Materials And Methods For Treating Disorders Associated With Sulfatase Enzymes

Abstract

The subject invention concerns materials and methods for treating or preventing disease and conditions associated with various sulfatase enzymes that are defective or that are not properly expressed in a person or animal. In one embodiment, the disease is Sanfilippo A (MPS-IIIA) disease. The subject invention also concerns materials and methods for treating or preventing multiple sulfatase deficiency (MSD) in a person or animal. Compounds of the invention include a fusion protein comprising i) a mammalian sulfatase, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In a specific embodiment, the mammalian sulfatase is a human sulfatase, or an enzymatically active fragment or variant thereof. Polynucleotides encoding the fusion proteins are also contemplated for the subject invention. The subject invention also concerns materials and methods for producing proteins of the invention.

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of U.S. Provisional Application Ser. No. 62/023,571, filed Jul. 11, 2014, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings.

BACKGROUND OF THE INVENTION

[0002] There is a need in the art for an effective enzyme replacement therapy (ERT) for patients having disorders associated with sulfatase enzymes. For example, Sanfilippo A (mucopolysaccharidosis IIIA; MPS-IIIA) is a rare genetic lysosomal storage disorder (LSD) affecting about 1 in 150,000 births, with prevalence as high as 1/24,000 in some regions. MPS-IIIA is caused by a genetic defect in the gene for the lysosomal enzyme heparan N-sulfatase (N-sulfoglucosamine sulfohydrolase; SGSH) and is characterized by relatively mild somatic features but severe neurological manifestations (decline of learning abilities, hyperactivity, behavior problems, sleep difficulties, seizures) leading to dementia and death during puberty or early adulthood. Currently treatment options are limited to symptom management and development of an effective ERT drug has been hindered by the challenges of severe central nervous system (CNS) involvement in this disease. Humans have multiple sulfatases wherein deficiencies are linked to complex pathologies.

[0003] In lysosomal ERT development, the targeting of drug delivery to disease susceptible organs, tissues, cells, and intracellular lysosomes remains challenging. Of the ERTs commercially available for lysosomal disorders, none address neurological pathologies of these diseases. For these ERTs, delivery is based on ERT glycan structure to exploit uptake by high-mannose or mannose-6P receptors. The inventors use genetic engineering to test the potential of fusions of ERT's with non-toxic plant lectin subunits of ricin (RTB) and nigrin (NBB) to facilitate cell uptake and lysosomal delivery. In preliminary studies, it has been demonstrated that RTB a) efficiently carries proteins (>70 kDa) into a broad array of human cells, including brain microvessel endothelial cell layers using mannose/M6P-independent routes, b) transports associated proteins across oral or nasal mucosal surfaces, and c) that RTB:ERT fusions reduce disease substrate levels to normal in lysosomal disease cells including Hurler (MPS I), GM1 gangliosidosis, and Sanfilippo (MPS IIIA) patient fibroblasts. These lectin carriers will provide a fundamental advance in ERTs by improving efficacy through enzyme delivery to a broader array of diseased cells and pathologies and by introducing transmucosal administration strategies to reduce the burden of current patient treatment options.

[0004] The promise of plant-made bioproduction systems to effectively meet the stringent manufacture and regulatory criteria for ERT biologics has now been recognized with recent FDA approval of ELELYSO, Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher disease. This plant-based product is less expensive and less susceptible to viral contamination issues that have recently plagued traditional CHO-based manufacture of LSD ERTs. BioStrategies LC founders, Radin and Cramer, pioneered development of plant-based expression of human lysosomal enzymes (U.S. Pat. No. 5,929,304) and continue to develop new technologies to improve production and efficacy of these ERTs. Nevertheless, since plants do not possess the class of mammalian sulfatase related enzymes described in this patent specification, it was not obvious that active forms of these proteins could be successfully expressed in plants.

BRIEF SUMMARY OF THE INVENTION

[0005] The subject invention concerns materials and methods for treating or preventing disease and conditions associated with various sulfatase enzymes that are defective or that are not properly expressed in a person or animal. In one embodiment, the disease is Sanfilippo A (MPS-IIIA) disease. The subject invention also concerns materials and methods for treating or preventing multiple sulfatase deficiency (MSD) in a person or animal. The present invention utilizes the ability of plants to produce bioactive sulfatases and employ a new transient expression system to bring additional advantages of speed and flexible scaled up manufacture that could be particularly well suited for lysosomal stage disorders and other rare disease targets.

[0006] Compounds within the scope of the invention include, but are not limited to, a mammalian sulfatase, sulfatase modifying factor (SUMF1), or a fusion protein comprising i) a mammalian sulfatase or SUMF1, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In a specific embodiment, the mammalian sulfatase is a human sulfatase, or an enzymatically active fragment or variant thereof. In another embodiment, the enzyme is a sulfatase modifying factor. In still another embodiment the mammalian sulfatase and sulfatase modifying factor (SUMF1) are co-expressed in a plant cell so as to produce an enzymatically active sulfatase product. In one embodiment, the plant lectin is the non-toxic subunit of the lectin ricin (RTB) or nigrin (NBB). Polynucleotides encoding the fusion proteins are also contemplated for the subject invention. In one embodiment, the polynucleotide is optimized for expression in a plant, e.g., using codons preferred for plant expression.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1. Western blots of crude leaf extracts (72 h post-infiltration) probed with anti-SGSH antibodies showing comparative yields of SGSH constructs (Table 6). Std, rhSGSH [100 ng]; pBK, leaves infiltrated with "empty vector" control.

[0008] FIG. 2. Western blots of crude leaf extracts (72 h post-infiltration) probed with anti-SUMF1 antibodies showing comparative yields of SUMF1 constructs (Table 7). Std, rhSUMF1 [100 ng]; pBK, leaves infiltrated with "empty vector" control.

[0009] FIG. 3. Enzyme units of plant-made SGSH. rhSGSH and rhSUMF1, mammalian cell-derived SGSH and SUMF1, respectively. 1 U: sulfamidase catalyzing hydrolysis of 1 nmol of 4 MU per min.

[0010] FIG. 4. Correction of MPS IIIA fibroblast cell by SGSH:RTB. Normal (Corriel #GM00010) and MPS IIIA (#GM01881) cells were incubated with SGSH constructs for 72 h. Cells were stained with Lysotracker-red and DAPI and analyzed for lysosomal volume/cell by high-through put imaging (BD Pathway 855 Bioimager). MPS IIIA cells treated with "empty vector control" fractions (pBK) was used as reference unit to estimate the impact of each treatment.

[0011] FIG. 5. Enzyme units of plant-made SGSH using viral and bacterial vectors. Timing expression of SUMF1 and SGSH using viral vector. 1 U: sulfamidase catalyzing hydrolysis of 1 nmol of 4 MU per min.

BRIEF DESCRIPTION OF THE SEQUENCES

[0012] SEQ ID NO:1 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0013] SEQ ID NO:2 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0014] SEQ ID NO:3 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0015] SEQ ID NO:4 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0016] SEQ ID NO:5 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0017] SEQ ID NO:6 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0018] SEQ ID NO:7 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0019] SEQ ID NO:8 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0020] SEQ ID NO:9 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0021] SEQ ID NO:10 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0022] SEQ ID NO:11 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0023] SEQ ID NO:12 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0024] SEQ ID NO:13 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0025] SEQ ID NO:14 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0026] SEQ ID NO:15 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0027] SEQ ID NO:16 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0028] SEQ ID NO:17 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0029] SEQ ID NO:18 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0030] SEQ ID NO:19 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0031] SEQ ID NO:20 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0032] SEQ ID NO:21 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0033] SEQ ID NO:22 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0034] SEQ ID NO:23 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0035] SEQ ID NO:24 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0036] SEQ ID NO:25 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0037] SEQ ID NO:26 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0038] SEQ ID NO:27 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0039] SEQ ID NO:28 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0040] SEQ ID NO:29 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0041] SEQ ID NO:30 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0042] SEQ ID NO:31 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0043] SEQ ID NO:32 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0044] SEQ ID NO:33 is a nucleotide sequence encoding a sulfatase enzyme of the present invention.

