Leu Arg Ser Lys Ile Arg Val Pro Arg Ala Thr Ser Val Asn 1445 1450 1455Pro Glu Met Ile Gly Asp Asp Glu Ala Asp Thr Thr Leu Thr Ala Leu 1460 1465 1470Gln Ser Ala Leu Gly Asn Ala Ser Leu Ser Leu Pro Ala Ser Pro Pro 1475 1480 1485Pro Asn Thr Glu Thr Thr Lys Val Asn Thr Thr Val Ile Pro Ser Asp 1490 1495 1500Val Leu Ala Thr Arg Met Thr Met Ser Gln Ser Ser Thr Lys Ser Ser1505 1510 1515 1520Asn Val Ser Val Ser Ser Arg His Arg Asp Asn Gln Ser Ala Pro Pro 1525 1530 1535Arg His His His His Gln Pro His Pro Pro His His Pro His Leu Gln 1540 1545 1550Asn His Tyr His Pro Pro Gln Asn His Thr Ser Ala Thr Ala Pro Cys 1555 1560 1565Pro Ser Ala Met Val Gln Leu Gln Ala Val Ser Asn Asn Asn Val Asn 1570 1575 1580Pro Leu His Gln Pro Pro His Pro Val Ser Ser Gln Ile Pro Pro Gln1585 1590 1595 1600Ala41638PRTHomo sapiens 41Met Ser Ala Leu Ala Gly Glu Asp Val Trp Arg Cys Pro Gly Cys Gly1 5 10 15Asp His Ile Ala Pro Ser Gln Ile Trp Tyr Arg Thr Val Asn Glu Thr 20 25 30Trp His Gly Ser Cys Phe Arg Cys Ser Glu Cys Gln Asp Ser Leu Thr 35 40 45Asn Trp Tyr Tyr Glu Lys Asp Gly Lys Leu Tyr Cys Pro Lys Asp Tyr 50 55 60Trp Gly Lys Phe Gly Glu Phe Cys His Gly Cys Ser Leu Leu Met Thr65 70 75 80Gly Pro Phe Met Val Ala Gly Glu Phe Lys Tyr His Pro Glu Cys Phe 85 90 95Ala Cys Met Ser Cys Lys Val Ile Ile Glu Asp Gly Asp Ala Tyr Ala 100 105 110Leu Val Gln His Ala Thr Leu Tyr Cys Gly Lys Cys His Asn Glu Val 115 120 125Val Leu Ala Pro Met Phe Glu Arg Leu Ser Thr Glu Ser Val Gln Glu 130 135 140Gln Leu Pro Tyr Ser Val Thr Leu Ile Ser Met Pro Ala Thr Thr Glu145 150 155 160Gly Arg Arg Gly Phe Ser Val Ser Val Glu Ser Ala Cys Ser Asn Tyr 165 170 175Ala Thr Thr Val Gln Val Lys Glu Val Asn Arg Met His Ile Ser Pro 180 185 190Asn Asn Arg Asn Ala Ile His Pro Gly Asp Arg Ile Leu Glu Ile Asn 195 200 205Gly Thr Pro Val Arg Thr Leu Arg Val Glu Glu Val Glu Asp Ala Ile 210 215 220Ser Gln Thr Ser Gln Thr Leu Gln Leu Leu Ile Glu His Asp Pro Val225 230 235 240Ser Gln Arg Leu Asp Gln Leu Arg Leu Glu Ala Arg Leu Ala Pro His 245 250 255Met Gln Asn Ala Gly His Pro His Ala Leu Ser Thr Leu Asp Thr Lys 260 265 270Glu Asn Leu Glu Gly Thr Leu Arg Arg Arg Ser Leu Arg Arg Ser Asn 275 280 285Ser Ile Ser Lys Ser Pro Gly Pro Ser Ser Pro Lys Glu Pro Leu Leu 290 295 300Phe Ser Arg Asp Ile Ser Arg Ser Glu Ser Leu Arg Cys Ser Ser Ser305 310 315 320Tyr Ser Gln Gln Ile Phe Arg Pro Cys Asp Leu Ile His Gly Glu Val 325 330 335Leu Gly Lys Gly Phe Phe Gly Gln Ala Ile Lys Val Thr His Lys Ala 340 345 350Thr Gly Lys Val Met Val Met Lys Glu Leu Ile Arg Cys Asp Glu Glu 355 360 365Thr Gln Lys Thr Phe Leu Thr Glu Val Lys Val Met Arg Ser Leu Asp 370 375 380His Pro Asn Val Leu Lys Phe Ile Gly Val Leu Tyr Lys Asp Lys Lys385 390 395 400Leu Asn Leu Leu Thr Glu Tyr Ile Glu Gly Gly Thr Leu Lys Asp Phe 405 410 415Leu Arg Ser Met Asp Pro Phe Pro Trp Gln Gln Lys Val Arg Phe Ala 420 425 430Lys Gly Ile Ala Ser Gly Met Ala Tyr Leu His Ser Met Cys Ile Ile 435 440 445His Arg Asp Leu Asn Ser His Asn Cys Leu Ile Lys Leu Asp Lys Thr 450 455 460Val Val Val Ala Asp Phe Gly Leu Ser Arg Leu Ile Val Glu Glu Arg465 470 475 480Lys Arg Ala Pro Met Glu Lys Ala Thr Thr Lys Lys Arg Thr Leu Arg 485 490 495Lys Asn Asp Arg Lys Lys Arg Tyr Thr Val Val Gly Asn Pro Tyr Trp 500 505 510Met Ala Pro Glu Met Leu Asn Gly Lys Ser Tyr Asp Glu Thr Val Asp 515 520 525Ile Phe Ser Phe Gly Ile Val Leu Cys Glu Ile Ile Gly Gln Val Tyr 530 535 540Ala Asp Pro Asp Cys Leu Pro Arg Thr Leu Asp Phe Gly Leu Asn Val545 550 555 560Lys Leu Phe Trp Glu Lys Phe Val Pro Thr Asp Cys Pro Pro Ala Phe 565 570 575Phe Pro Leu Ala Ala Ile Cys Cys Arg Leu Glu Pro Glu Ser Arg Pro 580 585 590Ala Phe Ser Lys Leu Glu Asp Ser Phe Glu Ala Leu Ser Leu Tyr Leu 595 600 605Gly Glu Leu Gly Ile Pro Leu Pro Ala Glu Leu Glu Glu Leu Asp His 610 615 620Thr Val Ser Met Gln Tyr Gly Leu Thr Arg Asp Ser Pro Pro625 630 63542733PRTHomo sapiens 42Met Gly Ser Tyr Leu Ser Val Pro Ala Tyr Phe Thr Ser Arg Asp Leu1 5 10 15Phe Arg Cys Ser Glu Cys Gln Asp Ser Leu Thr Asn Trp Tyr Tyr Glu 20 25 30Lys Asp Gly Lys Leu Tyr Cys Pro Lys Asp Tyr Trp Gly Lys Phe Gly 35 40 45Glu Phe Cys His Gly Cys Ser Leu Leu Met Thr Gly Pro Phe Met Val 50 55 60Ala Gly Glu Phe Lys Tyr His Pro Glu Cys Phe Ala Cys Met Ser Cys65 70 75 80Lys Val Ile Ile Glu Asp Gly Asp Ala Tyr Ala Leu Val Gln His Ala 85 90 95Thr Leu Tyr Cys Gly Lys Cys His Asn Glu Val Val Leu Ala Pro Met 100 105 110Phe Glu Arg Leu Ser Thr Glu Ser Val Gln Glu Gln Leu Pro Tyr Ser 115 120 125Val Thr Leu Ile Ser Met Pro Ala Thr Thr Glu Gly Arg Arg Gly Phe 130 135 140Ser Val Ser Val Glu Ser Ala Cys Ser Asn Tyr Ala Thr Thr Val Gln145 150 155 160Val Lys Glu Val Asn Arg Met His Ile Ser Pro Asn Asn Arg Asn Ala 165 170 175Ile His Pro Gly Asp Arg Ile