[0045] SEQ ID NO:34 is an amino acid sequence of a sulfatase enzyme of the present invention.

[0046] SEQ ID NO:35 is a nucleotide sequence encoding a SUMF1 enzyme of the present invention.

[0047] SEQ ID NO:36 is an amino acid sequence of a SUMF1 enzyme of the present invention.

[0048] SEQ ID NO:37 is the amino acid sequence of a modified patatin sequence that can be used in the present invention.

[0049] SEQ ID NOs:38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, and 80 are nucleotide sequences of a construct of the invention as denoted in Tables 6 and 7.

[0050] SEQ ID NOs:39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, and 81 are amino acid sequences of a polypeptide encoded by a construct of the invention as denoted in Tables 6 and 7.

DETAILED DESCRIPTION OF THE INVENTION

[0051] The subject invention concerns materials and methods for treating or preventing disease and conditions associated with various sulfatase enzymes that are defective or that are not properly expressed in a person or animal. In one embodiment, the disease is Sanfilippo A (MPS-IIIA) disease. The subject invention also concerns materials and methods for treating or preventing multiple sulfatase deficiency (MSD) in a person or animal. Examples of diseases and their associated enzymes are shown in Table 1.

TABLE-US-00001 TABLE 1 Gene (symbol) Accession No Disease Enzyme Reference Galactosamine NM_000512 Mucoposysaccharidosis N-acetylgalactosamine- [1] (N-acetyl)-6 IVA (MPS-IVA), 6-sulfatase sulfate sulfatase Morquio A syndrome (SEQ ID NO: 2) (GALNS) (SEQ ID NO: 1) Glucosamine (N- NM_002076 Mucoposysaccharidosis N-acetylglucosamine-6- [2] acetyl)-6 sulfatase IIID (MPS-IIID), sulfatase (GNS) Sanfilippo D syndrome (SEQ ID NO: 4) (SEQ ID NO: 3) N-sulfoglucosamine NM_000199 Mucopolysaccharidosis N-sulphoglucosamine [3] sulfohydrolase IIIA (MPS-IIIA), sulphohydrolase, (SGSH) Sanfilippo A syndrome sulfamidase (SEQ ID NO: 5) (SEQ ID NO: 6) Sulfatase 1 NM_015170 NI Extracellular sulfatase [4] (SULF1) Sulf-1 (hSulf1) (SEQ ID NO: 7) (SEQ ID NO: 8) Sulfatase 2 NM_018837 NI Extracellular sulfatase [4] (SULF2) Sulf-2 (hSulf2) (SEQ ID NO: 9) (SEQ ID NO: 10) Iduronate 2- NM_000202 Mucopolysaccharidosis Iduronate 2-sulfatase [5] sulfatase (IDS) II (MPS-II), Hunter (SEQ ID NO: 12) (SEQ ID NO: 11) syndrome Arylsulfatase A NM_000487 Metachromatic Arylsulfatase A (ASA) [6] (ARSA) leukodystrophy (MLD) (SEQ ID NO: 14) (SEQ ID NO: 13) Arylsulfatase B NM_000046 Mucopolysaccharidosis Arylsulfatase B (ASB) [7] (ARSB) VI (MPS-VI), (SEQ ID NO: 16) (SEQ ID NO: 15) Maroteaux-Lamy syndrome Steroid sulfatase NM_000351 X-linked ichthyosis Steryl-sulfatase [8] (STS) (XLI) (SEQ ID NO: 18) Arylsulfatase C (ARSC) (SEQ ID NO: 17) Arylsulfatase D NM_001669 NI Arylsulfatase D (ASD) [9] (ARSD) (SEQ ID NO: 20) (SEQ ID NO: 19) Arylsulfatase E NM_000047 Chondrodysplasia Arylsulfatase E (ASE) [9] (ARSE) punctata 1 (CDPX1) (SEQ ID NO: 22) (SEQ ID NO: 21) Arylsulfatase F NM_004042 NI Arylsulfatase F (ASF) [9] (ARSF) (SEQ ID NO: 24) (SEQ ID NO: 23) Arylsulfatase G NM_014960 NI Arylsulfatase G (ASG) [10] (ARSG) (SEQ ID NO: 26) (SEQ ID NO: 25) Arylsulfatase H NM_001011719 NI Arylsulfatase H (ASH) [11] (ARSH) (SEQ ID NO: 28) (SEQ ID NO: 27) Arylsulfatase I NM_001012301 NI Arylsulfatase I (ASI) [11] (ARSI) (SEQ ID NO: 30) (SEQ ID NO: 29) Arylsulfatase J NM_024590 NI Arylsulfatase J (ASJ) [11] (ARSJ) (SEQ ID NO: 32) (SEQ ID NO: 31) Arylsulfatase K NM_198150 NI Arylsulfatase K (ASK) [11] (ARSK) (SEQ ID NO: 34) (SEQ ID NO: 33) Sulfatase NM_182760 Multiple sulfatase Sulfatase-modifying [12, 13] modifying factor deficiency (MSD) factor 1 1 (SUMF1) C-.alpha.-formylglycine- (SEQ ID NO: 35) generating enzyme (FGE) (SEQ ID NO: 36) NI, not identified

[0052] Compounds within the scope of the invention include, but are not limited to a mammalian sulfatase and/or sulfatase modifying factor 1 (SUMF1) or an enzymatically active fragment or variant thereof, or a fusion protein comprising i) a mammalian sulfatase protein, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In one embodiment, the sulfatase, or fusion protein containing the sulfatase, are co-expressed with the SUMF1 so as to activate the sulfatase during synthesis. In another embodiment, a fusion protein comprises i) a mammalian sulfatase modifying factor 1 (SUMF1) protein, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. The mammalian sulfatase can be one that normalizes the cellular phenotype of a lysosomal disease when expressed in a cell or that reduces the symptoms of a lysosomal disease in an animal or human (examples of diseases are shown in Table 1). In one embodiment, the sulfatase is activated by a co-expressed SUMF1 enzyme by converting a cysteine at the active site to a formyl glycine amino acid. Examples of sulfatases contemplated by the present invention are shown in Table 1. Optionally, the sulfatase or the SUMF1 protein can be linked to the plant lectin by a linker sequence of amino acids. In a specific embodiment, the mammalian protein is a human protein, or an enzymatically active fragment or variant thereof. In one embodiment, the mammalian SUMF1 protein or the SUMF1 fusion protein comprises an ER retention sequence, such as KDEL. In a specific embodiment, the ER retention sequence is located at the C-terminus of the SUMF1 or SUMF1 fusion protein. In some embodiments, the mammalian sulfatase comprises the amino acid sequence shown in any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, or 34, or an enzymatically active fragment or variant thereof. In some embodiments, the SUMF1 protein comprises the amino acid sequence shown in SEQ ID NO:36, or an enzymatically active fragment or variant thereof. The plant lectin portion of the fusion protein can be any plant lectin such as those described herein. In one embodiment, the plant lectin is the non-toxic B subunit of the lectin ricin (RTB) or nigrin (NBB). Amino acid sequences of numerous plant lectins, and nucleotide sequences encoding them, are known in the art. In specific embodiments, the fusion protein comprises the amino acid sequence shown in any of SEQ ID NOs:39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, or 81, or an enzymatically active fragment or variant thereof. Polynucleotides encoding the fusion proteins are also contemplated for the subject invention. In some embodiments, the polynucleotides comprise the protein encoding nucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35. In one embodiment, the polynucleotide is optimized for expression in a plant, e.g., using codons preferred for plant expression. In a specific embodiment, the polynucleotide is optimized for expression in Nicotiana Sp. In a more specific embodiment, the polynucleotide is optimized for expression in Nicotiana benthamiana. In one embodiment, a polynucleotide of the invention comprises the nucleotide sequence of any of SEQ ID NOs:38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80. In one embodiment, the fusion protein is produced in plants using a plant-based expression system such as described in U.S. Pat. No. 5,929,304.

[0053] In one embodiment, a compound of the invention comprises a sulfatase or a fusion protein wherein the sulfatase is heparan N-sulfatase, or the fusion protein comprises i) the enzyme heparan N-sulfatase (SGSH), or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In a more specific embodiment, the heparan N-sulfatase comprises the amino acid sequence shown in SEQ ID NO:6, or an enzymatically active fragment or variant thereof. In a specific embodiment, the heparan N-sulfatase is a human heparan N-sulfatase, or an enzymatically active fragment or variant thereof. In one embodiment, the plant lectin is the non-toxic B subunit lectin of ricin (RTB) or nigrin (NBB). In one embodiment, the SGSH portion and the plant lectin portion of the fusion protein can be linked by a linker sequence of amino acids. In one embodiment of the invention, a fusion protein with SUMF1 comprises an ER retention sequence, such as KDEL. In a specific embodiment, the ER retention sequence is located at the C-terminus of the fusion protein.

[0054] The subject invention also concerns a mammalian sulfatase modifying factor 1 (SUMF1), or an enzymatically active fragment or variant thereof. In one embodiment, the mammalian SUMF1 protein is a human SUMF1 protein. In a specific embodiment, a SUMF1 protein comprises the amino acid sequence shown in SEQ ID NO:36. The subject invention also concerns polynucleotides encoding a SUMF1 protein. In one embodiment, a polynucleotide of the invention comprises the nucleotide sequence shown in SEQ ID NO:35. In one embodiment, the polynucleotide is optimized for expression in a plant, e.g., using codons preferred for plant expression. In one embodiment, the polynucleotide is optimized for expression in Nicotiana sp. In a specific embodiment, the polynucleotide is optimized for expression in N. benthamiana (SEQ ID NO:40). In one embodiment, a SUMF1 protein of the invention comprises an ER retention sequence, such as KDEL. In a specific embodiment, the ER retention sequence is located at the C-terminus of the SUMF1 protein (SEQ ID NOs:79 and 81).

[0055] The subject invention also concerns methods for treating or preventing diseases or conditions associated with sulfatase enzymes, such as MPS-IIIA disease, in a person or animal (e.g., a disease where the sulfatase enzyme is defective or non-functional or partially functional). Examples of diseases and the associated enzymes are shown in Table 1. In one embodiment, the method comprises administering a therapeutically effective amount of a sulfatase or a fusion protein of the present invention, or an enzymatically active fragment or variant thereof, to the person or animal. In one embodiment, the sulfatase or fusion protein comprises a human sulfatase. Human sulfatases that can be used in the subject method include, but are not limited to, those shown in Table 1. Human sulfatases contemplated for use in the fusion protein include, but are not limited to, those shown in Table 1. In specific embodiments, the sulfatase or fusion protein comprises a sulfatase sequence shown in any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, or 34, or an enzymatically active fragment or variant thereof. In one embodiment, the sulfatase or fusion protein is administered intravenously, by injection or infusion, or by inhalation via nasal cavity or lung, or orally, ocularly, vaginally, anally, rectally, or transmembraneously or transdermally, subcutaneously, intradermally, intravenously, intramuscularly, intraperitoneally, or intrasternally, such as by injection. In one embodiment, the person is a fetus, a newborn, or an infant. Optionally, the methods include screening the person or animal to determine if it has a disease or condition associated with sulfatase enzymes. In one embodiment, the method reduces disease phenotype in cells and tissue of the body. In a further embodiment, the method reduces disease symptoms in the central nervous system and/or brain.

[0056] The subject invention also concerns methods for treating multiple sulfatase deficiency (MSD) in a person or animal. In one embodiment, the method comprises administering a therapeutically effective amount of a mammalian SUMF1 protein, or an enzymatically active fragment or variant thereof, to the person or animal. In another embodiment, the method comprises administering a therapeutically effective amount of a fusion protein to the person or animal, wherein the fusion protein comprises i) a mammalian SUMF1 protein, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof. In one embodiment, the mammalian SUMF1 is a human SUMF1. Optionally, the SUMF1 protein or SUMF1 fusion protein can comprise an ER retention sequence, such as KDEL. In one embodiment, the ER retention sequence is located at the C-terminus of the protein. In one embodiment, the SUMF1 protein or SUMF1 fusion protein is expressed in a plant cell. In another embodiment, a SUMF1 protein or SUMF1 fusion protein is expressed in an animal cell. In a specific embodiment, the human SUMF1 protein or SUMF1 fusion protein comprises the amino acid sequence in SEQ ID NO:36, or an enzymatically active fragment or variant thereof. In one embodiment, the SUMF1 protein or the fusion protein is administered to the person or animal via intravenous injection or infusion. In one embodiment, the person is a fetus, a newborn, or an infant. Optionally, the methods include screening the person or animal to determine if it has MSD disease or a condition associated with MSD.

[0057] The subject invention also concerns methods for preparing sulfatase enzymes and sulfatase fusion proteins of the present invention. In one embodiment, a method comprises transforming a plant or plant cell with i) polynucleotide encoding a sulfatase enzyme or a sulfatase fusion protein of the invention, and ii) a polynucleotide encoding a mammalian sulfatase modifying factor 1 (SUMF1) or a SUMF1 fusion protein of the invention; and expressing the sulfatase or sulfatase fusion protein and the SUMF1 protein or SUMF1 fusion protein in the plant. Methods for transforming a plant or plant cell with a polynucleotide are known in the art and include, for example, Agrobacterium infection, biolistic methods, and electroporation. The plant or plant cell can be transiently or stably transformed with the polynucleotide(s). In another embodiment, a method comprises using a plant or plant cell that has a polynucleotide encoding a mammalian SUMF1 protein or a SUMF1 fusion protein stably incorporated into its genome and that expresses SUMF1, and transforming the plant or plant cell with a polynucleotide encoding a sulfatase enzyme or a sulfatase fusion protein of the invention, and expressing the sulfatase or sulfatase fusion protein in the plant or plant cell, wherein the sulfatase or sulfatase fusion protein is activated by the expressed SUMF1 or SUMF1 fusion protein. In a further embodiment, a method comprises using a plant or plant cell that has a polynucleotide encoding a mammalian sulfatase enzyme or a sulfatase fusion protein of the invention stably incorporated into its genome and that expresses the sulfatase enzyme or the sulfatase fusion protein, and transforming the plant or plant cell with a polynucleotide encoding a mammalian SUMF1 protein or a SUMF1 fusion protein of the invention, and expressing the SUMF1 or SUMF1 fusion protein in the plant or plant cell, wherein the sulfatase or sulfatase fusion protein is activated by the expressed SUMF1 or SUMF1 fusion protein. In a further embodiment, a method comprises using a plant or plant cell that has i) a polynucleotide encoding a mammalian SUMF1 protein or a SUMF1 fusion protein stably incorporated into its genome and that expresses SUMF1 and that has ii) a polynucleotide encoding a mammalian sulfatase enzyme or a sulfatase fusion protein of the invention stably incorporated into its genome and that expresses the sulfatase enzyme or the sulfatase fusion protein, wherein the expressed sulfatase or sulfatase fusion protein is activated by the expressed SUMF1 or SUMF1 fusion protein. Methods for stably incorporating a polynucleotide into the genome of a plant or plant cell are known in the art. The polynucleotides utilized in the methods can be provided in an expression construct. In one embodiment, the cells are grown in tissue culture. In another embodiment, the cells are grown in a bioreactor.