Leu Glu Ile Asn Gly Thr Pro Val Arg 180 185 190Thr Leu Arg Val Glu Glu Val Glu Asp Ala Ile Ser Gln Thr Ser Gln 195 200 205Thr Leu Gln Leu Leu Ile Glu His Asp Pro Val Ser Gln Arg Leu Asp 210 215 220Gln Leu Arg Leu Glu Ala Arg Leu Ala Pro His Met Gln Asn Ala Gly225 230 235 240His Pro His Ala Leu Ser Thr Leu Asp Thr Lys Glu Asn Leu Glu Gly 245 250 255Thr Leu Arg Arg Arg Ser Leu Arg Arg Ser Asn Ser Ile Ser Lys Ser 260 265 270Pro Gly Pro Ser Ser Pro Lys Glu Pro Leu Leu Phe Ser Arg Asp Ile 275 280 285Ser Arg Ser Glu Ser Leu Arg Cys Ser Ser Ser Tyr Ser Gln Gln Ile 290 295 300Phe Arg Pro Cys Asp Leu Ile His Gly Glu Val Leu Gly Lys Gly Phe305 310 315 320Phe Gly Gln Ala Ile Lys Val Thr His Lys Ala Thr Gly Lys Val Met 325 330 335Val Met Lys Glu Leu Ile Arg Cys Asp Glu Glu Thr Gln Lys Thr Phe 340 345 350Leu Thr Glu Val Lys Val Met Arg Ser Leu Asp His Pro Asn Val Leu 355 360 365Lys Phe Ile Gly Val Leu Tyr Lys Asp Lys Lys Leu Asn Leu Leu Thr 370 375 380Glu Tyr Ile Glu Gly Gly Thr Leu Lys Asp Phe Leu Arg Ser Met Asp385 390 395 400Pro Phe Pro Trp Gln Gln Lys Val Arg Phe Ala Lys Gly Ile Ala Ser 405 410 415Gly Met Ala Tyr Leu His Ser Met Cys Ile Ile His Arg Asp Leu Asn 420 425 430Ser His Asn Cys Leu Ile Lys Leu Asp Lys Thr Val Val Val Ala Asp 435 440 445Phe Gly Leu Ser Arg Leu Ile Val Glu Glu Arg Lys Arg Ala Pro Met 450 455 460Glu Lys Ala Thr Thr Lys Lys Arg Thr Leu Arg Lys Asn Asp Arg Lys465 470 475 480Lys Arg Tyr Thr Val Val Gly Asn Pro Tyr Trp Met Ala Pro Glu Met 485 490 495Leu Asn Gly Lys Ser Tyr Asp Glu Thr Val Asp Ile Phe Ser Phe Gly 500 505 510Ile Val Leu Cys Glu Ile Ile Gly Gln Val Tyr Ala Asp Pro Asp Cys 515 520 525Leu Pro Arg Thr Leu Asp Phe Gly Leu Asn Val Lys Leu Phe Trp Glu 530 535 540Lys Phe Val Pro Thr Asp Cys Pro Pro Ala Phe Phe Pro Leu Ala Ala545 550 555 560Ile Cys Cys Arg Leu Glu Pro Glu Ser Arg Ala Pro Pro Gly Ala Ala 565 570 575Gly Glu Gly Pro Gly Cys Ala Asp Asp Glu Gly Pro Val Arg Arg Gln 580 585 590Gly Lys Val Thr Ile Lys Tyr Asp Pro Lys Glu Leu Arg Lys His Leu 595 600 605Asn Leu Glu Glu Trp Ile Leu Glu Gln Leu Thr Arg Leu Tyr Asp Cys 610 615 620Gln Glu Glu Glu Ile Ser Glu Leu Glu Ile Asp Val Asp Glu Leu Leu625 630 635 640Asp Met Glu Ser Asp Asp Ala Trp Ala Ser Arg Val Lys Glu Leu Leu 645 650 655Val Asp Cys Tyr Lys Pro Thr Glu Ala Phe Ile Ser Gly Leu Leu Asp 660 665 670Lys Ile Arg Ala Met Gln Lys Leu Ser Thr Pro Gln Lys Lys Pro Ala 675 680 685Phe Ser Lys Leu Glu Asp Ser Phe Glu Ala Leu Ser Leu Tyr Leu Gly 690 695 700Glu Leu Gly Ile Pro Leu Pro Ala Glu Leu Glu Glu Leu Asp His Thr705 710 715 720Val Ser Met Gln Tyr Gly Leu Thr Arg Asp Ser Pro Pro 725 73043626PRTHomo sapiens 43Met Ala Gly Glu Arg Pro Pro Leu Arg Gly Pro Gly Pro Gly Pro Gly1 5 10 15Glu Val Pro Gly Glu Gly Pro Pro Gly Pro Gly Gly Thr Gly Gly Gly 20 25 30Pro Gly Arg Gly Arg Pro Ser Ser Tyr Arg Val Leu Arg Ser Ala Val 35 40 45Ser Ser Leu Ala Arg Val Asp Asp Phe His Cys Ala Glu Lys Ile Gly 50 55 60Ala Gly Phe Phe Ser Glu Val Tyr Lys Val Arg His Arg Gln Ser Gly65 70 75 80Gln Val Met Val Leu Lys Met Asn Lys Leu Pro Ser Asn Arg Gly Asn 85 90 95Thr Leu Arg Glu Val Gln Leu Met Asn Arg Leu Arg His Pro Asn Ile 100 105 110Leu Arg Phe Met Gly Val Cys Val His Gln Gly Gln Leu His Ala Leu 115 120 125Thr Glu Tyr Met Asn Gly Gly Thr Leu Glu Gln Leu Leu Ser Ser Pro 130 135 140Glu Pro Leu Ser Trp Pro Val Arg Leu His Leu Ala Leu Asp Ile Ala145 150 155 160Arg Gly Leu Arg Tyr Leu His Ser Lys Gly Val Phe His Arg Asp Leu 165 170 175Thr Ser Lys Asn Cys Leu Val Arg Arg Glu Asp Arg Gly Phe Thr Ala 180 185 190Val Val Gly Asp Phe Gly Leu Ala Glu Lys Ile Pro Val Tyr Arg Glu 195 200 205Gly Ala Arg Lys Glu Pro Leu Ala Val Val Gly Ser Pro Tyr Trp Met 210 215 220Ala Pro Glu Val Leu Arg Gly Glu Leu Tyr Asp Glu Lys Ala Asp Val225 230 235 240Phe Ala Phe Gly Ile Val Leu Cys Glu Leu Ile Ala Arg Val Pro Ala 245 250 255Asp Pro Asp Tyr Leu Pro Arg Thr Glu Asp Phe Gly Leu Asp Val Pro 260 265 270Ala Phe Arg Thr Leu Val Gly Asp Asp Cys Pro Leu Pro Phe Leu Leu 275 280 285Leu Ala Ile His Cys Cys Asn Leu Glu Pro Ser Thr Arg Ala Pro Phe 290 295 300Thr Glu Ile Thr Gln His Leu Glu Trp Ile Leu Glu Gln Leu Pro Glu305 310 315 320Pro Ala Pro Leu Thr Arg Thr Ala Leu Thr His Asn Gln Gly Ser Val 325 330 335Ala Arg Gly Gly Pro Ser Ala Thr Leu Pro Arg Pro Asp Pro Arg Leu 340 345 350Ser Arg Ser Arg Ser Asp Leu Phe Leu Pro Pro Ser Pro Glu Ser Pro 355 360 365Pro Asn Trp Gly Asp Asn Leu Thr Arg Val Asn Pro Phe Ser Leu Arg 370 375 380Glu Asp Leu Arg Gly Gly Lys Ile Lys Leu Leu Asp Thr Pro Ser Lys385 390 395 400Pro Val Leu Pro Leu Val Pro Pro Ser Pro Phe Pro Ser Thr Gln Leu 405 410 415Pro Leu Val Thr Thr Pro Glu Thr Leu Val Gln Pro Gly Thr Pro Ala 420 425 430Arg Arg Cys Arg Ser Leu Pro Ser Ser Pro Glu Leu Pro Arg Arg Met 435 440 445Glu Thr Ala Leu Pro Gly Pro Gly Pro Pro Ala Val Gly Pro Ser Ala 450 455 460Glu Glu Lys Met Glu Cys Glu Gly Ser Ser Pro Glu Pro Glu Pro Pro465 470 475 480Gly Pro Ala Pro Gln Leu Pro Leu Ala Val Ala Thr Asp Asn Phe Ile 485 490 495Ser Thr Cys Ser Ser Ala Ser Gln Pro Trp Ser Pro Arg Ser Gly Pro 500 505 510Val Leu Asn Asn Asn Pro Pro Ala Val Val Val Asn Ser Pro Gln Gly 515 520 525Trp Ala Gly Glu Pro Trp Asn Arg Ala Gln His Ser Leu Pro Arg Ala 530 535 540Ala Ala Leu Glu Arg Thr Glu Pro Ser Pro Pro Pro Ser Ala Pro Arg545 550 555 560Glu Pro Asp Glu Gly Leu Pro Cys Pro Gly Cys Cys Leu Gly Pro Phe 565 570 575Ser Phe Gly Phe Leu Ser Met Cys Pro Arg Pro Thr Pro Ala Val Ala 580 585 590Arg Tyr Arg Asn Leu Asn Cys Glu Ala Gly Ser Leu Leu Cys His Arg 595 600 605Gly His His Ala Lys Pro Pro Thr Pro Ser Leu Gln Leu Pro Gly Ala 610 615 620Arg Ser62544617PRTMus musculus 44Met Gly Ser Tyr Leu Ser Val Pro Ala Tyr Phe Thr Ser Arg Asp Pro1 5 10 15Phe Arg Cys Ser Glu Cys Gln Glu Ser Leu Thr Asn Trp Tyr Tyr Glu 20 25 30Lys Asp Gly Lys Leu Tyr Cys His Lys Asp Tyr Trp Ala Lys Phe Gly 35 40 45Glu Phe Cys His Gly Cys Ser Leu Leu Met Thr Gly Pro Ala Met Val 50 55 60Ala Gly Glu Phe Lys Tyr His Pro Glu Cys Phe Ala Cys Met Ser Cys65 70 75 80Lys Val Ile Ile Glu Asp Gly Asp Ala Tyr Ala Leu Val Gln His Ala 85 90 95Thr Leu Tyr Cys Gly Lys Cys His Asn Glu Val Val Leu Ala Pro Met 100 105 110Phe Glu Arg Leu Ser Thr Glu Ser Val Gln Asp Gln Leu Pro Tyr Ser 115 120 125Val Thr Leu Ile Ser Met Pro Ala Thr Thr Glu Cys Arg Arg Gly Phe 130 135 140Ser Val Thr Val Glu Ser Ala Ser Ser Asn Tyr Ala Thr Thr Val Gln145 150 155 160Val Lys Glu Val Asn Arg Met His Ile Ser Pro Asn Asn Arg Asn Ala 165 170 175Ile His Pro Gly Asp Arg Ile Leu Glu Ile Asn Gly Thr Pro Val Arg 180 185 190Thr Leu Arg Val Glu Glu Val Glu Asp Ala Ile Lys Gln Thr Ser Gln 195 200 205Thr Leu Gln Leu Leu Ile Glu His Asp Pro Val Pro Gln Arg Leu Asp 210 215 220Gln Leu Arg Leu Asp Ala Arg Leu Pro Pro His Met Gln Ser Thr Gly225 230 235 240His Thr Leu Met Leu Ser Thr Leu Asp Thr Lys Glu Asn Gln Glu Gly 245 250 255Thr Leu Arg Arg Arg Ser Leu Arg Arg Ser Asn Ser Ile Ser Lys Ser 260 265 270Pro Gly Pro Ser Ser Pro Lys Glu Pro Leu Leu Leu Ser Arg Asp Ile 275 280 285Ser Arg Ser Glu Ser Leu Arg Cys Ser Ser Ser Tyr Ser Gln Gln Ile 290 295 300Phe Arg Pro Cys Asp Leu Ile His Gly Glu Val Leu Gly Lys Gly Phe305 310 315 320Phe Gly Gln Ala Ile Lys Val Thr His Lys Ala Thr Gly Lys Val Met 325 330 335Val Met Lys Glu Leu Ile Arg Cys Asp Glu Glu Thr Gln Lys Thr Phe 340 345 350Leu Thr Glu Val Lys Val Met Arg Ser Leu Asp His Pro Asn Val Leu 355 360 365Lys Phe Ile Gly Val Leu Tyr Lys Asp Lys Lys Leu Asn Leu Leu Thr 370 375 380Glu Tyr Ile Glu Gly Gly Thr Leu Lys Asp Phe Leu Arg Ser Val Asp385 390 395 400Pro Phe Pro Trp Gln Gln Lys Val Arg Phe Ala Lys Gly Ile Ser Ser 405 410 415Gly Met Ala Tyr Leu His Ser Met Cys Ile Ile His Arg Asp Leu Asn 420 425 430Ser His Asn Cys Leu Ile Lys Leu Asp Lys Thr Val Val Val Ala Asp 435 440 445Phe Gly Leu Ser Arg Leu Ile Val Glu Glu Arg Lys Arg Pro Pro Val 450 455 460Glu Lys Ala Thr Thr Lys Lys Arg Thr Leu Arg Lys Ser Asp Arg Lys465 470 475 480Lys Arg Tyr Thr Val Val Gly Asn Pro Tyr Trp Met Ala Pro Glu Met 485 490 495Leu Asn Gly Lys Ser Tyr Asp Glu Thr Val Asp Val Phe Ser Phe Gly 500 505 510Ile Val Leu Cys Glu Ile Ile Gly Gln Val Tyr Ala Asp Pro Asp Cys 515 520 525Leu Pro Arg Thr Leu Asp Phe Gly Leu Asn Val Lys Leu Phe Trp Glu 530 535 540Lys Phe Val Pro Thr Asp Cys Pro Pro Ala Phe Phe Pro Leu Ala Ala545 550 555 560Ile Cys Cys Lys Leu Glu Pro Glu Ser Arg Pro Ala Phe Ser Lys Leu 565 570 575Glu Asp Ser Phe Glu Ala Leu Ser Leu Phe Leu Gly Glu Leu Ala Ile 580 585 590Pro Leu Pro Ala Glu Leu Glu Asp Leu Asp His Thr Val Ser Met Glu 595 600 605Tyr Gly Leu Thr Arg Asp Ser Pro Pro 610 61545451PRTMus musculus 45Met His Ile Ser Pro Asn Asn Arg Asn Ala Ile His Pro Gly Asp Arg1 5 10 15Ile Leu Glu Ile Asn Gly Thr Pro Val Arg Thr Leu Arg Val Glu Glu 20 25 30Val Glu Asp Ala Ile Lys Gln Thr Ser Gln Thr Leu Gln Leu Leu Ile 35 40 45Glu His Asp Pro Val Pro Gln Arg Leu Asp Gln Leu Arg Leu Asp Ala 50 55 60Arg Leu Pro Pro His Met Gln Ser Thr Gly His Thr Leu Met Leu Ser65 70 75 80Thr Leu Asp Thr Lys Glu Asn Gln Glu Gly Thr Leu Arg Arg Arg Ser 85 90 95Leu Arg Arg Ser Asn Ser Ile Ser Lys Ser Pro Gly Pro Ser Ser Pro 100 105 110Lys Glu Pro Leu Leu Leu Ser Arg Asp Ile Ser Arg Ser Glu Ser Leu 115 120 125Arg Cys Ser Ser Ser Tyr Ser Gln Gln Ile Phe Arg Pro Cys Asp Leu 130 135 140Ile His Gly Glu Val Leu Gly Lys Gly Phe Phe Gly Gln Ala Ile Lys145 150 155 160Val Thr His Lys Ala Thr Gly Lys Val Met Val Met Lys Glu Leu Ile 165 170 175Arg Cys Asp Glu Glu Thr Gln Lys Thr Phe Leu Thr Glu Val Lys Val 180 185 190Met Arg Ser Leu Asp His Pro Asn Val Leu Lys Phe Ile Gly Val Leu 195 200 205Tyr Lys Asp Lys Lys Leu Asn Leu Leu Thr Glu Tyr Ile Glu Gly Gly 210 215 220Thr Leu Lys Asp Phe Leu Arg Ser Val Asp Pro Phe Pro Trp Gln Gln225 230 235 240Lys Val Arg Phe Ala Lys Gly Ile Ser Ser Gly Met Ala Tyr Leu His 245 250 255Ser Met Cys Ile Ile His Arg Asp Leu Asn Ser His Asn Cys Leu Ile 260 265 270Lys Leu Asp Lys Thr Val Val Val Ala Asp Phe Gly Leu Ser Arg Leu 275 280 285Ile Val Glu Glu Arg Lys Arg Pro Pro Val Glu Lys Ala Thr Thr Lys 290 295 300Lys Arg Thr Leu Arg Lys Ser Asp Arg Lys Lys Arg Tyr Thr Val Val305 310 315 320Gly Asn Pro Tyr Trp Met Ala Pro Glu Met Leu Asn Gly Lys Ser Tyr 325 330 335Asp Glu Thr Val Asp Val Phe Ser Phe Gly Ile Val Leu Cys Glu Ile 340 345 350Ile Gly Gln Val Tyr Ala Asp Pro Asp Cys Leu Pro Arg Thr Leu Asp 355 360 365Phe Gly Leu Asn Val Lys Leu Phe Trp Glu Lys Phe Val Pro Thr Asp 370 375 380Cys Pro Pro Ala Phe Phe Pro Leu Ala Ala Ile Cys Cys Lys Leu Glu385 390 395 400Pro Glu Ser Arg Pro Ala Phe Ser Lys Leu Glu Asp Ser Phe Glu Ala 405 410 415Leu Ser Leu Phe Leu Gly Glu Leu Ala Ile Pro Leu Pro Ala Glu Leu 420 425 430Glu Asp Leu Asp His Thr Val Ser Met Glu Tyr Gly Leu Thr Arg Asp 435 440 445Ser Pro Pro 45046627PRTMus musculus 46Met Ala Gly Glu Arg Pro Pro Leu Arg Gly Pro Gly Pro Gly Glu Ala1 5 10 15Pro Gly Glu Gly Pro Gly Gly Ala Gly Gly Gly Pro Gly Arg Gly Arg 20 25 30Pro Ser Ser Tyr Arg Ala Leu Arg Ser Ala Val Ser Ser Leu Ala Arg 35 40 45Val Asp Asp Phe Asp Cys Ala Glu Lys Ile Gly Ala Gly Phe Phe Ser 50 55 60Glu Val Tyr Lys Val Arg His Arg Gln Ser Gly Gln Val Met Val Leu65 70 75 80Lys Met Asn Lys Leu Pro Ser Asn Arg Ser Asn Thr Leu Arg Glu Val 85 90 95Gln Leu Met Asn Arg Leu Arg His Pro Asn Ile Leu Arg Phe Met Gly 100 105 110Val Cys Val His Gln Gly Gln Leu His Ala Leu Thr Glu Tyr Met Asn 115 120 125Gly Gly Thr Leu Glu Gln Leu Leu Ser Ser Pro Glu Pro Leu Ser Trp 130 135 140Pro Val Arg Leu His Leu Ala Leu Asp Ile Ala Gln Gly Leu Arg Tyr145 150 155 160Leu His Ala Lys Gly Val Phe His Arg Asp Leu Thr Ser Lys Asn Cys 165 170 175Leu Val Arg Arg Glu Asp Arg Gly Phe Thr Ala Val Val Gly Asp Phe 180 185 190Gly Leu Ala Glu Lys Ile Pro Val Tyr Arg Lys Gly Gln Gly Arg Ser 195 200 205Pro Trp Leu Trp Trp Ala Pro Arg Thr Gly Trp Leu Gln Arg Cys Cys 210 215