[0058] Following transient or stable expression in the plant or plant cell, the sulfatase enzyme or sulfatase fusion protein and/or the SUMF1 protein or the SUMF1 fusion protein can be isolated from the plant. In one embodiment, transient expression of the enzyme or fusion protein in the plant or plant cell occurs for 1 to 5 days (typically, 2 to 5 days) prior to isolation of the enzyme or fusion protein from the plant or plant cell. Methods for protein isolation and purification are known in the art and include, for example, affinity chromatography. Co-expression of the sulfatase or sulfatase fusion protein and SUMF1 or SUMF1 fusion protein results in activation of the sulfatase or sulfatase fusion protein by the SUMF1 or SUMF1 fusion protein. The activated sulfatase or sulfatase fusion protein can be used to treat or prevent diseases or conditions in a person or animal that are associated with defective sulfatases and/or improper expression of sulfatases. Plants and plant cells that can be used in the synthesis methods include, but are not limited to, rice, wheat, barley, oats, rye, sorghum, maize, sugarcane, pineapple, onion, bananas, coconut, lilies, turfgrasses, millet, tomato, cucumber, squash, peas, alfalfa, melon, chickpea, chicory, clover, kale, lentil, soybean, beans, tobacco, potato, sweet potato, yams, cassava, radish, broccoli, spinach, cabbage, rape, apple trees, citrus (including oranges, mandarins, grapefruit, lemons, limes and the like), grape, cotton, sunflower, strawberry, lettuce, and hop. In one embodiment, the plant is a Nicotiana sp. In a specific embodiment, the plant is N. benthamiana.

[0059] The subject invention also concerns methods for producing a SUMF1 protein or a SUMF1 fusion protein of the present invention. In one embodiment, a method comprises transforming a cell with a polynucleotide encoding a SUMF1 protein or a SUMF1 fusion protein, or an enzymatically active fragment or variant thereof, and expressing the SUMF1 protein or the SUMF1 fusion protein in the cell. Following expression, the SUMF1 or SUMF1 fusion protein can be isolated from the cell. Optionally, the SUMF1 or SUMF1 fusion protein can be co-expressed in the cell along with a sulfatase enzyme or sulfatase fusion protein of the present invention. In one embodiment, the cell is a plant cell. The cell can be transiently or stably transformed with the polynucleotide. In one embodiment, the cell is an animal cell. In a specific embodiment, the animal cell is a cell line, such as a mammalian cell line (e.g., Chinese hamster ovary (CHO) cell line). In one embodiment, the cells are grown in tissue culture. In another embodiment, the cells are grown in a bioreactor. In one embodiment, the mammalian SUMF1 is a human SUMF1. Optionally, the SUMF1 protein can comprise an ER retention sequence, such as KDEL located at the C-terminus of the protein. Plants and plant cells that can be used in the synthesis methods include, but are not limited to, rice, wheat, barley, oats, rye, sorghum, maize, sugarcane, pineapple, onion, bananas, coconut, lilies, turfgrasses, millet, tomato, cucumber, squash, peas, alfalfa, melon, chickpea, chicory, clover, kale, lentil, soybean, beans, tobacco, potato, sweet potato, yams, cassava, radish, broccoli, spinach, cabbage, rape, apple trees, citrus (including oranges, mandarins, grapefruit, lemons, limes and the like), grape, cotton, sunflower, strawberry, lettuce, and hop. In one embodiment, the plant is a Nicotiana sp. In a specific embodiment, the plant is N. benthamiana.

[0060] Plant lectins for use in the fusion proteins that are contemplated within the scope of the invention include, but are not limited to, those B subunits from AB toxins such as ricins, abrins, nigrins, and mistletoe toxins, viscumin toxins, ebulins, pharatoxin, hurin, phasin, and pulchellin. They may also include lectins such as wheat germ agglutinin, peanut agglutinin, and tomato lectin that, while not part of the AB toxin class, are still capable of binding to animal cell surfaces and mediating endocytosis and transcytosis. Specific examples of plant lectins including their binding affinities and trafficking behavior are discussed further below. Therapeutic compounds and agents contemplated within the scope of the invention include, but are not limited to large molecular weight molecules including therapeutic proteins and peptides. Examples of therapeutic compounds and agents are discussed further below.

[0061] Within the scope of the present invention, selection of a specific plant lectin candidate to use in delivery of a particular therapeutic compound or agent is based on the specific sugar affinity of the lectin, its uptake efficiency into specific target cells, its pattern of intracellular trafficking, its in vivo biodistribution and pharmacodynamics, or other features of the lectin or therapeutic compound. Alternatively, multiple lectins can be tested to identify the lectin-therapeutic compound combination that provides greatest efficacy. For example, two lectins, RTB and NNB, were selected for proof-of-concept of the invention based on trafficking of their respective AB toxins, ricin from Ricinus communis and nigrin-b from Sambucus nigra (e.g., see Sandvig, K. and van Deurs, B. (1999); Simmons et al. (1986); Citores et al. (1999); Citores et al. (2003)). The uptake and trafficking of ricin and/or RTB, a galactose/galactosamine-specific lectin, has been extensively studied. This lectin has high affinity for surface glycolipids and glycoproteins providing access to a broad array of cells and enters cells by multiple endocytotic routes. These include absorptive-mediated endocytosis involving clathrin-dependent and clathrin-independent routes; caveolin-dependent and independent routes; dynamin-dependent and independent routes, and macropinocytosis based on the lectin binding to cell surface glycoproteins and glycolipids. RTB also accesses cells by receptor-mediated endocytosis based on interaction with its N-linked glycans with the high-mannose receptor (MMR) of animal cells. Upon endocytosis, RTB traverses preferentially to lysosomes (lysosomal pathway) or cycles back to the cell membrane (transcytosis pathway), with a small amount (generally less than 5%) moving "retrograde" to the endoplasmic reticulum. The NBB lectin, Nigrin B B-subunit from Sambucus nigra, exploits different uptake and intracellular trafficking routes compared to RTB, and thus provides unique in vivo pharmacodynamics. In contrast to RTB, NBB has strong affinity for N-acetyl-galactosamine, low affinity for lactose, very limited retrograde trafficking but strong accumulation in lysosomes. Plant-made DsReD:NNB (red fluorescent protein-NBB fusion) is rapidly taken up into multiple mammalian cells and efficiently delivered to lysosomes. Recombinantly produced RTB and NBB have been operatively associated with both small molecules (by chemical conjugation technologies) and protein macromolecule by genetic fusion that retain selective lectin binding as well as functionality of the associated protein or agent. These operatively associated products are rapidly endocytosed into multiple cell types and tissues and deliver fully functional `payload` into internal structures including lysosomes, endosomes, endoplasmic reticulum, and sarcoplasmic reticulum. Of particular significance, these lectins mobilize delivery of enzymes and other large proteins into "hard-to-treat" cells of the central nervous system (including, but not limited to, brain capillary endothelial cells, neurons, glial cells, and astrocytes), skeletal systems (including, but not limited to, cartilage, osteoblasts, chondrocytes, fibroblasts, and monocytes), and the respiratory system (including, but not limited to, lung airway epithelium, lung smooth muscle cells, and macrophages) (Radin et al., unpublished). These cells and tissues represent some of the most challenging targets for delivery of therapeutic agents highlighting the utility and novelty of the invention to address currently unmet needs in therapeutic compound delivery in human and animal medicine.