220Gly Glu Ser Cys Met Met Arg Arg Pro Met Ser Ser Pro Ser Gly Ser225 230 235 240Ser Ser Val Ser Ser Ser Pro Glu Tyr Leu Gln Thr Leu Thr Thr Tyr 245 250 255Pro Val Leu Arg Asp Phe Gly Leu Asp Val Pro Ala Phe Arg Thr Leu 260 265 270Val Gly Asn Asp Cys Pro Leu Pro Phe Leu Leu Leu Ala Ile His Cys 275 280 285Cys Ser Met Glu Pro Ser Thr Arg Ala Pro Phe Thr Glu Ile Thr Gln 290 295 300His Leu Glu Gln Ile Leu Glu Gln Gln Pro Glu Ala Thr Pro Leu Ala305 310 315 320Lys Pro Pro Leu Thr Lys Ala Pro Leu Thr Tyr Asn Gln Gly Ser Val 325 330 335Pro Arg Gly Gly Pro Ser Ala Thr Leu Pro Arg Pro Asp Pro Arg Leu 340 345 350Ser Arg Ser Arg Ser Asp Leu Phe Leu Pro Pro Ser Pro Glu Ser Pro 355 360 365Pro Ser Trp Gly Asp Asn Leu Thr Arg Val Asn Pro Phe Ser Leu Arg 370 375 380Glu Asp Leu Arg Gly Gly Lys Ile Lys Leu Leu Asp Thr Pro Cys Lys385 390 395 400Pro Ala Thr Pro Leu Pro Leu Val Pro Pro Ser Pro Leu Thr Ser Thr 405 410 415Gln Leu Pro Leu Val Thr Thr Pro Asp Ile Leu Val Gln Pro Glu Thr 420 425 430Pro Val Arg Arg Cys Arg Ser Leu Pro Ser Ser Pro Glu Leu Pro Arg 435 440 445Arg Met Glu Thr Ala Leu Pro Gly Pro Gly Pro Ser Pro Met Gly Pro 450 455 460Thr Glu Glu Arg Met Asp Cys Glu Gly Ser Ser Pro Glu Pro Glu Pro465 470 475 480Pro Gly Leu Ala Pro Gln Leu Pro Leu Ala Val Ala Thr Asp Asn Phe 485 490 495Ile Ser Thr Cys Ser Ser Ala Ser Gln Pro Trp Ser Pro Arg Ser Gly 500 505 510Pro Pro Leu Asn Asn Asn Pro Pro Ala Val Val Val Asn Ser Pro Gln 515 520 525Gly Trp Ala Arg Glu Pro Trp Asn Arg Ala Gln His Ser Leu Pro Arg 530 535 540Ala Ala Ala Leu Glu Gln Thr Glu Pro Ser Pro Pro Pro Ser Ala Pro545 550 555 560Arg Glu Pro Glu Glu Gly Leu Pro Cys Pro Gly Cys Cys Leu Gly Pro 565 570 575Phe Ser Phe Gly Phe Leu Ser Met Cys Pro Arg Pro Thr Pro Ala Val 580 585 590Ala Arg Tyr Arg Asn Leu Asn Cys Glu Ala Gly Ser Leu Leu Cys His 595 600 605Arg Gly His His Ala Lys Pro Pro Thr Pro Ser Leu Gln Leu Pro Gly 610 615 620Ala Arg Ser62547627PRTMus musculus 47Met Ala Gly Glu Arg Pro Pro Leu Arg Gly Pro Gly Pro Gly Glu Ala1 5 10 15Pro Gly Glu Gly Pro Gly Gly Ala Gly Gly Gly Pro Gly Arg Gly Arg 20 25 30Pro Ser Ser Tyr Arg Ala Leu Arg Ser Ala Val Ser Ser Leu Ala Arg 35 40 45Val Asp Asp Phe Asp Cys Ala Glu Lys Ile Gly Ala Gly Phe Phe Ser 50 55 60Glu Val Tyr Lys Val Arg His Arg Gln Ser Gly Gln Val Met Val Leu65 70 75 80Lys Met Asn Lys Leu Pro Ser Asn Arg Ser Asn Thr Leu Arg Glu Val 85 90 95Gln Leu Met Asn Arg Leu Arg His Pro Asn Ile Leu Arg Phe Met Gly 100 105 110Val Cys Val His Gln Gly Gln Leu His Ala Leu Thr Glu Tyr Met Asn 115 120 125Gly Gly Thr Leu Glu Gln Leu Leu Ser Ser Pro Glu Pro Leu Ser Trp 130 135 140Pro Val Arg Leu His Leu Ala Leu Asp Ile Ala Gln Gly Leu Arg Tyr145 150 155 160Leu His Ala Lys Gly Val Phe His Arg Asp Leu Thr Ser Lys Asn Cys 165 170 175Leu Val Arg Arg Glu Asp Arg Gly Phe Thr Ala Val Val Gly Asp Phe 180 185 190Gly Leu Ala Glu Lys Ile Pro Val Tyr Arg Glu Gly Thr Arg Lys Glu 195 200 205Pro Leu Ala Val Val Gly Ser Pro Tyr Trp Met Ala Pro Glu Val Leu 210 215 220Arg Gly Glu Leu Tyr Asp Glu Lys Ala Asp Val Phe Ala Phe Gly Ile225 230 235 240Val Leu Cys Glu Leu Ile Ala Arg Val Pro Ala Asp Pro Asp Tyr Leu 245 250 255Pro Arg Thr Glu Asp Phe Gly Leu Asp Val Pro Ala Phe Arg Thr Leu 260 265 270Val Gly Asn Asp Cys Pro Leu Pro Phe Leu Leu Leu Ala Ile His Cys 275 280 285Cys Ser Met Glu Pro Ser Thr Arg Ala Pro Phe Thr Glu Ile Thr Gln 290 295 300His Leu Glu Gln Ile Leu Glu Gln Gln Pro Glu Ala Thr Pro Leu Ala305 310 315 320Lys Pro Pro Leu Thr Lys Ala Pro Leu Thr Tyr Asn Gln Gly Ser Val 325 330 335Pro Arg Gly Gly Pro Ser Ala Thr Leu Pro Arg Pro Asp Pro Arg Leu 340 345 350Ser Arg Ser Arg Ser Asp Leu Phe Leu Pro Pro Ser Pro Glu Ser Pro 355 360 365Pro Ser Trp Gly Asp Asn Leu Thr Arg Val Asn Pro Phe Ser Leu Arg 370 375 380Glu Asp Leu Arg Gly Gly Lys Ile Lys Leu Leu Asp Thr Pro Cys Lys385 390 395 400Pro Ala Thr Pro Leu Pro Leu Val Pro Pro Ser Pro Leu Thr Ser Thr 405 410 415Gln Leu Pro Leu Val Thr Thr Pro Asp Ile Leu Val Gln Pro Glu Thr 420 425 430Pro Val Arg Arg Cys Arg Ser Leu Pro Ser Ser Pro Glu Leu Pro Arg 435 440 445Arg Met Glu Thr Ala Leu Pro Gly Pro Gly Pro Ser Pro Met Gly Pro 450 455 460Thr Glu Glu Arg Met Asp Cys Glu Gly Ser Ser Pro Glu Pro Glu Pro465 470 475 480Pro Gly Leu Ala Pro Gln Leu Pro Leu Ala Val Ala Thr Asp Asn Phe 485 490 495Ile Ser Thr Cys Ser Ser Ala Ser Gln Pro Trp Ser Pro Arg Ser Gly 500 505 510Pro Pro Leu Asn Asn Asn Pro Pro Ala Val Val Val Asn Ser Pro Gln 515 520 525Gly Trp Ala Arg Glu Pro Trp Asn Arg Ala Gln His Ser Leu Pro Arg 530 535 540Ala Ala Ala Leu Glu Gln Thr Glu Pro Ser Pro Pro Pro Ser Ala Pro545 550 555 560Arg Glu Pro Glu Glu Gly Leu Pro Cys Pro Gly Cys Cys Leu Gly Pro 565 570 575Phe Ser Phe Gly Phe Leu Ser Met Cys Pro Arg Pro Thr Pro Ala Val 580 585 590Ala Arg Tyr Arg Asn Leu Asn Cys Glu Ala Gly Ser Leu Leu Cys His 595 600 605Arg Gly His His Ala Lys Pro Pro Thr Pro Ser Leu Gln Leu Pro Gly 610 615 620Ala Arg Ser62548628PRTRattus norvegicus 48Met Ala Gly Glu Arg Pro Pro Leu Arg Gly Pro Gly Pro Gly Glu Thr1 5 10 15Pro Val Glu Gly Pro Gly Gly Ala Gly Gly Gly Pro Gly Arg Gly Arg 20 25 30Pro Ser Ser Tyr Arg Ala Leu Arg Ser Ala Val Ser Ser Leu Ala Arg 35 40 45Val Asp Asp Phe Asp Cys Ala Glu Lys Ile Gly Ala Gly Phe Phe Ser 50 55 60Glu Val Tyr Lys Val Arg His Arg Gln Ser Gly Gln Val Met Val Leu65 70 75 80Lys Met Asn Lys Leu Pro Ser Asn Arg Ser Asn Thr Leu Arg Glu Val 85 90 95Gln Leu Met Asn Arg Leu Arg His Pro Asn Ile Leu Arg Phe Met Gly 100 105 110Val Cys Val His Gln Gly Gln Leu His Ala Leu Thr Glu Tyr Met Asn 115 120 125Gly Gly Thr Leu Glu Gln Leu Leu Ser Ser Pro Glu Pro Leu Ser Trp 130 135 140Pro Val Arg Leu His Leu Ala Leu Asp Ile Ala Gln Gly Leu Arg Tyr145 150 155 160Leu His Ala Lys Gly Val Phe His Arg Asp Leu Thr Ser Lys Asn Cys 165 170 175Leu Val Arg Arg Glu Asp Gly Gly Phe Thr Ala Val Val Gly Asp Phe 180 185 190Gly Leu Ala Glu Lys Ile Pro Val Tyr Arg Glu Gly Ala Arg Lys Glu 195 200 205Pro Leu Ala Val Val Gly Ser Pro Tyr Trp Met Ala Pro Glu Val Leu 210 215 220Arg Gly Glu Leu Tyr Asp Glu Lys Ala Asp Val Phe Ala Phe Gly Ile225 230 235 240Val Leu Cys Glu Leu Ile Ala Arg Val Pro Ala Asp Pro Asp Tyr Leu 245 250 255Pro Arg Thr Glu Asp Phe Gly Leu Asp Val Pro Ala Phe Arg Thr Leu 260 265 270Val Gly Asn Asp Cys Pro Leu Pro Phe Leu Leu Leu Ala Ile His Cys 275 280 285Cys Ser Met Glu Pro Ser Ala Arg Ala Pro Phe Thr Glu Ile Thr Gln 290 295 300His Leu Glu Gln Ile Leu Glu Gln Leu Pro Glu Pro Thr Pro Leu Ala305 310 315 320Lys Met Pro Leu Ala Lys Ala Pro Leu Thr Tyr Asn Gln Gly Ser Val 325 330 335Pro Arg Gly Gly Pro Ser Ala Thr Leu Pro Arg Ser Asp Pro Arg Leu 340 345 350Ser Arg Ser Arg Ser Asp Leu Phe Leu Pro Pro Ser Pro Glu Ser Pro 355 360 365Pro Ser Trp Gly Asp Asn Leu Thr Arg Val Asn Pro Phe Ser Leu Arg 370 375 380Glu Asp Leu Arg Gly Gly Lys Ile Lys Leu Leu Asp Thr Pro Cys Lys385 390 395 400Pro Ala Thr Pro Leu Pro Leu Val Pro Pro Ser Pro Leu Thr Ser Thr 405 410 415Gln Leu Pro Leu Val Ala Ser Pro Glu Ser Leu Val Gln Pro Glu Thr 420 425 430Pro Val Arg Arg Cys Arg Ser Leu Pro Ser Ser Pro Glu Leu Pro Arg 435 440 445Arg Met Glu Thr Ala Leu Pro Gly Pro Gly Pro Ser Pro Val Gly Pro 450 455 460Ser Thr Glu Glu Arg Met Asp Cys Glu Gly Ser Ser Pro Glu Pro Glu465 470 475 480Pro Pro Gly Pro Ala Pro Gln Leu Pro Leu Ala Val Ala Thr Asp Asn 485 490 495Phe Ile Ser Thr Cys Ser Ser Ala Ser Gln Pro Trp Ser Ala Arg Pro 500 505 510Gly Pro Ser Leu Asn Asn Asn Pro Pro Ala Val Val Val Asn Ser Pro 515 520 525Gln Gly Trp Ala Arg Glu Pro Trp Asn Arg Ala Gln His Ser Leu Pro 530 535 540Arg Ala Ala Ala Leu Glu Arg Thr Glu Pro Ser Pro Pro Pro Ser Ala545 550 555 560Pro Arg Glu Gln Glu Glu Gly Leu Pro Cys Pro Gly Cys Cys Leu Ser 565 570 575Pro Phe Ser Phe Gly Phe Leu Ser Met Cys Pro Arg Pro Thr Pro Ala 580 585 590Val Ala Arg Tyr Arg Asn Leu Asn Cys Glu Ala Gly Ser Leu Leu Cys 595 600 605His Arg Gly His His Ala Lys Pro Pro Thr Pro Ser Leu Gln Leu Pro 610 615 620Gly Ala Arg Ser62549615PRTXenopus laevis 49Met Arg Leu Met Leu Leu Cys Cys Ser Trp Ser Glu Glu His Met Gly1 5 10 15Glu Glu Glu Gly Asn Val Leu Pro Leu Cys Ala Ser Cys Gly Gln Ser 20 25 30Ile Tyr Asp Gly Cys Tyr Leu Gln Ala Leu Ala Leu Asp Trp His Ser 35 40 45Asp Cys Phe Arg Cys Ser Asp Cys Gly Val Ser Leu Ser His Arg Tyr 50 55 60Tyr Glu Lys Asp Gly Arg Leu Phe Cys Lys Lys His Tyr Trp Thr Arg65 70 75 80Phe Gly Gly Met Cys Gln Gly Cys Ser Glu Asn Ile Thr Lys Gly Leu 85 90 95Val Met Val Ala Gly Glu His Lys Tyr His Pro Glu Cys Phe Met Cys 100 105 110Ser Arg Cys Lys Ala Tyr Ile Gly Asp Gly Glu Thr Tyr Ala Leu Val 115 120 125Glu Arg Ser Lys Leu Tyr Cys Gly Pro Cys Tyr Tyr Gln Phe Ser Val 130 135 140Thr Pro Val Ile Asp Ser Pro Gly Ser Arg Ser Pro His Thr Val Thr145 150 155 160Leu Val Ser Leu Pro Ala Ser Asp Gly Lys Arg Gly Leu Ser Val Ser 165 170 175Ile Thr Pro Ser Cys Ala Glu His Ser His Thr Val Arg Val Thr Glu 180 185 190Leu Asp Ala Asp Phe Leu Gly Pro Asp Ile Gln Ser Ser Ile His Ile 195 200 205Gly Asp Arg Ile Leu Glu Ile Asn Gly Thr Pro Ile Arg Ser Val Pro 210 215 220Leu Asp Glu Ile Asp Val Leu Ile Gln Glu Thr Ser Arg Leu Leu Gln225 230 235 240Leu Thr Ile Glu His Asp Pro His Glu Thr Pro Thr Met Pro Ser Pro 245 250 255Cys Ala Glu Ile Ala Val Arg Arg Gln Arg Pro Val Met Arg Ser Cys 260 265 270Ser Ile Asp Arg Ser Pro Gly Ser Ser Cys Val Gly Ser Pro Ser Cys 275 280 285Ser Arg Arg Asp Met Ser Arg Ser Glu Ser Val Arg Thr Val Thr Gly 290 295 300Val His Arg Ile Phe Arg Pro Ser Asp Leu Ile Pro Gly Glu Val Leu305 310 315 320Gly Arg Gly Cys Phe Gly Gln Ala Ile Lys Val Thr His Arg Val Thr 325 330 335Gly Glu Val Met Val Met Lys Glu Leu Ile Arg Phe Asp Glu Glu Thr 340 345 350Gln Arg Thr Phe Leu Lys Glu Val Lys Val Met Arg Cys Leu Glu His 355 360 365Pro His Val Leu Lys Phe Ile Gly Val Leu Tyr Lys Asp Lys Arg Leu 370 375 380Asn Phe Ile Thr Glu Tyr Ile Pro Gly Gly Thr Leu Arg Arg Val Ile385 390 395 400Lys Ser Met Asp Thr His Cys Pro Trp Asn Gln Arg Val Ser Phe Ala 405 410 415Arg Asp Ile Ala Ala Gly Met Thr Tyr Leu His Ser Met Asn Ile Ile 420 425 430His Arg Asp Leu Asn Ser His Asn Cys Leu Val Arg Glu Asp Gly Gly 435 440 445Leu Val Val Ala Asn Phe Gly Leu Ser Arg Leu Ile Pro Glu Glu Thr 450 455 460Arg Asp Leu Arg Lys Asp Arg Arg Lys Arg Tyr Thr Val Val Gly Asn465 470 475 480Pro Tyr Trp Met Ala Pro Glu Met Ile Asn Gly Arg Ser Tyr Asp Glu 485 490 495Ser Val Asp Val Phe Ser Phe Gly Ile Val Ile Cys Glu Ile Ile Gly 500 505 510Leu Val Asn Ala Asp Pro Asp Tyr Leu Pro Arg Thr Met Asp Phe Gly 515 520 525Leu Asn Val Arg Ala Phe Leu Asp Arg Phe Cys Pro Pro Asn Cys Pro 530 535 540Pro Gly Phe Phe Pro Ser Ala Val Leu Cys Cys Asp Leu Asp Pro Glu545 550 555 560Lys Arg Pro Arg Phe Ser Gln Leu Gln Leu Trp Leu Asp Ser Leu Leu 565 570 575Arg His Leu Asn Leu Gln Leu Pro Leu Ser Ser His Ile Glu Gln Leu 580 585 590Glu Gln Asn Phe Trp Glu Asn Tyr Arg Arg Gly Asp Ser Thr Leu His 595 600 605Val His Pro Glu Ile Pro Glu 610 61550653PRTCaenorhabditis elegans 50Met Thr Thr Thr Ser Ser Asp Glu Leu Pro Arg Gln Ala Asp Asp Asp1 5 10 15Ser Met Lys Trp Asp Arg Ile Tyr Ile Gln Lys Leu Asp Pro Glu Val 20 25 30Ile Phe Thr Lys Gln Glu Arg Ile Gly Arg Gly Ser Phe Gly Glu Val 35 40 45Tyr Lys Gly Ile Asp Asn Arg Thr Gly Arg Val Val Ala Ile Lys Ile 50 55 60Ile Asp Leu Glu Gln Ala Glu Asp Glu Ile Glu Asp Ile Gln Gln Glu65 70 75 80Ile Gln Val Leu Ser Gln Cys Asp Ser Gln Tyr Val Thr Lys Tyr Phe 85 90 95Gly Ser Phe Leu Lys Gly Ser Lys Leu Trp Ile Ile Met Glu Tyr Leu 100 105 110Gly Gly Gly Ser Ala Leu Asp Leu Thr Lys Ser Gly Lys Leu Asp Glu 115 120 125Ser His Ile Ala Val Ile Leu Arg Glu Ile Leu Lys Gly Leu Glu Tyr 130 135 140Leu His Ser Glu Arg Lys Ile His Arg Asp Ile Lys Ala Ala Asn Val145 150 155 160Leu Val Ser Glu His Gly Asp Val Lys Val Ala Asp Phe Gly Val Ala 165 170 175Gly Gln Leu Thr Glu Thr Val Lys Lys Arg Ile Thr Phe Val Gly Ser 180 185 190Pro