[0062] Additional plant lectins that are contemplated within the scope of the invention are those having particular carbohydrate binding affinities including, but not limited to, lectins that bind glucose, glucosamine, galactose, galactosamine, N-acetyl-glucosamine, N-acetyl-galactosamine, mannose, fucose, sialic acid, neuraminic acid, and/or N-acetylneuraminic acid, or have high affinity for certain target tissue or cells of interest. There are hundreds of plant lectins that have been identified and experimental strategies to identify plant lectins, their respective genes, and their sugar binding affinities are widely known by those skilled in the art. The diversity of plant sources for lectins and their sugar binding affinities is exemplified in Table 2 (adapted from Table 3 of Van Damme et al., (1998)).

TABLE-US-00002 TABLE 2 Type 2 Ribosome-Inactivating Proteins and Related Lectins: Occurrence, Molecular Structure, and Specificity Sequence Species Tissue Structure.sup.a Specificity available.sup.b Merolectins Sambucus nigra Bark [P22] NANA Nu Fruit [P22] NANA Nu Hololectins Sambucus nigra Bark II [P30].sub.2 GalNAc > Gal Nu Seed III [P30].sub.2 GalNAc > Gal Fruit IVf [P32].sub.2 Gal/GalNAc Nu (SNA-IV) Leaf IVI [P32].sub.2 Gal/GalNAc Nu Leaf IV4I [P32].sub.4 Gal/GalNAc Chimerolectins Abrus precatorius Seed [P(34 + 32)] Gal > GalNAc Ps, Nu (Abrin) Seed [P(33 + 29)].sub.2 Gal Ps (APA) Adenia digitata Root [P(28 + 38)] Gal > GalNAc Adenia volkensii Root [P(28 + 38)] Gal Cinnamomum camphora Seed [P(30 + 33)].sub.3 Unknown Eranthis hyemalis Tuber [P(30 + 32)] GalNAc Bulb [P(27 + 34)] GalNAc Momordica charantia Seed [P(28 + 30)].sub.2 Gal > GalNAc Phoradendron californicum Plant [P(31 + 38)] Gal Ricinus communis Seed [P(32 + 34)] Gal > GalNAc Ps, Nu (Ricin) Iris hybrid Seed [P(32 + 38)].sub.2 Gal >> GalNAc Ps, Nu (RCA) Sambucus canadensis Bark I [P(32 + 35)].sub.2 NANA Sambucus ebulus Bark I [P(32 + 37)].sub.2 NANA Leaf [P(26 + 30)].sub.2 GalNAc Sambucus nigra Seed Vs[P(26 + 32)].sub.2 GalNAc > Gal Bark I [P(32 + 35)].sub.c NANA Nu (SNA-I) Bark I' [P(32 + 35)].sub.2 NANA Nu (SNA-I') Bark V [P(26 + 32)].sub.3 GalNAc > Gal Nu (SNA-V) Fruit If [P(32 + 35)].sub.2 NANA Nu Fruit Vf [P(26 + 32)].sub.2 GalNAc > Gal Nu Sambucus racemosa Bark I [P(30 + 38)].sub.4 NANA Sambucus sieboldiana Bark I [P(31 + 37)].sub.4 NANA Nu (SSA-I) Bark [P(27 + 32)] GalNAc > Gal Nu (Sieboldin) Viscum album Plant I [P(29 + 34)].sub.1-2 Gal Plant II [P(29 + 34)] Gal/GalNAc Plant III [P(25 + 30)] GalNAc > Gal Type 2 RIP with inactive B chain Sambucus nigra Bark [P(32 + 32)] -- Nu (LRPSN) .sup.a[PX] stands for promoter with a molecular mass of X kDa. [P(Y + Z)] indicates that the promoter is cleaved in two polypeptides of Y and Z kDa. .sup.bPr. proton sequence; Nu, nucleotoids sequence. The abbreviation in brackets refers to the sequence name used in the dendrogram (FIG. 20).

[0063] As a further example of plant lectins contemplated herein, Table 3 exemplifies the large number of different lectins identified from the Sambucus species alone. This group includes nigrin B, the source on NBB.

TABLE-US-00003 TABLE 3 Ribosome-inactivating proteins (RIPs) and lectins from Sambucus species. Adapted from Table 1 of Ferreras et al. (2011) Proteins Species Tissues Type 1 RIPs Ebulitins .alpha., .beta. and .gamma. S. ebulus Leaves Nigritius f1 and f2 S. nigra Fruits Heterodimeric type 2 RIPs Ebulin l S. ebulus Leaves Ebulin f S. ebulus Fruits Ebulins r1 and r2 S. ebulus Rhizome Nigrin b, basic nigrib b, SNA I', SNLRPs S. nigra Bark Nigrins I1 and I2 S. nigra Leaves Nigrin f S. nigra Fruits Nigrin s S. nigra Seeds Sieboldin b S. sieboldiana Bark Basic racemosin b S. racemosa Bark Tetrameric type 2 RIPs SEA S. ebulus Rhizome SNA I S. nigra Bark SNAIf S. nigra Fruits SNAflu-I S. nigra Flowers SSA S. sieboldiana Bark SRA S. racemosa Bark Monomeric lectins SELIm S. ebulus Leaves SEA II S. ebulus Rhizome SNA II S. nigra Bark SNAIm and SNAIVI S. nigra Leaves SNA IV S. nigra Fruits SNA III S. nigra Seeds SSA-b-3 and SSA-b-4 S. sieboldiana Bark SRAbm S. racemosa Bark Homodimeric lectins SELId S. ebulus Leaves SELfd S. ebulus Fruits SNAId S. nigra Leaves

[0064] The subject invention also concerns polynucleotides that comprise nucleotide sequences encoding a sulfatase and/or a SUMF1 protein and/or fusion protein (or compound) of the invention. In one embodiment, the polynucleotides comprise nucleotide sequences that are optimized for expression in a particular expression system, e.g., a plant expression system, such as a tobacco plant. In one embodiment, the polynucleotide is optimized for expression in Nicotiana sp. In a specific embodiment, the polynucleotide is optimized for expression in N. benthamiana. The subject invention also concerns the sulfatases, SUMF1 proteins, and fusion polypeptides encoded by polynucleotides of the invention.

[0065] The present invention contemplates products in which the plant lectin is operatively associated with the therapeutic component by one of many methods known in the art. For example, genetic fusions between a plant lectin protein and a therapeutic protein can orient the lectin partner on either the C- or N-terminus of the therapeutic component. The coding regions can be linked precisely such that the last C-terminal residue of one protein is adjacent to the first N-terminal residue of the mature (i.e., without signal peptide sequences) second protein. Alternatively, additional amino acid residues can be inserted between the two proteins as a consequence of restriction enzyme sites used to facilitate cloning at the DNA level. Additionally, the fusions can be constructed to have amino acid linkers between the proteins to alter the physical spacing. These linkers can be short or long, flexible (e.g., the commonly used (Gly.sub.4Ser).sub.3 `flexi` linker) or rigid (e.g., containing spaced prolines), provide a cleavage domain (e.g., see Chen et al. (2010)), or provide cysteines to support disulfide bond formation. The plant lectins are glycoproteins and in nature are directed through the plant endomembrane system during protein synthesis and post-translational processing. For this reason, production of recombinant fusion proteins comprising a plant lectin and a therapeutic protein partner may require that a signal peptide be present on the N-terminus of the fusion product (either on the lectin or on the therapeutic protein depending on the orientation of the fusion construct) in order to direct the protein into the endoplasmic reticulum during synthesis. This signal peptide can be of plant or animal origin and is typically cleaved from the mature plant lectin or fusion protein product during synthesis and processing in the plant or other eukaryotic cell. In one embodiment, a modified patatin signal sequence (PoSP) is utilized: MASSATTKSFLILFFMILATTSSTCAVD (SEQ ID NO:37) (see GenBank accession number CAA27588.1, version GI:21514 by Bevan et al. and referenced at "The structure and transcription start site of a major potato tuber protein gene" Nucleic Acid Res. 14 (11), 4625-4638 (1986)).

[0066] Compounds of the subject invention can also be prepared by producing the plant lectin and the therapeutic drug or protein separately and operatively linking them by a variety of chemical methods. Examples of such in vitro operative associations include conjugation, covalent binding, protein-protein interactions or the like (see, e.g., Lungwitz et al. (2005); Lovrinovic and Niemeyer (2005)). For example, N-hydroxysuccinimde (NHS)-derivatized small molecules and proteins can be attached to recombinant plant lectins by covalent interactions with primary amines (N-terminus and lysine residues). This chemistry can also be used with NHS-biotin to attach biotin molecules to the plant lectin supporting subsequent association with streptavidin (which binds strongly to biotin) and which itself can be modified to carry additional payload(s). In another example, hydrazine-derivatized small molecules or proteins can be covalently bound to oxidized glycans present on the N-linked glycans of the plant lectin. Proteins can also be operatively linked by bonding through intermolecular disulfide bond formation between a cysteine residue on the plant lectins and a cysteine residue on the selected therapeutic protein. It should be noted that the plant AB toxins typically have a single disulfide bond that forms between the A and B subunits. Recombinant production of plant B subunit lectins such as RTB and NBB yield a product with an `unpaired` cysteine residue that is available for disulfide bonding with a "payload" protein. Alternatively, this cysteine (e.g., Cys.sub.4 in RTB) can be eliminated in the recombinant plant lectin product by replacement with a different amino acid or elimination of the first 4-6 amino acids of the N-terminus to eliminate the potential for disulfide bonding with itself or other proteins. [0067] NBB: See GenBank accession number P33183.2, version GI:17433713 (containing subunits A and B) by Van Damme et al. and referenced at "Characterization and molecular cloning of Sambucus nigra agglutinin V (nigrin b), a GalNAc-specific type-2 ribosome-inactivating protein from the bark of elderberry (Sambucus nigra)" Eur. J. Biochem. 237 (2), 505-513 (1996). PDB ID: 3CA3 (for B subunit) by Maveyraud et al. and referenced at "Structural basis for sugar recognition, including the to carcinoma antigen, by the lectin sna-ii from sambucus nigra" Proteins 75 p. 89 (2009). [0068] SGSH: See GenBank accession number NP_000190.1, version GI:4506919 by Van de Kamp et al. and referenced at "Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (type A, B, and C)" Clin. Genet. 20 (2), 152-160 (1981). [0069] RTB: See GenBank accession number pbd/2AAI/B, version GI:494727 (containing subunits A and B) by Montfort et al. and referenced at "The three-dimensional structure of ricin at 2.8A" J. Biol Chem. 262 (11), 5398-5403 (1987).

[0070] In vivo administration of the subject compounds, polynucleotides and compositions containing them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. The subject compounds can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral, nasal, rectal, transdermal, vaginal, and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the subject compounds of the invention can be a single administration, or at continuous or distinct intervals as can be readily determined by a person skilled in the art. In one embodiment, a polynucleotide encoding a therapeutic fusion product of the invention is stably incorporated into the genome of a person of animal in need of treatment. Methods for providing gene therapy are well known in the art. In one embodiment, a polynucleotide is provided in an expression construct and encodes an amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36, or an enzymatically active fragment or variant thereof.

[0071] The compounds of the subject invention, and compositions comprising them, can also be administered utilizing liposome and nano-technology, slow release capsules, implantable pumps, and biodegradable containers, and orally or intestinally administered intact plant cells expressing the therapeutic product. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time.

[0072] Compounds of the subject invention can be formulated according to known methods for preparing physiologically acceptable compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by E. W. Martin describes formulations which can be used in connection with the subject invention. In general, the compositions of the subject invention will be formulated such that an effective amount of the compound is combined with a suitable carrier in order to facilitate effective administration of the composition. The compositions used in the present methods can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended mode of administration and therapeutic application. The compositions also preferably include conventional physiologically-acceptable carriers and diluents which are known to those skilled in the art. Examples of carriers or diluents for use with the subject compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for the administration of such dosages for the desired therapeutic treatment, compositions of the invention will advantageously comprise between about 0.1% and 99%, and especially, 1 and 15% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent.

[0073] Compounds and agents of the invention, and compositions thereof, may be locally administered at one or more anatomical sites, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and agents of the invention, and compositions thereof, may be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent, or an assimilable edible carrier for oral delivery. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, aerosol sprays, and the like.

[0074] The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0075] Compounds and agents, and compositions of the invention, including pharmaceutically acceptable salts or analogs thereof, can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection. Solutions of the active agent or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[0076] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Optionally, the prevention of the action of microorganisms can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0077] Sterile injectable solutions are prepared by incorporating a compound and/or agent of the invention in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0078] Useful dosages of the compounds and agents and pharmaceutical compositions of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

[0079] The present invention also concerns pharmaceutical compositions comprising a compound and/or agent of the invention in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of a compound constitute a preferred embodiment of the invention. The dose administered to a patient, particularly a human, in the context of the present invention should be sufficient to achieve a therapeutic response in the patient over a reasonable time frame, without lethal toxicity, and preferably causing no more than an acceptable level of side effects or morbidity. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition (health) of the subject, the body weight of the subject, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, as well as the severity and stage of the pathological condition.

[0080] To provide for the administration of such dosages for the desired therapeutic treatment, in some embodiments, pharmaceutical compositions of the invention can comprise between about 0.1% and 45%, and especially, 1 and 15%, by weight of the total of one or more of the compounds based on the weight of the total composition including carrier or diluents. Illustratively, dosage levels of the administered active ingredients can be: intravenous, 0.01 to about 20 mg/kg; intraperitoneal, 0.01 to about 100 mg/kg; subcutaneous, 0.01 to about 100 mg/kg; intramuscular, 0.01 to about 100 mg/kg; orally 0.01 to about 200 mg/kg, and preferably about 1 to 100 mg/kg; intranasal instillation, 0.01 to about 20 mg/kg; and aerosol, 0.01 to about 20 mg/kg of animal (body) weight.

[0081] The subject invention also concerns kits comprising a compound and/or composition and/or agent and/or polynucleotide of the invention in one or more containers. Kits of the invention can optionally include pharmaceutically acceptable carriers and/or diluents. In one embodiment, a kit of the invention includes one or more other components, adjuncts, or adjuvants as described herein. In one embodiment, a kit of the invention includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration. In one embodiment, a compound and/or agent and/or polynucleotide of the invention is provided in the kit as a solid, such as a tablet, pill, or powder form. In another embodiment, a compound and/or agent and/or polynucleotide of the invention is provided in the kit as a liquid or solution. In one embodiment, the kit comprises an ampoule or syringe containing a compound and/or agent of the invention in liquid or solution form.