Phe Trp Met Ala Pro Glu Leu Ile Lys Gln Ser Ser Tyr Asp Tyr 195 200 205Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu Ala Asn 210 215 220Gly Glu Pro Pro His Ser Asp Leu His Pro Met Arg Val Leu Phe Leu225 230 235 240Ile Pro Lys Asn Pro Pro Pro Val Leu Gln Gly Ser Gln Trp Ser Lys 245 250 255Pro Phe Lys Glu Phe Val Glu Met Cys Leu Asn Lys Asp Pro Glu Asn 260 265 270Arg Pro Ser Ala Ser Thr Leu Leu Lys His Gln Phe Ile Lys Arg Ala 275 280 285Lys Lys Asn Ser Ile Leu Val Asp Leu Ile Glu Arg Ala Ala Glu Tyr 290 295 300Arg Leu Arg Thr Gly Val Ser Ser Asp Ser Asp Leu Asp Glu Asp Ser305 310 315 320Asp Gly Gly Gly Gly Thr Ser Lys Trp Asp Tyr Pro Thr Val Arg Gly 325 330 335Pro Arg Val Ser Ala Asp Asp Asp Gly Thr Val Arg Gln Arg Thr Asp 340 345 350Arg Pro Arg Ala Gln Val Asp Arg Arg Ser Pro Ser Gly Ser Pro Gly 355 360 365Gly Thr Ile Val Arg Gly Ser Pro Gln Val Ala Ala Val Ala Glu Gln 370 375 380Leu Arg Asn Ser Ser Val Gly Ser Ser Gly Tyr Gly Ser Gly Gly Asn385 390 395 400Ser Ala Ser Ser Gln Tyr Ala Thr Ser Ser Leu Pro Gln Ser His Thr 405 410 415Ala Ser Ser Gly Gly Ala Thr Thr Ile Thr Leu Gly Ser Pro Asn Gly 420 425 430Ser Pro Thr Ser Ser Leu Ala Arg Thr Gln Ser Met Val Ser Pro Ser 435 440 445Gly Gln Arg Ser Gly Ser Ala Gln Ser Trp Glu Leu Glu Arg Gly Asn 450 455 460Arg Pro Met Ser Glu Arg Val Ser Ser Gln Val Ser Pro Ser Lys Tyr465 470 475 480Asn Gln His Arg Thr Ser Ser Ser Asn Gly Val Gln Gly Gly Ser Gly 485 490 495Gly Arg Arg Glu Tyr Ile Asn Gly Ser Gly Ser Gly Leu Asn Gly Asn 500 505 510Ser Ser Asn Gln Asn His Ser Glu Tyr Ser Asp Ala Val Arg Gln Arg 515 520 525Gly Pro Gly Gly Ser Gly Gly Arg Leu Asp Tyr Arg Glu Ser His Val 530 535 540Pro Thr Ser Ser Gln Glu Asn Leu Asn His Gly Arg Met Tyr Gly Tyr545 550 555 560Gly Ala Pro Pro Pro Ser Arg Glu Ala Asn Asn Val Pro Met Pro Arg 565 570 575Val Lys Gly Ala Leu Asp Cys Ser Leu Leu Pro Ala Ile Glu His Leu 580 585 590Ser Arg Thr Arg His Ala Thr Ala Ala Leu Asp Gln Leu Arg His Val 595 600 605Phe Arg Asp Val Glu Asp Ser Cys Pro Gly Ile Cys Asn Glu Leu Ile 610 615 620Glu Glu Leu Met Gln Arg Ile Ala Val Pro Gln Val Ser Gln Ser Asp625 630 635 640Leu Asp Ala Ala Ile Arg Arg Leu Thr Thr Pro Pro Ser 645 65051478PRTDictyostelium discoideum 51Met Ala Ser Lys Lys Gly Asp Pro Glu Glu Leu Tyr Val Arg Gln Glu1 5 10 15Lys Ile Gly Lys Gly Ser Phe Gly Glu Val Phe Lys Gly Ile Asn Lys 20 25 30Lys Thr Asn Glu Thr Ile Ala Ile Lys Thr Ile Asp Leu Glu Asp Ala 35 40 45Glu Asp Glu Ile Glu Asp Ile Gln Gln Glu Ile Asn Val Leu Ser Gln 50 55 60Cys Glu Ser Pro Phe Val Thr Lys Tyr Phe Gly Ser Phe Leu Lys Gly65 70 75 80Ser Lys Leu Trp Ile Ile Met Glu Tyr Leu Ala Gly Gly Ser Val Leu 85 90 95Asp Leu Met Lys Pro Gly Pro Phe Asp Glu Gly Tyr Ile Ala Ile Ile 100 105 110Leu Arg Glu Leu Leu Lys Gly Leu Glu Tyr Leu His Ser Glu Gly Lys 115 120 125Ile His Arg Asp Ile Lys Ala Ala Asn Val Leu Leu Ser Ala Ser Gly 130 135 140Asp Val Lys Leu Ala Asp Phe Gly Val Ser Gly Gln Leu Thr Asp Gln145 150 155 160Met Thr Lys Arg Asn Thr Phe Val Gly Thr Pro Phe Trp Met Ala Pro 165 170 175Glu Val Ile Lys Gln Thr Gly Tyr Asp Ser Lys Ala Asp Ile Trp Ser 180 185 190Met Gly Ile Thr Ala Leu Glu Met Ala Lys Gly Glu Pro Pro Arg Ala 195 200 205Asp Leu His Pro Met Arg Ala Leu Phe Leu Ile Pro Lys Asp Pro Pro 210 215 220Pro Thr Leu Glu Gly Asn Phe Ser Lys Gly Phe Lys Glu Phe Cys Ala225 230 235 240Leu Cys Leu Asn Lys Asp Pro Asn Gln Arg Pro Thr Ala Lys Asp Leu 245 250 255Leu Lys His Lys Phe Ile Lys Ala Ala Lys Lys Thr Ser Ser Leu Thr 260 265 270Asp Leu Ile Glu Arg Arg Gln Lys Trp Leu Gln Leu Asn Gly Asn Asn 275 280 285Ala Asp Asp Glu Asn Asp Asp Leu Asp Arg Asp Ala Lys Ser Asn Glu 290 295 300Glu Asp Phe Gly Trp Glu Phe Pro Thr Ile Lys Gln Lys Ser Pro Val305 310 315 320Ala Val Gln Glu Gln Gln Gln Thr Pro Gln Lys Pro Thr Val Val Ser 325 330 335Thr Pro Ile Lys Glu Gln Gln Gln Gln Gln Gln Pro Thr Pro Val Thr 340 345 350Thr Pro Gln Gln Pro Val Thr Thr Thr Thr Thr Thr Pro Thr Thr Glu 355 360 365Thr Lys Val Arg Ser Leu Ser Asn Ser Ser Gln Thr Thr Pro Val Lys 370 375 380Thr Thr Val Ala Ala Thr Thr Ala Pro Ala Thr Thr Pro Ala Ser Asn385 390 395 400Ala Pro Thr Ser Thr Thr Pro Asn Gly Ala Ala Val Thr Gln Gln Gln 405 410 415Ala Pro Arg Ala Ser Ala Leu Thr Ser Val Ile Tyr Pro Val Leu Ser 420 425 430Lys Leu Leu Lys Asn Thr Ser Asp Glu Asn Val Ile Asn Ala Leu Ala 435 440 445Gln Leu Lys Met Ala Phe Asp Asn Ala Glu Lys Ala Lys Pro Gly Ile 450 455 460Thr His Ser Leu Ile Ala Gln Ile Ile Glu Thr Leu Lys Arg465 470 47552426PRTHomo sapiens 52Met Ala His Leu Arg Gly Phe Ala Asn Gln His Ser Arg Val Asp Pro1 5 10 15Glu Glu Leu Phe Thr Lys Leu Asp Arg Ile Gly Lys Gly Ser Phe Gly 20 25 30Glu Val Tyr Lys Gly Ile Asp Asn His Thr Lys Glu Val Val Ala Ile 35 40 45Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile Glu Asp Ile Gln 50 55 60Gln Glu Ile Thr Val Leu Ser Gln Cys Asp Ser Pro Tyr Ile Thr Arg65 70 75 80Tyr Phe Gly Ser Tyr Leu Lys Ser Thr Lys Leu Trp Ile Ile Met Glu 85 90 95Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Lys Pro Gly Pro Leu 100 105 110Glu Glu Thr Tyr Ile Ala Thr Ile Leu Arg Glu Ile Leu Lys Gly Leu 115 120 125Asp Tyr Leu His Ser Glu Arg Lys Ile His Arg Asp Ile Lys Ala Ala 130 135 140Asn Val Leu Leu Ser Glu Gln Gly Asp Val Lys Leu Ala Asp Phe Gly145 150 155 160Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg Asn Thr Phe Val 165 170 175Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Lys Gln Ser Ala Tyr 180 185 190Asp Phe Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu 195 200 205Ala Lys Gly Glu Pro Pro Asn Ser Asp Leu His Pro Met Arg Val Leu 210 215 220Phe Leu Ile Pro Lys Asn Ser Pro Pro Thr Leu Glu Gly Gln His Ser225 230 235 240Lys Pro Phe Lys Glu Phe Val Glu Ala Cys Leu Asn Lys Asp Pro Arg 245 250 255Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys Phe Ile Thr Arg 260 265 270Tyr Thr Lys Lys Thr Ser Phe Leu Thr Glu Leu Ile Asp Arg Tyr Lys 275 280 285Arg Trp Lys Ser Glu Gly His Gly Glu Glu Ser Ser Ser Glu Asp Ser 290 295 300Asp Ile Asp Gly Glu Ala Glu Asp Gly Glu Gln Gly Pro Ile Trp Thr305 310 315 320Phe Pro Pro Thr Ile Arg Pro Ser Pro His Ser Lys Leu His Lys Gly 325 330 335Thr Ala Leu His Ser Ser Gln Lys Pro Ala Asp Ala Val Lys Arg Gln 340 345 350Pro Arg Ser Gln Cys Leu Ser Thr Leu Val Arg Pro Val Phe Gly Glu 355 360 365Leu Lys Glu Lys His Lys Gln Ser Gly Gly Ser Val Gly Ala Leu Glu 370 375 380Glu Leu Glu Asn Ala Phe Ser Leu Ala Glu Glu Ser Cys Pro Gly Ile385 390 395 400Ser Asp Lys Leu Met Val His Leu Val Glu Arg Val Gln Arg Phe Ser 405 410 415His Asn Arg Asn His Leu Thr Ser Thr Arg 420 42553431PRTHomo sapiens 53Met Ala His Ser Pro Val Gln Ser Gly Leu Pro Gly Met Gln Asn Leu1 5 10 15Lys Ala Asp Pro Glu Glu Leu Phe Thr Lys Leu Glu Lys Ile Gly Lys 20 25 30Gly Ser Phe Gly Glu Val Phe Lys Gly Ile Asp Asn Arg Thr Gln Lys 35 40 45Val Val Ala Ile Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile 50 55 60Glu Asp Ile Gln Gln Glu Ile Thr Val Leu Ser Gln Cys Asp Ser Pro65 70 75 80Tyr Val Thr Lys Tyr Tyr Gly Ser Tyr Leu Lys Asp Thr Lys Leu Trp 85 90 95Ile Ile Met Glu Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Glu 100 105 110Pro Gly Pro Leu Asp Glu Thr Gln Ile Ala Thr Ile Leu Arg Glu Ile 115 120 125Leu Lys Gly Leu Asp Tyr Leu His Ser Glu Lys Lys Ile His Arg Asp 130 135 140Ile Lys Ala Ala Asn Val Leu Leu Ser Glu His Gly Glu Val Lys Leu145 150 155 160Ala Asp Phe Gly Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg 165 170 175Asn Thr Phe Val Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Lys 180 185 190Gln Ser Ala Tyr Asp Ser Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr 195 200 205Ala Ile Glu Leu Ala Arg Gly Glu Pro Pro His Ser Glu Leu His Pro 210 215 220Met Lys Val Leu Phe Leu Ile Pro Lys Asn Asn Pro Pro Thr Leu Glu225 230 235 240Gly Asn Tyr Ser Lys Pro Leu Lys Glu Phe Val Glu Ala Cys Leu Asn 245 250 255Lys Glu Pro Ser Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys 260 265 270Phe Ile Leu Arg Asn Ala Lys Lys Thr Ser Tyr Leu Thr Glu Leu Ile 275 280 285Asp Arg Tyr Lys Arg Trp Lys Ala Glu Gln Ser His Asp Asp Ser Ser 290 295 300Ser Glu Asp Ser Asp Ala Glu Thr Asp Gly Gln Ala Ser Gly Gly Ser305 310 315 320Asp Ser Gly Asp Trp Ile Phe Thr Ile Arg Glu Lys Asp Pro Lys Asn 325 330 335Leu Glu Asn Gly Ala Leu Gln Pro Ser Asp Leu Asp Arg Asn Lys Met 340 345 350Lys Asp Ile Pro Lys Arg Pro Phe Ser Gln Cys Leu Ser Thr Ile Ile 355 360 365Ser Pro Leu Phe Ala Glu Leu Lys Glu Lys Ser Gln Ala Cys Gly Gly 370 375 380Asn Leu Gly Ser Ile Glu Glu Leu Arg Gly Ala Ile Tyr Leu Ala Glu385 390 395 400Glu Val Cys Pro Gly Ile Ser Asp Thr Met Val Ala Gln Leu Val Gln 405 410 415Arg Leu Gln Arg Tyr Ser Leu Ser Gly Gly Gly Thr Ser Ser His 420 425 43054426PRTHomo sapiens 54Met Ala His Leu Arg Gly Phe Ala Asn Gln His Ser Arg Val Asp Pro1 5 10 15Glu Glu Leu Phe Thr Lys Leu Asp Arg Ile Gly Lys Gly Ser Phe Gly 20 25 30Glu Val Tyr Lys Gly Ile Asp Asn His Thr Lys Glu Val Val Ala Ile 35 40 45Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile Glu Asp Ile Gln 50 55 60Gln Glu Ile Thr Val Leu Ser Gln Cys Asp Ser Pro Tyr Ile Thr Arg65 70 75 80Tyr Phe Gly Ser Tyr Leu Lys Ser Thr Lys Leu Trp Ile Ile Met Glu 85 90 95Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Lys Pro Gly Pro Leu 100 105 110Glu Glu Thr Tyr Ile Ala Thr Ile Leu Arg Glu Ile Leu Lys Gly Leu 115 120 125Asp Tyr Leu His Ser Glu Arg Lys Ile His Arg Asp Ile Lys Ala Ala 130 135 140Asn Val Leu Leu Ser Glu Gln Gly Asp Val Lys Leu Ala Asp Phe Gly145 150 155 160Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg Asn Thr Phe Val 165 170 175Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Lys Gln Ser Ala Tyr 180 185 190Asp Phe Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu 195 200 205Ala Lys Gly Glu Pro Pro Asn Ser Asp Leu His Pro Met Arg Val Leu 210 215 220Phe Leu Ile Pro Lys Asn Ser Pro Pro Thr Leu Glu Gly Gln His Ser225 230 235 240Lys Pro Phe Lys Glu Phe Val Glu Ala Cys Leu Asn Lys Asp Pro Arg 245 250 255Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys Phe Ile Thr Arg 260 265 270Tyr Thr Lys Lys Thr Ser Phe Leu Thr Glu Leu Ile Asp Arg Tyr Lys 275 280 285Arg Trp Lys Ser Glu Gly His Gly Glu Glu Ser Ser Ser Glu Asp Ser 290 295 300Asp Ile Asp Gly Glu Ala Glu Asp Gly Glu Gln Gly Pro Ile Trp Thr305 310 315 320Phe Pro Pro Thr Ile Arg Pro Ser Pro His Ser Lys Leu His Lys Gly 325 330 335Thr Ala Leu His Ser Ser Gln Lys Pro Ala Glu Pro Val Lys Arg Gln 340 345 350Pro Arg Ser Gln Cys Leu Ser Thr Leu Val Arg Pro Val Phe Gly Glu 355 360 365Leu Lys Glu Lys His Lys Gln Ser Gly Gly Ser Val Gly Ala Leu Glu 370 375 380Glu Leu Glu Asn Ala Phe Ser Leu Ala Glu Glu Ser Cys Pro Gly Ile385 390 395 400Ser Asp Lys Leu Met Val His Leu Val Glu Arg Val Gln Arg Phe Ser 405 410 415His Asn Arg Asn His Leu Thr Ser Thr Arg 420 42555426PRTMus musculus 55Met Ala His Leu Arg Gly Phe Ala His Gln His Ser Arg Val Asp Pro1 5 10 15Glu Glu Leu Phe Thr Lys Leu Asp Arg Ile Gly Lys Gly Ser Phe Gly 20 25 30Glu Val Tyr Lys Gly Ile Asp Asn His Thr Lys Glu Val Val Ala Ile 35 40 45Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile Glu Asp Ile Gln 50 55 60Gln Glu Ile Thr Val Leu Ser Gln Cys Asp Ser Pro Tyr Ile Thr Arg65 70 75 80Tyr Phe Gly Ser Tyr Leu Lys Ser Thr Lys Leu Trp Ile Ile Met Glu 85 90 95Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Lys Pro Gly Pro Leu 100 105 110Glu Glu Thr Tyr Ile Ala Thr Ile Leu Arg Glu Ile Leu Lys Gly Leu 115 120 125Asp Tyr Leu His Ser Glu Arg Lys Ile His Arg Asp Ile Lys Ala Ala 130 135 140Asn Val Leu Leu Ser Glu Gln Gly Asp Val Lys Met Ala Asp Phe Gly145 150 155 160Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg Asn Thr Phe Val 165 170 175Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Lys Gln Ser Ala Tyr 180 185 190Asp Phe Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu 195 200 205Ala Lys Gly Glu Pro Pro Asn Ser Asp Leu His Pro Met Arg Val Leu 210 215 220Phe Leu Ile Pro Lys Asn Asn Pro Pro Thr Leu Glu Gly His His Ser225 230