[0082] Mammalian species which benefit from the disclosed methods include, but are not limited to, primates, such as apes, chimpanzees, orangutans, humans, monkeys; domesticated animals (e.g., pets) such as dogs, cats, guinea pigs, hamsters, Vietnamese pot-bellied pigs, rabbits, and ferrets; domesticated farm animals such as cows, buffalo, bison, horses, donkey, swine, sheep, and goats; exotic animals typically found in zoos, such as bear, lions, tigers, panthers, elephants, hippopotamus, rhinoceros, giraffes, antelopes, sloth, gazelles, zebras, wildebeests, prairie dogs, koala bears, kangaroo, opossums, raccoons, pandas, hyena, seals, sea lions, elephant seals, otters, porpoises, dolphins, and whales. Other species that may benefit from the disclosed methods include fish, amphibians, avians, and reptiles. As used herein, the terms "patient" and "subject" are used interchangeably and are intended to include such human and non-human species. Likewise, in vitro methods of the present invention can be carried out on cultured cells or tissues of such human and non-human species.

[0083] The subject invention also concerns bacterial cells, and animals, animal tissue, and animal cells, and plants, plant tissue, and plant cells of the invention that comprise or express a polynucleotide or the protein encoded by the polynucleotide of the invention, or a fragment or variant thereof. Plant tissue includes, but is not limited to, leaf, stem, seed, scion, roots, and rootstock. Plants within the scope of the present invention include monocotyledonous plants, such as, for example, rice, wheat, barley, oats, rye, sorghum, maize, sugarcane, pineapple, onion, bananas, coconut, lilies, turfgrasses, and millet. Plants within the scope of the present invention also include dicotyledonous plants, such as, for example, tomato, cucumber, squash, peas, alfalfa, melon, chickpea, chicory, clover, kale, lentil, soybean, beans, tobacco, potato, sweet potato, yams, cassava, radish, broccoli, spinach, cabbage, rape, apple trees, citrus (including oranges, mandarins, grapefruit, lemons, limes and the like), grape, cotton, sunflower, strawberry, lettuce, and hop. In one embodiment, the plant is a Nicotiana sp. In a specific embodiment, the plant is N. benthamiana. Herb plants containing a polynucleotide of the invention are also contemplated within the scope of the invention. Herb plants include parsley, sage, rosemary, thyme, and the like. Trees are also contemplated within the scope of the subject invention. In one embodiment, a plant, plant tissue, or plant cell is a transgenic plant, plant tissue, or plant cell. In another embodiment, a plant, plant tissue, or plant cell is one that has been obtained through a breeding program.

[0084] Polynucleotides encoding a sulfatase, a SUMF1 protein, and/or a fusion product of the present invention, or an enzymatically active fragment or variant thereof, can be provided in an expression construct. Expression constructs of the invention generally include regulatory elements that are functional in the intended host cell in which the expression construct is to be expressed. Thus, a person of ordinary skill in the art can select regulatory elements for use in bacterial host cells, yeast host cells, plant host cells, insect host cells, mammalian host cells, and human host cells. Regulatory elements include promoters, transcription termination sequences, translation termination sequences, enhancers, and polyadenylation elements. As used herein, the term "expression construct" refers to a combination of nucleic acid sequences that provides for transcription of an operably linked nucleic acid sequence. As used herein, the term "operably linked" refers to a juxtaposition of the components described wherein the components are in a relationship that permits them to function in their intended manner. In general, operably linked components are in contiguous relation. In one embodiment, an expression construct comprises a polynucleotide encoding an amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36, or an enzymatically active fragment or variant thereof.

[0085] An expression construct of the invention can comprise a promoter sequence operably linked to a polynucleotide sequence of the invention, for example a sequence encoding a fusion polypeptide of the invention. Promoters can be incorporated into a polynucleotide using standard techniques known in the art. Multiple copies of promoters or multiple promoters can be used in an expression construct of the invention. In a preferred embodiment, a promoter can be positioned about the same distance from the transcription start site in the expression construct as it is from the transcription start site in its natural genetic environment. Some variation in this distance is permitted without substantial decrease in promoter activity. A transcription start site is typically included in the expression construct.

[0086] Constitutive promoters (such as the CaMV, ubiquitin, actin, or NOS promoter), developmentally-regulated promoters, and inducible promoters (such as those promoters that can be induced by heat, light, hormones, or chemicals) are also contemplated for use with polynucleotide expression constructs of the invention. If the expression construct is to be provided in or introduced into a plant cell, then plant viral promoters, such as, for example, a cauliflower mosaic virus (CaMV) 35S (including the enhanced CaMV 35S promoter (see, for example U.S. Pat. No. 5,106,739)) or a CaMV 19S promoter or a cassava vein mosaic can be used. Other promoters that can be used for expression constructs in plants include, for example, prolifera promoter, Ap3 promoter, heat shock promoters, T-DNA 1'- or 2'-promoter of A. tumefaciens, polygalacturonase promoter, chalcone synthase A (CHS-A) promoter from petunia, tobacco PR-1a promoter, ubiquitin promoter, actin promoter, alcA gene promoter, pin2 promoter (Xu et al., 1993), maize WipI promoter, maize trpA gene promoter (U.S. Pat. No. 5,625,136), maize CDPK gene promoter, and RUBISCO SSU promoter (U.S. Pat. No. 5,034,322) can also be used. Tissue-specific promoters, for example fruit-specific promoters, such as the E8 promoter of tomato (accession number: AF515784; Good et al. (1994)) can be used. Fruit-specific promoters such as flower organ-specific promoters can be used with an expression construct of the present invention for expressing a polynucleotide of the invention in the flower organ of a plant. Examples of flower organ-specific promoters include any of the promoter sequences described in U.S. Pat. Nos. 6,462,185; 5,639,948; and 5,589,610. Seed-specific promoters such as the promoter from a .beta.-phaseolin gene (for example, of kidney bean) or a glycinin gene (for example, of soybean), and others, can also be used. Endosperm-specific promoters include, but are not limited to, MEG1 (EPO application No. EP1528104) and those described by Wu et al. (1998), Furtado et al. (2002), and Hwang et al. (2002). Root-specific promoters, such as any of the promoter sequences described in U.S. Pat. No. 6,455,760 or U.S. Pat. No. 6,696,623, or in published U.S. patent application Nos. 20040078841; 20040067506; 20040019934; 20030177536; 20030084486; or 20040123349, can be used with an expression construct of the invention.

[0087] Expression constructs of the invention may optionally contain a transcription termination sequence, a translation termination sequence, a sequence encoding a signal peptide, and/or enhancer elements. Transcription termination regions can typically be obtained from the 3' untranslated region of a eukaryotic or viral gene sequence. Transcription termination sequences can be positioned downstream of a coding sequence to provide for efficient termination. A signal peptide sequence is a short amino acid sequence typically present at the amino terminus of a protein that is responsible for the relocation of an operably linked mature polypeptide to a wide range of post-translational cellular destinations, ranging from a specific organelle compartment to sites of protein action and the extracellular environment. Targeting gene products to an intended cellular and/or extracellular destination through the use of an operably linked signal peptide sequence is contemplated for use with the polypeptides of the invention. Classical enhancers are cis-acting elements that increase gene transcription and can also be included in the expression construct. Classical enhancer elements are known in the art, and include, but are not limited to, the CaMV 35S enhancer element, cytomegalovirus (CMV) early promoter enhancer element, and the SV40 enhancer element. Intron-mediated enhancer elements that enhance gene expression are also known in the art. These elements must be present within the transcribed region and are orientation dependent. Examples include the maize shrunken-1 enhancer element (Clancy and Hannah, 2002).