235 240Lys Pro Phe Lys Glu Phe Val Glu Ala Cys Leu Asn Lys Asp Pro Arg 245 250 255Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys Phe Ile Thr Arg 260 265 270Tyr Thr Lys Lys Thr Ser Phe Leu Thr Glu Leu Ile Asp Arg Tyr Lys 275 280 285Arg Trp Lys Ser Glu Gly His Gly Glu Glu Ser Ser Ser Glu Asp Ser 290 295 300Asp Ile Asp Gly Glu Ala Glu Asp Gly Glu Gln Gly Pro Ile Trp Thr305 310 315 320Phe Pro Pro Thr Ile Arg Pro Ser Pro His Ser Lys Leu His Lys Gly 325 330 335Thr Ala Leu His Ser Ser Gln Lys Pro Ala Glu Pro Ile Lys Arg Gln 340 345 350Pro Arg Ser Gln Cys Leu Ser Thr Leu Val Arg Pro Val Phe Gly Glu 355 360 365Leu Lys Glu Lys His Lys Gln Ser Gly Gly Ser Val Gly Ala Leu Glu 370 375 380Glu Leu Glu Asn Ala Phe Ser Leu Ala Glu Glu Ser Cys Pro Gly Ile385 390 395 400Ser Asp Lys Leu Met Val His Leu Val Glu Arg Val Gln Arg Phe Ser 405 410 415His Ser Arg Asn His Leu Thr Ser Thr Arg 420 4255621DNAArtificial SequenceOligonucleotide Primer for h12832 56ttttcacctc cgacctttcc t 215721DNAArtificial SequenceOligonucleotide Primer for h12832 57atcccttcca ttgtgaaagc c 215825DNAArtificial SequenceOligonucleotide Primer for h12832 58ccaggcggtg agactctgga ctgag 255926DNAArtificial SequenceOligonucleotide Primer for h14138 59cacgaggcta gactaaaagg aaaatt 266022DNAArtificial SequenceOligonucleotide Primer for h14138 60tgaagccagg aatactgctc ag 226134DNAArtificial SequenceOligonucleotide Primer for h14138 61ttgtgctaca gactaaatcc agatacggtc aggt 346218DNAArtificial SequenceOligonucleotide Primer for h14833 62cctgcctccc actcatcg 186323DNAArtificial SequenceOligonucleotide Primer for h14833 63cagctggttc tgtagaggac gaa 236427DNAArtificial SequenceOligonucleotide Primer for h14833 64atgctctgac tgctcactgc ctggatc 276516DNAArtificial SequenceOligonucleotide Primer for h15990 65ggcaaaggcg ggttcg 166619DNAArtificial SequenceOligonucleotide Primer for h15990 66ttgaccgcca catcgtagc 196722DNAArtificial SequenceOligonucleotide Primer for h15990 67ccgggcgcaa cataggaagt gg 226826DNAArtificial SequenceOligonucleotide Primer for h16341 68cagttgctag acagtaacct gcattt 266920DNAArtificial SequenceOligonucleotide Primer for h16341 69tgaggcccac tgctatgtca 207027DNAArtificial SequenceOligonucleotide Primer for h16341 70ccttggactg tgagggtaaa actggcc 277120DNAArtificial SequenceOligonucleotide Primer for h2252 71tctgattccg agggctctga 207221DNAArtificial SequenceOligonucleotide Primer for h2252 72acggtggtaa agtctcattc a 217333DNAArtificial SequenceOligonucleotide Primer for h2252 73cggaatctac cagcagggaa aacaatactc atc 337421DNAArtificial SequenceOligonucleotide Primer for b-2 microglobulin 74cacccccact gaaaaagatg a 217526DNAArtificial SequenceOligonucleotide Primer for b-2 microglobulin 75cttaactatc ttgggctgtg acaaag 267623DNAArtificial SequenceOligonucleotide Primer for b-2 microglobulin 76atgcctgccg tgtgaaccac gtg 2377256PRTDictyostelium discoideum 77Gln Gln Ser Gln Gln Gln Ser Gln Gln Gln Gln Gln Thr Thr Pro Pro1 5 10 15Leu Pro Pro His Asn Ile His Arg Lys Leu Ser Cys Val Gly Thr Pro 20 25 30Asp Tyr Leu Ala Pro Glu Ile Leu Leu Gly Ile Gly His Gly Ala Ser 35 40 45Ala Asp Trp Phe Ser Leu Gly Val Ile Leu Tyr Glu Phe Leu Cys Gly 50 55 60Val Ser Pro Phe Asn Gly Ser Ser Val Gln Glu Thr Phe Gln Asn Ile65 70 75 80Leu Gln Arg Asn Ile Ser Trp Pro Glu Asp Met Ser Pro Glu Ala Arg 85 90 95Asp Leu Ile Asp Lys Leu Leu Ala Leu Asp Pro Arg Gln Arg Leu Gly 100 105 110Phe Asn Gly Ala Glu Glu Ile Lys Ser His Pro Phe Phe Lys Ser Ile 115 120 125Asn Trp Lys Thr Ile Leu Thr Gln Glu Pro Tyr Phe Lys Pro Lys Ile 130 135 140Glu Asn Leu Gln Asp Thr Ser Tyr Phe Asp Pro Arg Lys Glu Ile Tyr145 150 155 160Lys Val Ser Asp Asp Phe Ala Glu Ser Cys Lys Pro Phe Val Gln Asn 165 170 175Gln Asn Gln Asn Lys Glu Ser Ser Thr Ile Leu Thr Thr Ser Pro Pro 180 185 190Ser Thr Ser Ser Thr Thr Ala Thr Ala Thr Ala Thr Thr Ser Asn Leu 195 200 205Asp Ser Ile Thr Ile Asn Gln Asn Thr Asn Ala Asn Phe Asp Asp Phe 210 215 220Leu Tyr Val Asn Phe Gln Ser Leu Leu Glu Leu Asn Lys Asn Tyr Leu225 230 235 240Ala Glu Ala Lys Pro Phe Asn Ser Asn His Arg Arg Arg Asn Ser Thr 245 250 255781237PRTHomo sapiens 78Gly Arg Ser Ser Lys Ala Lys Lys Pro Pro Gly Glu Asn Asp Phe Asp1 5 10 15Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Tyr Leu Val 20 25 30Arg His Arg Asp Thr Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys 35 40 45Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg 50 55 60Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe Val Val Gly Met Phe Cys65 70 75 80Ser Phe Glu Thr Arg Arg His Leu Cys Met Val Met Glu Tyr Val Glu 85 90 95Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn Ile Gly Ala Leu Pro Val 100 105 110Glu Met Ala Arg Met Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr 115 120 125Leu His Asn Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu 130 135 140Leu Ile Thr Ser Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser145 150 155 160Lys Met Gly Leu Met Ser Leu Thr Thr Asn Leu Tyr Glu Gly His Ile 165 170 175Glu Lys Asp Ala Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro 180 185 190Glu Tyr Ile Ala Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro 195 200 205Val Asp Trp Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly 210 215 220Cys Val Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val225 230 235 240Ile Ser Asp Asp Ile Leu Trp Pro Glu Gly Asp Glu Ala Leu Pro Thr 245 250 255Glu Ala Gln Leu Leu Ile Ser Ser Leu Leu Gln Thr Asn Pro Leu Val 260 265 270Arg Leu Gly Ala Gly Gly Ala Phe Glu Val Lys Gln His Ser Phe Phe 275 280 285Arg Asp Leu Asp Trp Thr Gly Leu Leu Arg Gln Lys Ala Glu Phe Ile 290 295 300Pro His Leu Glu Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser305 310 315 320Asp Arg Tyr His His Val Asn Ser Tyr Asp Glu Asp Asp Thr Thr Glu 325 330 335Glu Glu Pro Val Glu Ile Arg Gln Phe Ser Ser Cys Ser Pro Arg Phe 340 345 350Ser Lys Val Tyr Ser Ser Met Glu Gln Leu Ser Gln His Glu Pro Lys 355 360 365Thr Pro Val Ala Ala Ala Gly Ser Ser Lys Arg Glu Pro Ser Thr Lys 370 375 380Gly Pro Glu Glu Lys Val Ala Gly Lys Arg Glu Gly Leu Gly Gly Leu385 390 395 400Thr Leu Arg Glu Lys Thr Trp Arg Gly Gly Ser Pro Glu Ile Lys Arg 405 410 415Phe Ser Ala Ser Glu Ala Ser Phe Leu Glu Gly Glu Ala Ser Pro Pro 420 425 430Leu Gly Ala Arg Arg Arg Phe Ser Ala Leu Leu Glu Pro Ser Arg Phe 435 440 445Ser Ala Pro Gln Glu Asp Glu Asp Glu Ala Arg Leu Arg Arg Pro Pro 450 455 460Arg Pro Ser Ser Asp Pro Ala Gly Ser Leu Asp Ala Arg Ala Pro Lys465 470 475 480Glu Glu Thr Gln Gly Glu Gly Thr Ser Ser Ala Gly Asp Ser Glu Ala 485 490 495Ser Pro Arg Ala Thr Asn Asp Leu Val Leu Arg Arg Ala Arg His Gln 500 505 510Gln Met Ser Gly Asp Val Ala Val Glu Lys Arg Pro Ser Arg Thr Gly 515 520 525Gly Lys Val Ile Lys Ser Ala Ser Ala Thr Ala Leu Ser Ala Gly Pro 530 535 540Met Arg Gly Cys Ser Ala Thr Ala Leu Gly Gly Gly Arg Ser Arg Tyr545 550 555 560Arg Glu Met Ser Ile Phe Leu Val Leu Ile Ser Asp His Gly Cys Val 565 570 575Ser Val Val Asp Pro His Gly Ser Ser Pro Leu Ala Ser Pro Met Ser 580 585 590Pro Arg Ser Leu Ser Ser Asn Pro Ser Ser Arg Asp Ser Ser Pro Ser 595 600 605Arg Asp Tyr Ser Pro Ala Val Ser Gly Leu Arg Ser Pro Ile Thr Ile 610 615 620Gln Arg Ser Gly Lys Lys Tyr Gly Phe Thr Leu Arg Ala Ile Arg Val625 630 635 640Tyr Met Gly Asp Thr Asp Val Tyr Ser Val His His Ile Val Trp His 645 650 655Val Glu Glu Gly Gly Pro Ala Gln Glu Ala Gly Leu Cys Ala Gly Asp 660 665 670Leu Ile Thr His Val Asn Gly Glu Pro Val His Gly Met Val His Pro 675 680 685Glu Val Val Glu Leu Ile Leu Lys Ser Gly Asn Lys Val Ala Val Thr 690 695 700Thr Thr Pro Phe Glu Asn Thr Ser Ile Arg Ile Gly Pro Ala Arg Arg705 710 715 720Ser Ser Tyr Lys Ala Lys Met Ala Arg Arg Asn Lys Arg Pro Ser Ala 725 730 735Lys Glu Gly Gln Glu Ser Lys Lys Arg Ser Ser Leu Phe Arg Lys Ile 740 745 750Thr Lys Gln Ser Asn Leu Leu His Thr Ser Arg Ser Leu Ser Ser Leu 755 760 765Asn Arg Ser Leu Ser Ser Ser Asp Ser Leu Pro Gly Ser Pro Thr His 770 775 780Gly Leu Pro Ala Arg Ser Pro Thr His Ser Tyr Arg Ser Thr Pro Asp785 790 795 800Ser Ala Tyr Leu Gly Ile Thr Ser Cys Thr Cys Ala Gly Thr Glu Gln 805 810 815Arg Gly Val Ala Trp Leu Ser Ser Ser Pro Ala Ser Ser Thr Pro Asn 820 825 830Ser Pro Ala Ser Ser Ala Ser His His Ile Arg Pro Ser Thr Leu His 835 840 845Gly Leu Ser Pro Lys Leu His Arg Gln Tyr Arg Ser Ala Arg Cys Lys 850 855 860Ser Ala Gly Asn Ile Pro Leu Ser Pro Leu Ala His Thr Pro Ser Pro865 870 875 880Thr Gln Ala Ser Pro Pro Pro Leu Pro Gly His Thr Val Gly Ser Ser 885 890 895His Thr Thr Gln Ser Phe Pro Ala Lys Leu His Ser Ser Pro Pro Val 900 905 910Val Arg Pro Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu 915 920 925Lys Arg Val Gln Ser Ala Glu Lys Leu Gly Ala Ser Leu Ser Ala Asp 930 935 940Lys Lys Gly Ala Leu Arg Lys His Ser Leu Glu Val Gly His Pro Asp945 950 955 960Phe Arg Lys Asp Phe His Gly Glu Leu Ala Leu His Ser Leu Ala Glu 965 970 975Ser Asp Gly Glu Thr Pro Pro Val Glu Gly Leu Gly Ala Pro Arg Gln 980 985 990Val Ala Val Arg Arg Leu Gly Arg Gln Glu Ser Pro Leu Ser Leu Gly 995 1000 1005Ala Asp Pro Leu Leu Pro Glu Gly Ala Ser Arg Pro Pro Val Ser Ser 1010 1015 1020Lys Glu Lys Glu Ser Pro Gly Gly Ala Glu Ala Cys Thr Pro Pro Arg1025 1030 1035 1040Ala Thr Thr Pro Gly Gly Arg Thr Leu Glu Arg Asp Val Gly Cys Thr 1045 1050 1055Arg His Gln Ser Val Gln Thr Glu Asp Gly Thr Gly Gly Met Ala Arg 1060 1065 1070Ala Val Ala Lys Ala Ala Leu Ser Pro Val Gln Glu His Glu Thr Gly 1075 1080 1085Arg Arg Ser Ser Ser Gly Glu Ala Gly Thr Pro Leu Val Pro Ile Val 1090 1095 1100Val Glu Pro Ala Arg Pro Gly Ala Lys Ala Val Val Pro Gln Pro Leu1105 1110 1115 1120Gly Ala Asp Ser Lys Gly Leu Gln Glu Pro Ala Pro Leu Ala Pro Ser 1125 1130 1135Val Pro Glu Ala Pro Arg Gly Arg Glu Arg Trp Val Leu Glu Val Val 1140 1145 1150Glu Glu Arg Thr Thr Leu Ser Gly Pro Arg Ser Lys Pro Ala Ser Pro 1155 1160 1165Lys Leu Ser Pro Glu Pro Gln Thr Pro Ser Leu Ala Pro Ala Lys Cys 1170 1175 1180Ser Ala Pro Ser Ser Ala Val Thr Pro Val Pro Pro Ala Ser Leu Leu1185 1190 1195 1200Gly Ser Gly Thr Lys Pro Gln Val Gly Leu Thr Ser Arg Cys Pro Ala 1205 1210 1215Glu Ala Val Pro Pro Ala Gly Leu Thr Lys Lys Gly Val Ser Ser Pro 1220 1225 1230Ala Pro Pro Gly Pro 1235791308PRTHomo sapiens 79Asp Glu Ser Ser Leu Leu Arg Arg Arg Gly Leu Gln Lys Glu Leu Ser1 5 10 15Leu Pro Arg Arg Gly Arg Gly Cys Arg Ser Gly Asn Arg Lys Ser Leu 20 25 30Val Val Gly Thr Pro Ser Pro Thr Leu Ser Arg Pro Leu Ser Pro Leu 35 40 45Ser Val Pro Thr Ala Gly Ser Ser Pro Leu Asp Ser Pro Arg Asn Phe 50 55 60Ser Ala Ala Ser Ala Leu Asn Phe Pro Phe Ala Arg Arg Ala Asp Gly65 70 75 80Arg Arg Trp Ser Leu Ala Ser Leu Pro Ser Ser Gly Tyr Gly Thr Asn 85 90 95Thr Pro Ser Ser Thr Leu Ser Ser Ser Ser Ser Ser Arg Glu Arg Leu 100 105 110His Gln Leu Pro Phe Gln Pro Thr Pro Asp Glu Leu His Phe Leu Ser 115 120 125Lys His Phe Arg Ser Ser Glu Asn Val Leu Asp Glu Glu Gly Gly Arg 130 135 140Ser Pro Arg Leu Arg Pro Arg Ser Arg Ser Leu Ser Pro Gly Arg Ala145 150 155 160Thr Gly Thr Phe Asp Asn Glu Ile Val Met Met Asn His Val Tyr Arg 165 170 175Glu Arg Phe Pro Lys Ala Thr Ala Gln Met Glu Gly Arg Leu Gln Glu 180 185 190Phe Leu Thr Ala Tyr Ala Pro Gly Ala Arg Leu Ala Leu Ala Asp Gly 195 200 205Val Leu Gly Phe Ile His His Gln Ile Val Glu Leu Ala Arg Asp Cys 210 215 220Leu Ala Lys Ser Gly Glu Asn Leu Val Thr Ser Arg Tyr Phe Leu Glu225 230 235 240Met Gln Glu Lys Leu Glu Arg Leu Leu Gln Asp Ala His Glu Arg Ser 245 250 255Asp Ser Glu Glu Val Ser Phe Ile Val Gln Leu Val Arg Lys Leu Leu 260 265 270Ile Ile Ile Ser Arg Pro Ala Arg Leu Leu Glu Cys Leu Glu Phe Asp 275 280 285Pro Glu Glu Phe Tyr His Leu Leu Glu Ala Ala Glu Gly His Ala Arg 290 295 300Glu Gly Gln Gly Ile Lys Thr Asp Leu Pro Gln Tyr Ile Ile Gly Gln305 310 315 320Leu Gly Leu Ala Lys Asp Pro Leu Glu Glu Met Val Pro Leu Ser His 325 330 335Leu Glu Glu Glu Gln Pro Pro Ala Pro Glu Ser Pro Glu Ser Arg Ala 340 345 350Leu Val Gly Gln Ser Arg Arg Lys Pro Cys Glu Ser Asp Phe Glu Thr 355 360 365Ile

Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Tyr Leu Val Arg 370 375 380His Arg Asp Thr Arg Gln Arg Phe Ala Ile Lys Lys Ile Asn Lys Gln385 390 395 400Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Val Phe Val Glu Arg Asp 405 410 415Ile Leu Thr Phe Ala Glu Asn Pro Phe Val Val Ser Met Phe Cys Ser 420 425 430Phe Glu Thr Arg Arg His Leu Cys Met Val Met Glu Tyr Val Glu Gly 435 440 445Gly Asp Cys Ala Thr Leu Leu Lys Asn Met Gly Pro Leu Pro Val Asp 450 455 460Met Ala Arg Leu Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu465 470 475 480His Asn Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu 485 490 495Ile Thr Ser Leu Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys 500 505 510Ile Gly Leu Met Ser Met Ala Thr Asn Leu Tyr Glu Gly His Ile Glu 515 520 525Lys Asp Ala Arg Glu Phe Ile Asp Lys Gln Val Cys Gly Thr Pro Glu 530 535 540Tyr Ile Ala Pro Glu Val Ile Phe Arg Gln Gly Tyr Gly Lys Pro Val545 550 555 560Asp Trp Trp Ala Met Gly Val Val Leu Tyr Glu Phe Leu Val Gly Cys 565 570 575Val Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Val 580 585 590Ser Asp Glu Ile Met Trp Pro Glu Gly Asp Glu Ala Leu Pro Ala Asp 595 600 605Ala Gln Asp Leu Ile Thr Arg Leu Leu Arg Gln Ser Pro Leu Asp Arg 610 615 620Leu Gly Thr Gly Gly Thr His Glu Val Lys Gln His Pro Phe Phe Leu625 630 635 640Ala Leu Asp Trp Ala Gly Leu Leu Arg His Lys Ala Glu Phe Val Pro 645 650 655Gln Leu Glu Ala Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu 660 665 670Arg Tyr Arg His Leu Gly Ser Glu Asp Asp Glu Thr Asn Asp Glu Glu 675 680 685Ser Ser Thr Glu Ile Pro Gln Phe Ser Ser Cys Ser His Arg Phe Ser 690 695 700Lys Val Tyr Ser Ser Ser Glu Phe Leu Ala Val Gln Pro Thr Pro Thr705 710 715 720Phe Ala Glu Arg Ser Phe Ser Glu Asp Arg Glu Glu Gly Trp Glu Arg 725 730 735Ser Glu Val Asp Tyr Gly Arg Arg Leu Ser Ala Asp Ile Arg Leu Arg 740 745 750Ser Trp Thr Ser Ser Gly Ser Ser Cys Gln Ser Ser Ser Ser Gln Pro 755 760 765Glu Arg Gly Pro Ser Pro Ser Leu Leu Asn Thr Ile Ser Leu Asp Thr 770 775 780Met Pro Lys Phe Ala Phe Ser Ser Glu Asp Glu Gly Val Gly Pro Gly785 790 795 800Pro Ala Gly Pro Lys Arg Pro Val Phe Ile Leu Gly Glu Pro Asp Pro 805 810 815Pro Pro Ala Ala Thr Pro Val Met Pro Lys Pro Ser Ser Leu Ser Ala 820 825 830Asp Thr Ala Ala Leu Ser His Ala Arg Leu Arg Ser Asn Ser Ile Gly 835 840 845Ala Arg His Ser Thr Pro Arg Pro Leu Asp Ala Gly Arg Gly Arg Arg 850 855 860Leu Gly Gly Pro Arg Asp Pro Ala Pro Glu Lys Ser Arg Ala Ser Ser865 870 875 880Ser Gly Gly Ser Gly Gly Gly Ser Gly Gly Arg Val Pro Lys Ser Ala 885 890 895Ser Val Ser Ala Leu Ser Leu Ile Ile Thr Ala Asp Asp Gly Ser Gly 900 905 910Gly Pro Leu Met Ser Pro Leu Ser Pro Arg Ser Leu Ser Ser Asn Pro 915 920 925Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Pro Ser Pro Val Cys Gly 930 935 940Ser Leu Arg Pro Pro Ile Val Ile His Ser Ser Gly Lys Lys Tyr Gly945 950 955 960Phe Ser Leu Arg Ala Ile Arg Val Tyr Met Gly Asp Ser Asp Val Tyr 965 970 975Thr Val His His Val Val Trp Ser Val Glu Asp Gly Ser Pro Ala Gln 980 985 990Glu Ala Gly Leu Arg Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu 995 1000 1005Ser Val Leu Gly Leu Val His Met Asp Val Val Glu Leu Leu Leu Lys 1010 1015 1020Ser Gly Asn Lys Ile Ser Leu Arg Thr Thr Ala Leu Glu Asn Thr Ser1025 1030 1035 1040Ile Lys Val Gly Pro Ala Arg Lys Asn Val Ala Lys Gly Arg Met Ala 1045 1050 1055Arg Arg Ser Lys Arg Ser Arg Arg Arg Glu Thr Gln Asp Arg Arg Lys 1060 1065 1070Ser Leu Phe Lys Lys Ile Ser Lys Gln Thr Ser Val Leu His Thr Ser 1075 1080 1085Arg Ser Phe Ser Ser Gly Leu His His Ser Leu Ser Ser Ser Glu Ser 1090 1095 1100Leu Pro Gly Ser Pro Thr His Ser Leu Ser Pro Ser Pro Thr Thr Pro1105 1110 1115 1120Cys Arg Ser Pro Ala Pro Asp Val Pro Ala Asp Thr Thr Ala Ser Pro 1125 1130 1135Pro Ser Ala Ser Pro Ser Ser Ser Ser Pro Ala Ser Pro Ala Ala Ala 1140 1145 1150Gly His Thr Arg Pro Ser Ser Leu His Gly Leu Ala Ala Lys Leu Gly 1155 1160 1165Pro Pro Arg Pro Lys Thr Gly Arg Arg Lys Ser Thr Ser Ser Ile Pro 1170 1175 1180Pro Ser Pro Leu Ala Cys Pro Pro Ile Ser Ala Pro Pro Pro Arg Ser1185 1190 1195 1200Pro Ser Pro Leu Pro Gly His Pro Pro Ala Pro Ala Arg Ser Pro Arg 1205 1210 1215Leu Arg Arg Gly Gln Ser Ala Asp Lys Leu Gly Thr Gly Glu Arg Leu 1220 1225 1230Asp Gly Glu Ala Gly Arg Arg Thr Arg Gly Pro Glu Ala Glu Leu Val 1235 1240 1245Val Met Arg Arg Leu His Leu Ser Glu Arg Arg Asp Ser Phe Lys Lys 1250 1255 1260Gln Glu Ala Val Gln Glu Val Ser Phe Asp Glu Pro Gln Glu Glu Ala1265 1270 1275 1280Thr Gly Leu Pro Thr Ser Val Pro Gln Ile Ala Val Glu Gly Glu Glu 1285 1290 1295Ala Val Pro Val Ala Leu Gly Pro Thr Gly Arg Asp 1300 1305801265PRTHomo sapiens 80Arg Asp Pro Leu Glu Glu Met Ala Gln Leu Ser Ser Cys Asp Ser Pro1 5 10 15Asp Thr Pro Glu Thr Asp Asp Ser Ile Glu Gly His Gly Ala Ser Leu 20 25 30Pro Ser Lys Lys Thr Pro Ser Glu Glu Asp Phe Glu Thr Ile Lys Leu 35 40 45Ile Ser Asn Gly Ala Tyr Gly Ala Val Phe Leu Val Arg His Lys Ser 50 55 60Thr Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile65 70 75 80Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr 85 90 95Phe Ala Glu Asn Pro Phe Val Val Ser Met Phe Cys Ser Phe Asp Thr 100 105 110Lys Arg His Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys 115 120 125Ala Thr Leu Leu Lys Asn Ile Gly Ala Leu Pro Val Asp Met Val Arg 130 135 140Leu Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr145 150 155 160Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu Ile Thr Ser 165 170 175Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Met Gly Leu 180 185 190Met Ser Leu Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala 195 200 205Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala 210 215 220Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp225 230 235 240Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe 245 250 255Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu 260 265 270Ile Val Trp Pro Glu Gly Asp Glu Ala Leu Pro Pro Asp Ala Gln Asp 275 280 285Leu Thr Ser Lys Leu Leu His Gln Asn Pro Leu Glu Arg Leu Gly Thr 290 295 300Gly Ser Ala Tyr Glu Val Lys Gln His Pro Phe Phe Thr Gly Leu Asp305 310 315 320Trp Thr Gly Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu 325 330 335Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Arg Tyr His 340 345 350His Met Asp Ser Glu Asp Glu Glu Glu Val Ser Glu Asp Gly Cys Leu 355 360 365Glu Ile Arg Gln Phe Ser Ser Cys Ser Pro Arg Phe Asn Lys Val Tyr 370 375 380Ser Ser Met Glu Arg Leu Ser Leu Leu Glu Glu Arg Arg Thr Pro Pro385 390 395 400Pro Thr Lys Arg Ser Leu Ser Glu Glu Lys Glu Asp His Ser Asp Gly 405 410 415Leu Ala Gly Leu Lys Gly Arg Asp Arg Ser Trp Val Ile Gly Ser Pro 420 425 430Glu Ile Leu Arg Lys Arg Leu Ser Val Ser Glu Ser Ser His Thr Glu 435 440 445Ser Asp Ser Ser Pro Pro Met Thr Val Arg Arg Arg Cys Ser Gly Leu 450 455 460Leu Asp Ala Pro Arg Phe Pro Glu Gly Pro Glu Glu Ala Ser Ser Thr465 470 475 480Leu Arg Arg Gln Pro Gln Glu Gly Ile Trp Val Leu Thr Pro Pro Ser 485 490 495Gly Glu Gly Val Ser Gly Pro Val Thr Glu His Ser Gly Glu Gln Arg 500 505 510Pro Lys Leu Asp Glu Glu Ala Val Gly Arg Ser Ser Gly Ser Ser Pro 515 520 525Ala Met Glu Thr Arg Gly Arg Gly Thr Ser Gln Leu Ala Glu Gly Ala 530 535 540Thr Ala Lys Ala Ile Ser Asp Leu Ala Val Arg Arg Ala Arg His Arg545 550 555 560Leu Leu Ser Gly Asp Ser Thr Glu Lys Arg Thr Ala Arg Pro Val Asn 565 570 575Lys Val Ile Lys Ser Ala Ser Ala Thr Ala Leu Ser Leu Leu Ile Pro 580 585 590Ser Glu His His Thr Cys Ser Pro Leu Ala Ser Pro Met Ser Pro His 595 600 605Ser Gln Ser Ser Asn Pro Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp 610 615 620Phe Leu Pro Ala Leu Gly Ser Met Arg Pro Pro Ile Ile Ile His Arg625 630 635 640Ala Gly Lys Lys Tyr Gly Phe Thr Leu Arg Ala Ile Arg Val Tyr Met 645 650 655Gly Asp Ser Asp Val Tyr Thr Val His His Met Val Trp His Val Glu 660 665 670Asp Gly Gly Pro Ala Ser Glu Ala Gly Leu Arg Gln Gly Asp Leu Ile 675 680 685Thr His Val Asn Gly Glu Pro Val His Gly Leu Val His Thr Glu Val 690 695 700Val Glu Leu Ile Leu Lys Ser Gly Asn Lys Val Ala Ile Ser Thr Thr705 710 715 720Pro Leu Glu Asn Thr Ser Ile Lys Val Gly Pro Ala Arg Lys Gly Ser 725 730 735Tyr Lys Ala Lys Met Ala Arg Arg Ser Lys Arg Ser Arg Gly Lys Asp 740 745 750Gly Gln Glu Ser Arg Lys Arg Ser Ser Leu Phe Arg Lys Ile Thr Lys 755 760 765Gln Ala Ser Leu Leu His Thr Ser Arg Ser Leu Ser Ser Leu Asn Arg 770 775 780Ser Leu Ser Ser Gly Glu Ser Gly Pro Gly Ser Pro Thr His Ser His785 790 795 800Ser Leu Ser Pro Arg Ser Pro Thr Gln Gly Tyr Arg Val Thr Pro Asp 805 810 815Ala Val His Ser Val Gly Gly Asn Ser Ser Gln Ser Ser Ser Pro Ser 820 825 830Ser Ser Val Pro Ser Ser Pro Ala Gly Ser Gly His Thr Arg Pro Ser 835 840 845Ser Leu His Gly Leu Ala Pro Lys Leu Gln Arg Gln Tyr Arg Ser Pro 850 855 860Arg Arg Lys Ser Ala Gly Ser Ile Pro Leu Ser Pro Leu Ala His Thr865 870 875 880Pro Ser Pro Pro Pro Pro Thr Ala Ser Pro Gln Arg Ser Pro Ser Pro 885 890 895Leu Ser Gly His Val Ala Gln Ala Phe Pro Thr Lys Leu His Leu Ser 900 905 910Pro Pro Leu Gly Arg Gln Leu Ser Arg Pro Lys Ser Ala Glu Pro Pro 915 920 925Arg Ser Pro Leu Leu Lys Arg Val Gln Ser Ala Glu Lys Leu Ala Ala 930 935 940Ala Leu Ala Ala Ser Glu Lys Lys Leu Ala Thr Ser Arg Lys His Ser945 950 955 960Leu Asp Leu Pro His Ser Glu Leu Lys Lys Glu Leu Pro Pro Arg Glu 965 970 975Val Ser Pro Leu Glu Val Val Gly Ala Arg Ser Val Leu Ser Gly Lys 980 985 990Gly Ala Leu Pro Gly Lys Gly Val Leu Gln Pro Ala Pro Ser Arg Ala 995 1000 1005Leu Gly Thr Leu Arg Gln Asp Arg Ala Glu Arg Arg Glu Ser Leu Gln 1010 1015 1020Lys Gln Glu Ala Ile Arg Glu Val Asp Ser Ser Glu Asp Asp Thr Glu1025 1030 1035 1040Glu Gly Pro Glu Asn Ser Gln Gly Ala Gln Glu Leu Ser Leu Ala Pro 1045 1050 1055His Pro Glu Val Ser Gln Ser Val Ala Pro Lys Gly Ala Gly Glu Ser 1060 1065 1070Gly Glu Glu Asp Pro Phe Pro Ser Arg Gly Pro Arg Ser Leu Gly Pro 1075 1080 1085Met Val Pro Ser Leu Leu Thr Gly Ile Thr Leu Gly Pro Pro Arg Met 1090 1095 1100Glu Ser Pro Ser Gly Pro His Arg Arg Leu Gly Ser Pro Gln Ala Ile1105 1110 1115 1120Glu Glu Ala Ala Ser Ser Ser Ser Ala Gly Pro Asn Leu Gly Gln Ser 1125 1130 1135Gly Ala Thr Asp Pro Ile Pro Pro Glu Gly Cys Trp Lys Ala Gln His 1140 1145 1150Leu His Thr Gln Ala Leu Thr Ala Leu Ser Pro Ser Thr Ser Gly Leu 1155 1160 1165Thr Pro Thr Ser Ser Cys Ser Pro Pro Ser Ser Thr Ser Gly Lys Leu 1170 1175 1180Ser Met Trp Ser Trp Lys Ser Leu Ile Glu Gly Pro Asp Arg Ala Ser1185 1190 1195 1200Pro Ser Arg Lys Ala Thr Met Ala Gly Gly Leu Ala Asn Leu Gln Asp 1205 1210 1215Leu Glu Thr Gln Leu Gln Pro Ser Leu Arg Thr Cys Leu Pro Gly Ser 1220 1225 1230Arg Gly Arg His Ser His Leu Val Pro Pro Asp Trp Pro Ile His Leu 1235 1240 1245Met Arg Ile Pro Ala Arg Ala Gly Tyr Gly Ser Leu Ser Val His Lys 1250 1255 1260Gln1265811734PRTMus musculus 81Met Val Thr Gly Leu Ser Pro Leu Leu Phe Arg Lys Leu Ser Asn Pro1 5 10 15Asp Ile Phe Ala Pro Thr Gly Lys Val Lys Leu Gln Arg Gln Leu Ser 20 25 30Gln Asp Asp Cys Lys Leu Arg Arg Gly Ser Leu Ala Ser Ser Leu Ser 35 40 45Gly Lys Gln Leu Leu Pro Leu Ser Ser Ser Val His Ser Ser Val Gly 50 55 60Gln Val Thr Trp Gln Ser Thr Gly Glu Ala Ser Asn Leu Val Arg Met65 70 75 80Arg Asn Gln Ser Leu Gly Gln Ser Ala Pro Ser Leu Thr Ala Gly Leu 85 90 95Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser Phe Cys Arg Thr Ser Asn 100 105 110Arg Lys Ser Leu Ile Val Thr Ser Ser Thr Ser Pro Thr Leu Pro Arg 115 120 125Pro His Ser Pro Leu His Gly His Thr Gly Asn Ser Pro Leu Asp Ser 130 135 140Pro Arg Asn Phe Ser Pro Asn Ala Pro Ala His Phe Ser Phe Val Pro145 150 155 160Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro Ser 165 170 175Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser Cys 180 185 190Ser Ser Gln Glu Lys Leu His Gln Leu Pro Phe Gln Pro Thr Ala Asp 195 200 205Glu Leu His Phe Leu Thr Lys His Phe Ser Thr Glu Asn Val Pro Asp 210 215 220Glu Glu Gly Arg Arg Ser Pro Arg Met Arg Pro Arg Ser Arg Ser Leu225 230 235 240Ser Pro Gly Arg Ser Pro Val Ser Phe Asp Ser Glu Ile Ile Met Met 245 250 255Asn His Val Tyr

Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln Met Glu 260 265 270Glu Arg Pro Ser Leu Thr Phe Ile Ser Ser Asn Thr Pro Asp Ser Val 275 280 285Leu Pro Leu Ala Asp Gly Ala Leu Ser Phe Ile His His Gln Val Ile 290 295 300Glu Met Ala Arg Asp Cys Leu Asp Lys Ser Arg Ser Gly Leu Ile Thr305 310 315 320Ser His Tyr Phe Tyr Glu Leu Gln Glu Asn Leu Glu Lys Leu Leu Gln 325 330 335Asp Ala His Glu Arg Ser Glu Ser Ser Asp Val Ala Phe Val Ile Gln 340 345 350Leu Val Lys Lys Leu Met Ile Ile Ile Ala Arg Pro Ala Arg Leu Leu 355 360 365Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr His Leu Leu Glu Ala 370 375 380Ala Glu Gly His Ala Lys Glu Gly His Gly Ile Lys Cys Asp Ile Pro385 390 395 400Arg Tyr Ile Val Ser Gln Leu Gly Leu Thr Arg Asp Pro Leu Glu Glu 405 410 415Met Ala Gln Leu Ser Ser Tyr Asp Ser Pro Asp Thr Pro Glu Thr Asp 420 425 430Asp Ser Val Glu Gly Arg Gly Val Ser Gln Pro Ser Gln Lys Thr Pro 435 440 445Ser Glu Glu Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr 450 455 460Gly Ala Val Phe Leu Val Arg His Lys Ser Thr Arg Gln Arg Phe Ala465 470 475 480Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln 485 490 495Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe 500 505 510Val Val Ser Met Phe Cys Ser Phe Glu Thr Lys Arg His Leu Cys Met 515 520 525Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn 530 535 540Ile Gly Ala Leu Pro Val Asp Met Val Arg Leu Tyr Phe Ala Glu Thr545 550 555 560Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val His Arg Asp 565 570 575Leu Lys Pro Asp Asn Leu Leu Ile Thr Ser Met Gly His Ile Lys Leu 580 585 590Thr Asp Phe Gly Leu Ser Lys Ile Gly Leu Met Ser Leu Thr Thr Asn 595 600 605Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe Leu Asp Lys 610 615 620Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val Ile Leu Arg625 630 635 640Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly Ile Ile Leu 645 650 655Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp Thr Pro Glu 660 665 670Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Val Trp Pro Glu Gly 675 680 685Asp Asp Ala Leu Pro Pro Asp Ala Gln Asp Leu Thr Ser Lys Leu Leu 690 695 700His Gln Asn Pro Leu Glu Arg Leu Gly Thr Ser Ser Ala Tyr Glu Val705 710 715 720Lys Gln His Pro Phe Phe Met Gly Leu Asp Trp Thr Gly Leu Leu Arg 725 730 735Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp Asp Thr Ser 740 745 750Tyr Phe Asp Thr Arg Ser Glu Arg Tyr His His Val Asp Ser Glu Asp 755 760 765Glu Glu Glu Val Ser Glu Asp Gly Cys Leu Glu Ile Arg Gln Phe Ser 770 775 780Ser Cys Ser Pro Arg Phe Ser Lys Val Tyr Ser Ser Met Glu Arg Leu785 790 795 800Ser Leu Leu Glu Glu Arg Arg Thr Pro Pro Pro Thr Lys Arg Ser Leu 805 810 815Ser Glu Glu Lys Glu Asp His Ser Asp Gly Leu Ala Gly Leu Lys Gly 820 825 830Arg Asp Arg Ser Trp Val Ile Gly Ser Pro Glu Ile Leu Arg Lys Arg 835 840 845Leu Ser Val Ser Glu Ser Ser His Thr Glu Ser Asp Ser Ser Pro Pro 850 855 860Met Thr Val Arg His Arg Cys Ser Gly Leu Pro Asp Gly Pro His Cys865 870 875 880Pro Glu Glu Thr Ser Ser Thr Pro Arg Lys Gln Gln Gln Glu Gly Ile 885 890 895Trp Val Leu Ile Pro Pro Ser Gly Glu Gly Ser Ser Arg Pro Val Pro 900 905 910Glu Arg Pro Leu Glu Arg Gln Leu Lys Leu Asp Glu Glu Pro Pro Gly 915 920 925Gln Ser Ser Arg Cys Cys Pro Ala Leu Glu Thr Arg Gly Arg Gly Thr 930 935 940Pro Gln Leu Ala Glu Glu Ala Thr Ala Lys Ala Ile Ser Asp Leu Ala945 950 955 960Val Arg Arg Ala Arg His Arg Leu Leu Ser Gly Asp Ser Ile Glu Lys 965 970 975Arg Thr Thr Arg Pro Val Asn Lys Val Ile Lys Ser Ala Ser Ala Thr 980 985 990Ala Leu Ser Leu Leu Ile Pro Ser Glu His His Ala Cys Ser Pro Leu 995 1000 1005Ala Ser Pro Met Ser Pro His Ser Gln Ser Ser Asn Pro Ser Ser Arg 1010 1015 1020Asp Ser Ser Pro Ser Arg Asp Phe Leu Pro Ala Leu Gly Ser Leu Arg1025 1030 1035 1040Pro Pro Ile Ile Ile His Arg Ala Gly Lys Lys Tyr Gly Phe Thr Leu 1045 1050 1055Arg Ala Ile Arg Val Tyr Met Gly Asp Thr Asp Val Tyr Thr Val His 1060 1065 1070His Met Val Trp His Val Glu Asp Gly Gly Pro Ala Ser Glu Ala Gly 1075 1080 1085Leu Arg Gln Gly Asp Leu Ile Thr His Val Asn Gly Glu Pro Val His 1090 1095 1100Gly Leu Val His Thr Glu Val Val Glu Leu Val Leu Lys Ser Gly Asn1105 1110 1115 1120Lys Val Ser Ile Ser Thr Thr Pro Leu Glu Asn Thr Ser Ile Lys Val 1125 1130 1135Gly Pro Ala Arg Lys Gly Ser Tyr Lys Ala Lys Met Ala Arg Arg Ser 1140 1145 1150Lys Arg Ser Lys Gly Lys Asp Gly Gln Glu Ser Arg Lys Arg Ser Ser 1155 1160 1165Leu Phe Arg Lys Ile Thr Lys Gln Ala Ser Leu Leu His Thr Ser Arg 1170 1175 1180Ser Leu Ser Ser Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Gly Pro1185 1190 1195 1200Gly Ser Pro Thr His Ser His Ser Leu Ser Pro Arg Ser Pro Pro Gln 1205 1210 1215Gly Tyr Arg Val Ala Pro Asp Ala Val His Ser Val Gly Gly Asn Ser 1220 1225 1230Ser Gln Ser Ser Ser Pro Ser Ser Ser Val Pro Ser Ser Pro Ala Gly 1235 1240 1245Ser Gly His Thr Arg Pro Ser Ser Leu His Gly Leu Ala Pro Lys Leu 1250 1255 1260Gln Arg Gln Tyr Arg Ser Pro Arg Arg Lys Ser Ala Gly Ser Ile Pro1265 1270 1275 1280Leu Ser Pro Leu Ala His Thr Pro Ser Pro Pro Ala Thr Ala Ala Ser 1285 1290 1295Pro Gln Arg Ser Pro Ser Pro Leu Ser Gly His Gly Ser Gln Ser Phe 1300 1305 1310Pro Thr Lys Leu His Leu Ser Pro Pro Leu Gly Arg Gln Leu Ser Arg 1315 1320 1325Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys Arg Val Gln 1330 1335 1340Ser Ala Glu Lys Leu Ala Ala Ala Leu Ala Ala Ala Glu Lys Lys Leu1345 1350 1355 1360Ala Pro Ser Arg Lys His Ser Leu Asp Leu Pro His Gly Glu Leu Lys 1365 1370 1375Lys Glu Leu Thr Pro Arg Glu Ala Ser Pro Leu Glu Val Val Gly Thr 1380 1385 1390Arg Ser Val Leu Ser Gly Lys Gly Pro Leu Pro Gly Lys Gly Val Leu 1395 1400 1405Gln Pro Ala Pro Ser Arg Ala Leu Gly Thr Leu Arg Gln Asp Arg Ala 1410 1415 1420Glu Arg Arg Glu Ser Leu Gln Lys Gln Glu Ala Ile Arg Glu Val Asp1425 1430 1435 1440Ser Ser Glu Asp Asp Thr Asp Glu Glu Pro Glu Asn Ser Gln Ala Thr 1445 1450 1455Gln Glu Pro Arg Leu Ser Pro His Pro Glu Ala Ser His Asn Leu Leu 1460 1465 1470Pro Lys Gly Ser Gly Glu Gly Thr Glu Glu Asp Thr Phe Leu His Arg 1475 1480 1485Asp Leu Lys Lys Gln Gly Pro Val Leu Ser Gly Leu Val Thr Gly Ala 1490 1495 1500Thr Leu Gly Ser Pro Arg Val Asp Val Pro Gly Leu Ser Pro Arg Lys1505 1510 1515 1520Val Ser Arg Pro Gln Ala Phe Glu Glu Ala Thr Asn Pro Leu Gln Val 1525 1530 1535Pro Ser Leu Ser Arg Ser Gly Pro Thr Ser Pro Thr Pro Ser Glu Gly 1540 1545 1550Cys Trp Lys Ala Gln His Leu His Thr Gln Ala Leu Thr Ala Leu Cys 1555 1560 1565Pro Ser Phe Ser Glu Leu Thr Pro Thr Gly Cys Ser Ala Ala Thr Ser 1570 1575 1580Thr Ser Gly Lys Pro Gly Thr Trp Ser Trp Lys Phe Leu Ile Glu Gly1585 1590 1595 1600Pro Asp Arg Ala Ser Thr Asn Lys Thr Ile Thr Arg Lys Gly Glu Pro 1605 1610 1615Ala Asn Ser Gln Asp Thr Asn Thr Thr Val Pro Asn Leu Leu Lys Asn 1620 1625 1630Leu Ser Pro Glu Glu Glu Lys Pro Gln Pro Pro Ser Val Pro Gly Leu 1635 1640 1645Thr His Pro Leu Leu Glu Val Pro Ser Gln Asn Trp Pro Trp Glu Ser 1650 1655 1660Glu Cys Glu Gln Met Glu Lys Glu Glu Pro Ser Leu Ser Ile Thr Glu1665 1670 1675 1680Val Pro Asp Ser Ser Gly Asp Arg Arg Gln Asp Ile Pro Cys Arg Ala 1685 1690 1695His Pro Leu Ser Pro Glu Thr Arg Pro Ser Leu Leu Trp Lys Ser Gln 1700 1705 1710Glu Leu Gly Gly Gln Gln Asp His Gln Asp Leu Ala Leu Thr Ser Asp 1715 1720 1725Glu Leu Leu Lys Gln Thr 1730821309PRTSchizosaccharomyces pombeVARIANT(1)...(1309)Xaa = Any Amino Acid 82Met Lys His Ile Lys Asn Glu Arg Glu Glu Val Phe Leu Glu Asp Asp1 5 10 15Gln Ala Gln His Ser Gln Ala Glu Leu Leu Ser Ser Lys Asp Glu Asn 20 25 30Leu Gln Pro Ser Ile Pro Leu Ser Pro Val Ala Phe Glu Leu Asp Phe 35 40 45Ser Gly Asn Phe Gln Phe Ile Ser Asp Asn Ser Ser Glu Leu Leu Asp 50 55 60Ile Pro Lys Asp Lys Ile Ile Gly His Ser Val Ala Glu Val Leu Gly65 70 75 80Thr Asp Gly Tyr Asn Ala Phe Met Arg Ala Val Asn Cys Leu Leu Lys 85 90 95Asp Asp Ser His Ser Tyr His Val Arg Phe Gln His Ser Ile Asn Ala 100 105 110Asn His Ala Asn Gln Asn Tyr Tyr Thr Ala Lys Gly Asp Leu Pro Ser 115 120 125Asp Glu Lys Xaa Thr Lys Pro Phe Asp Ala Ile Gly Ile Leu Ile Arg 130 135 140His Pro Gly Xaa Ala Ile Pro Ala His Thr Met Trp Val Val Asn Pro145 150 155 160Ala Thr Asn Ser Leu Gly Ser Val Ser Pro Leu Val Thr Lys Leu Leu 165 170 175Asp Val Ile Gly Phe Gly Ala Ser Leu Leu Asp Lys Tyr Leu Cys Asp 180 185 190Leu Arg Thr Ser Tyr His Lys His Asn Ser Leu Asp Ala Leu Pro Leu 195 200 205Pro Thr Pro Glu Phe Cys Gln Ile Cys Glu Arg Glu Ile Gln Ser Trp 210 215 220Phe Phe Glu Leu His Ser Lys Phe Cys Leu Ser Thr Ser Thr Tyr Glu225 230 235 240Ser Val Val Gln Ala Ala Gln Asp Ser Leu Leu Tyr Phe Arg Ser Thr 245 250 255Leu Leu Glu Ile Gln Glu Gly Met Gln Lys Asp Ser Ser Leu Val Pro 260 265 270Val Tyr Lys Asn Glu Pro Leu Ile Val Asp Ala Asp Asp Tyr Phe Phe 275 280 285Thr Asp Glu Asn Lys Gln Thr Leu Ser Leu Cys Ser Phe Leu Ser Gln 290 295 300Val Met Tyr Tyr Leu Glu Val Ala Ile Asp Ile Thr Ile Pro Pro Val305 310 315 320Lys Ile Ile Val Asn Phe Asp Lys Val Asp Ser Leu Arg Val Gln Ser 325 330 335Pro Arg Ser Glu Lys Ala Thr Ile Glu Leu Asp Asn Tyr Asn Pro Ser 340 345 350Leu Glu Asn Cys Ser Ser Ala Val Ile Ala Leu Trp Glu Asp Ile Lys 355 360 365Thr Ala Val Asp Thr Lys Ile Thr Gly Val Leu Arg Leu Arg Asn Ala 370 375 380Ile Tyr Tyr Ser Glu Arg Xaa Arg Leu Glu Ile Asp His His Val Gln385 390 395 400Glu Ile Ile Asp Asp Val Val Ser Asn Leu Val Thr Asn His Ser Ser 405 410 415Thr Ser Leu Gly His Leu Glu Ser Lys Leu Ala Pro Ser Ile Thr Phe 420 425 430Pro Asp Ala Cys Asp Ala Leu Glu Ala Glu Glu Cys Ile Thr Arg Pro 435 440 445Gly Ser Ala Thr Asn Thr Pro Gln Ser Asp Arg Ser Leu Asp Ile Asn 450 455 460Asp Leu Ser Arg Ser Ser Ser Tyr Ser Arg His Leu Ser His Val Ser465 470 475 480Leu Ser Asn Pro Asp Phe Ala Ile Gly Ser Pro Met Ser Gln Asp Ser 485 490 495Ser Asn Tyr Ser Ser Pro Leu His Arg Arg Lys Ala Ser Asp Ser Asn 500 505 510Phe Ser Asp Pro Arg Phe Asp Asp Leu Lys Tyr Leu Ser Pro Asn Ser 515 520 525Ser Pro Arg Phe Val Ala Ser Asp Gly Pro Asn Arg Pro Ala Ser Asn 530 535 540Gly Arg Ser Ser Leu Phe Ser Arg Gly Arg Ala Ser Asn Leu Gly Asp545 550 555 560Val Gly Leu Arg Leu Pro Ser Pro Ser Pro Arg Ile His Thr Ile Val 565 570 575Pro Asn Ser Ala Pro Glu His Pro Ser Ile Asn Asp Tyr Lys Ile Leu 580 585 590Lys Pro Ile Ser Lys Gly Ala Phe Gly Ser Val Tyr Leu Ala Gln Lys 595 600 605Arg Thr Thr Gly Asp Tyr Phe Ala Ile Lys Ile Leu Lys Lys Ser Asn 610 615 620Met Ile Ala Lys Asn Gln Val Ile Asn Val Arg Ala Glu Arg Ala Ile625 630 635 640Leu Met Ser Gln Gly Glu Ser Pro Phe Val Ala Lys Leu Tyr Tyr Thr 645 650 655Phe Gln Ser Lys Asp Tyr Leu Tyr Leu Val Met Glu Tyr Leu Asn Gly 660 665 670Gly Asp Cys Gly Ser Leu Leu Lys Thr Met Gly Val Leu Asp Leu Asp 675 680 685Trp Ile Arg Thr Tyr Ile Ala Glu Thr Val Leu Cys Leu Gly Asp Leu 690 695 700His Asp Arg Gly Ile Ile His Arg Asp Ile Lys Pro Glu Asn Leu Leu705 710 715 720Ile Ser Gln Asn Gly His Leu Lys Leu Thr Asp Phe Gly Leu Ser Arg 725 730 735Val Gly Tyr Met Lys Arg His Arg Arg Lys Gln Ser Ser Ser Ile Pro 740 745 750Val Leu Asp Leu Arg Asp Arg Ser Ser Ala Ile Ser Asp Leu Ser Leu 755 760 765Ser Thr Ala Ser Ser Val Leu Glu Ala Gln Ser Leu Ile Thr Pro Glu 770 775 780Xaa Pro Lys Arg Pro Ser Leu Asn Glu Lys Leu Leu Ser Leu Asp Gly785 790 795 800Thr Ser Ile Arg Leu Ala Gly Gln Ser Phe Asn Tyr Glu Asn Ser Ala 805 810 815Glu Asp Ser Pro Thr Ala Thr Asn Thr Pro Thr Ser Gln Val Asp Glu 820 825 830Ser Asn Ile Phe Arg Ser Thr Asp Ser Pro Arg Val Gln Pro Phe Phe 835 840 845Glu Asn Lys Asp Pro Ser Lys Arg Phe Ile Gly Thr Pro Asp Tyr Ile 850 855 860Ala Pro Glu Val Ile Leu Gly Asn Pro Gly Ile Lys Ala Ser Asp Trp865 870 875 880Trp Ser Leu Gly Cys Val Val Phe Glu Phe Leu Phe Gly Tyr Pro Pro 885 890 895Phe Asn Ala Glu Thr Pro Asp Gln Val Phe Gln Asn Ile Leu Ala Arg 900 905 910Arg Ile Asn Trp Pro Ala Glu Val Phe Thr Ala Glu Ser Ser Val Ala 915 920 925Leu Asp Leu Ile Asp Arg Leu Leu Cys Met Asn Pro Ala Asn Arg Leu 930 935 940Gly Ala Asn Gly Val Glu Glu Ile Lys Ala His Pro Phe Phe Lys Ser945 950 955 960Val Asn Trp Asp Thr Ile Leu Glu Glu Asp Pro Pro Phe Val Pro Lys 965 970 975Pro Phe Ser Pro Glu Asp Thr Val Tyr Phe Asp Ser Arg Gly Leu Lys

980 985 990Gly Phe Asp Phe Ser Glu Tyr Tyr Asn Gln Pro Thr Val Thr Glu Ala 995 1000 1005Gln Lys Leu Glu Glu Glu Arg Pro Ala Ser Ser Ile Pro Gln His Val 1010 1015 1020Ser Gly Asn Arg Lys Gly Arg Leu Arg Ser Asn Thr Ile Ser Thr Pro1025 1030 1035 1040Glu Phe Gly Ser Phe Thr Tyr Arg Asn Leu Asp Phe Leu Asn Lys Ala 1045 1050 1055Asn Arg Asn Thr Ile Gln Lys Leu Arg Lys Glu His Met Ala Val Lys 1060 1065 1070Ser Ala Lys Thr Ser Val Asp Asp Thr Phe Ser Gln Tyr Met Ser Arg 1075 1080 1085Phe Lys Ala Lys Leu Ser Thr Ser Gln Ser Val Gly Pro Val Lys Ser 1090 1095 1100Ser Arg Arg Ala Ser Met Ala Asp Tyr Glu Ala Ser Thr Thr Thr Arg1105 1110 1115 1120Val Gln Asp Ile Thr Thr Asp Ser Ile Asp Ser Ile Asp Asp Phe Asp 1125 1130 1135Ser Leu Lys Glu Gly Arg Met Leu Ser Phe Phe Asp Asn Leu Ala Leu 1140 1145 1150Glu Asp His Lys Gly Val Ser Ser Thr Met Ser Ala Ser Gln Ser Gln 1155 1160 1165Ser Ser Met His Thr Ala Leu Pro Asp Val Thr Glu Gly Thr Ser Ser 1170 1175 1180Asp Glu His Thr Thr Ile Gln Lys Gly Arg Ile Asp Asn Leu Gln Ala1185 1190 1195 1200Gln Ser Leu Thr His Lys Arg Asn Ala Ile Ser Tyr Pro Gly Leu Phe 1205 1210 1215Gln Leu Asp Arg Leu Gln Met Ile Ile Pro Lys Asp Glu Ile Glu Leu 1220 1225 1230Ala Glu Ile Leu Lys Lys Ile Phe Pro Lys Leu Thr Leu Val Leu Ile 1235 1240 1245Asp Asp Pro Trp Ser Ile Leu Lys Lys Leu Leu Gln Asn Glu Gln Phe 1250 1255 1260Asn Val Val Phe Leu His Phe Gly Asn Asp Lys Val Ser Ser Ser Arg1265 1270 1275 1280Leu Met Tyr Ser Val Arg Thr Ser Ala Thr Ile Asn Ser Arg Val Pro 1285 1290 1295Val Cys Ile His Leu Arg Gly Arg Asp Leu His Ser Asp 1300 13058321PRTArtificial Sequenceconsensus 83Xaa Gly Xaa Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Xaa Xaa Xaa Lys 208413PRTArtificial Sequenceconsensus 84Xaa Xaa Xaa Xaa Asp Xaa Lys Xaa Xaa Asn Xaa Xaa Xaa1 5 108513PRTArtificial Sequenceconsensus 85Xaa Xaa Xaa Xaa Asp Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa1 5 108612PRTArtificial Sequenceconsensus 86Xaa Xaa Xaa Asp Gly Xaa Pro Arg Xaa Xaa Xaa Xaa1 5 108718PRTArtificial Sequenceconsensus 87Thr Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Xaa Xaa Tyr Xaa1 5 10 15Xaa Xaa8813PRTArtificial Sequenceconsensus 88Xaa Xaa Xaa Xaa Xaa Lys Xaa Glu Xaa Xaa Xaa Xaa Xaa1 5 108935PRTArtificial Sequenceconsensus 89Xaa Lys Xaa Xaa Xaa Xaa Arg Gln Xaa Xaa Xaa Xaa Xaa Gln Xaa Xaa1 5 10 15Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Arg His 20 25 30Xaa Xaa Asn 35

Claims

1. An isolated nucleic acid molecule selected from the group consisting of: a) a nucleic acid molecule comprising a nucleotide sequence which is at least 90% identical to the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:1 1, SEQ ID NO:13, or a complement thereof; b) a nucleic acid molecule comprising a fragment of at least 15 nucleotides of the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof; c) a nucleic acid molecule which encodes a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14; d) a nucleic acid molecule which encodes a polypeptide comprising a fragment of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO: 14; and e) a nucleic acid molecule which encodes a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof under conditions of hybridization in 6.times.SSC at 42.degree. C., followed by washing with 1.times.SSC at 55.degree. C.

2. The isolated nucleic acid molecule of claim 1, which is selected from the group consisting of: a) a nucleic acid comprising the nucleotide sequence of SEQ ID NO:1 SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof; and b) a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14.

3. The nucleic acid molecule of claim 1 further comprising vector nucleic acid sequences.

4. The nucleic acid molecule of claim 1 further comprising nucleic acid sequences encoding a heterologous polypeptide.

5. A host cell which contains the nucleic acid molecule of claim 1.

6. An isolated polypeptide selected from the group consisting of: (a) a polypeptide comprising a fragment of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14; b) a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof under conditions of hybridization in 6.times.SSC at 42.degree. C., followed by washing with 1.times.SSC at 55.degree. C.; c) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof; and d) a polypeptide comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14.

7. The isolated polypeptide of claim 6 comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14.

8. The polypeptide of claim 6 further comprising heterologous amino acid sequences.

9. An antibody which selectively binds to a polypeptide of claim 6.

10. A method for producing a polypeptide selected from the group consisting of: (a) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO: 14; b) a polypeptide comprising a fragment of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14; and c) a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, or SEQ ID NO:14, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, or a complement thereof under conditions of hybridization in 6.times.SSC at 42.degree. C., followed by washing with 1.times.SSC at 55.degree. C.; comprising culturing the host cell of claim 5 under conditions in which the nucleic acid molecule is expressed.

11. A method for detecting the presence of a polypeptide of claim 6 in a sample, comprising: a) contacting the sample with a compound which selectively binds to a polypeptide of claim 6; and b) determining whether the compound binds to the polypeptide in the sample.

12. The method of claim 11, wherein the compound which binds to the polypeptide is an antibody.

13. A kit comprising a compound which selectively binds to a polypeptide of claim 6 and instructions for use.

14. A method for detecting the presence of a nucleic acid molecule of claim 1 in a sample, comprising the steps of: a) contacting the sample with a nucleic acid probe or primer which selectively hybridizes to the nucleic acid molecule; and b) determining whether the nucleic acid probe or primer binds to a nucleic acid molecule in the sample.

15. The method of claim 14, wherein the sample comprises mRNA molecules and is contacted with a nucleic acid probe.

16. A kit comprising a compound which selectively hybridizes to a nucleic acid molecule of claim 1 and instructions for use.

17. A method for identifying a compound which binds to a polypeptide of claim 6 comprising the steps of: a) contacting a polypeptide, or a cell expressing a polypeptide of claim 6 with a test compound; and b) determining whether the polypeptide binds to the test compound.

18. The method of claim 17, wherein the binding of the test compound to the polypeptide is detected by a method selected from the group consisting of: a) detection of binding by direct detecting of test compound/polypeptide binding; b) detection of binding using a competition binding assay; c) detection of binding using an assay for kinase-mediated signal transduction.

19. A method for modulating the activity of a polypeptide of claim 6 comprising contacting a polypeptide or a cell expressing a polypeptide of claim 6 with a compound which binds to the polypeptide in a sufficient concentration to modulate the activity of the polypeptide.

20. A method for identifying a compound which modulates the activity of a polypeptide of claim 6, comprising: a) contacting a polypeptide of claim 6 with a test compound; and b) determining the effect of the test compound on the activity of the polypeptide to thereby identify a compound which modulates the activity of the polypeptide.

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