[0088] DNA sequences which direct polyadenylation of mRNA transcribed from the expression construct can also be included in the expression construct, and include, but are not limited to, an octopine synthase or nopaline synthase signal. The expression constructs of the invention can also include a polynucleotide sequence that directs transposition of other genes, i.e., a transposon.

[0089] Polynucleotides of the present invention can be composed of either RNA or DNA. Preferably, the polynucleotides are composed of DNA. In one embodiment, the DNA is complementary DNA (cDNA) prepared from or based on a messenger RNA (mRNA) template sequence. The subject invention also encompasses those polynucleotides that are complementary in sequence to the polynucleotides disclosed herein. Polynucleotides and polypeptides of the invention can be provided in purified or isolated form.

[0090] Because of the degeneracy of the genetic code, a variety of different polynucleotide sequences can encode polypeptides and enzymes of the present invention. A table showing all possible triplet codons (and where U also stands for T) and the amino acid encoded by each codon is described in Lewin (1985). In addition, it is well within the skill of a person trained in the art to create alternative polynucleotide sequences encoding the same, or essentially the same, polypeptides and enzymes of the subject invention. These variant or alternative polynucleotide sequences are within the scope of the subject invention. As used herein, references to "essentially the same" sequence refers to sequences which encode amino acid substitutions, deletions, additions, or insertions which do not materially alter the functional activity of the polypeptide encoded by the polynucleotides of the present invention. Allelic variants of the nucleotide sequences encoding a wild type polypeptide of the invention are also encompassed within the scope of the invention.

[0091] Substitution of amino acids other than those specifically exemplified or naturally present in a wild type polypeptide or enzyme of the invention are also contemplated within the scope of the present invention. For example, non-natural amino acids can be substituted for the amino acids of a polypeptide, so long as the polypeptide having the substituted amino acids retains substantially the same biological or functional activity as the polypeptide in which amino acids have not been substituted. Examples of non-natural amino acids include, but are not limited to, ornithine, citrulline, hydroxyproline, homoserine, phenylglycine, taurine, iodotyrosine, 2,4-diaminobutyric acid, .alpha.-amino isobutyric acid, 4-aminobutyric acid, 2-amino butyric acid, .gamma.-amino butyric acid, .epsilon.-amino hexanoic acid, 6-amino hexanoic acid, 2-amino isobutyric acid, 3-amino propionic acid, norleucine, norvaline, sarcosine, homocitrulline, cysteic acid, .tau.-butylglycine, .tau.-butylalanine, phenylglycine, cyclohexylalanine, .beta.-alanine, fluoro-amino acids, designer amino acids such as .beta.-methyl amino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogues in general. Non-natural amino acids also include amino acids having derivatized side groups. Furthermore, any of the amino acids in the protein can be of the D (dextrorotary) form or L (levorotary) form. Allelic variants of a protein sequence of a wild type polypeptide or enzyme of the present invention are also encompassed within the scope of the invention.

[0092] Amino acids can be generally categorized in the following classes: non-polar, uncharged polar, basic, and acidic. Conservative substitutions whereby a polypeptide or enzyme of the present invention having an amino acid of one class is replaced with another amino acid of the same class fall within the scope of the subject invention so long as the polypeptide having the substitution still retains substantially the same biological or functional activity (e.g., enzymatic) as the polypeptide that does not have the substitution. Polynucleotides encoding a polypeptide or enzyme having one or more amino acid substitutions in the sequence are contemplated within the scope of the present invention. Table 4 provides a listing of examples of amino acids belonging to each class.

TABLE-US-00004 TABLE 4 Class of Amino Acid Examples of Amino Acids Nonpolar Ala, Val, Leu, Ile, Pro, Met, Phe, Trp Uncharged Polar Gly, Ser, Thr, Cys, Tyr, Asn, Gln Acidic Asp, Glu Basic Lys, Arg, His

[0093] The subject invention also concerns variants of the polynucleotides of the present invention that encode functional polypeptides of the invention. Variant sequences include those sequences wherein one or more nucleotides of the sequence have been substituted, deleted, and/or inserted. The nucleotides that can be substituted for natural nucleotides of DNA have a base moiety that can include, but is not limited to, inosine, 5-fluorouracil, 5-bromouracil, hypoxanthine, 1-methylguanine, 5-methylcytosine, and tritylated bases. The sugar moiety of the nucleotide in a sequence can also be modified and includes, but is not limited to, arabinose, xylulose, and hexose. In addition, the adenine, cytosine, guanine, thymine, and uracil bases of the nucleotides can be modified with acetyl, methyl, and/or thio groups. Sequences containing nucleotide substitutions, deletions, and/or insertions can be prepared and tested using standard techniques known in the art.

[0094] Fragments and variants of a polypeptide or enzyme of the present invention can be generated as described herein and tested for the presence of biological or enzymatic function using standard techniques known in the art. Thus, an ordinarily skilled artisan can readily prepare and test fragments and variants of a polypeptide or enzyme of the invention and determine whether the fragment or variant retains functional or biological activity (e.g., enzymatic activity) relative to full-length or a non-variant polypeptide.

[0095] Polynucleotides and polypeptides contemplated within the scope of the subject invention can also be defined in terms of more particular identity and/or similarity ranges with those sequences of the invention specifically exemplified herein. The sequence identity will typically be greater than 60%, preferably greater than 75%, more preferably greater than 80%, even more preferably greater than 90%, and can be greater than 95%. The identity and/or similarity of a sequence can be 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% as compared to a sequence exemplified herein. Unless otherwise specified, as used herein percent sequence identity and/or similarity of two sequences can be determined using the algorithm of Karlin and Altschul (1990), modified as in Karlin and Altschul (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al. (1990). BLAST searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain sequences with the desired percent sequence identity. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al. (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (NBLAST and XBLAST) can be used. See NCBI/NIH website.

[0096] As used herein, the terms "nucleic acid" and "polynucleotide" refer to a deoxyribonucleotide, ribonucleotide, or a mixed deoxyribonucleotide and ribonucleotide polymer in either single- or double-stranded form, and unless otherwise limited, would encompass known analogs of natural nucleotides that can function in a similar manner as naturally-occurring nucleotides. The polynucleotide sequences include the DNA strand sequence that is transcribed into RNA and the strand sequence that is complementary to the DNA strand that is transcribed. The polynucleotide sequences also include both full-length sequences as well as shorter sequences derived from the full-length sequences. Allelic variations of the exemplified sequences also fall within the scope of the subject invention. The polynucleotide sequence includes both the sense and antisense strands either as individual strands or in the duplex.

[0097] Techniques for transforming plant cells with a polynucleotide or gene are known in the art and include, for example, Agrobacterium infection, transient uptake and gene expression in plant seedlings, biolistic methods, electroporation, calcium chloride treatment, PEG-mediated transformation, etc. U.S. Pat. No. 5,661,017 teaches methods and materials for transforming an algal cell with a heterologous polynucleotide. Transformed cells can be selected, redifferentiated, and grown into plants that contain and express a polynucleotide of the invention using standard methods known in the art. The seeds and other plant tissue and progeny of any transformed or transgenic plant cells or plants of the invention are also included within the scope of the present invention. In one embodiment, the cell is transformed with a polynucleotide sequence comprising a sequence encoding the amino acid sequence shown in any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36, or an enzymatically active fragment or variant thereof.

[0098] The subject invention also concerns cells transformed with a polynucleotide of the present invention encoding a polypeptide or enzyme of the invention. In one embodiment, the cell is transformed with a polynucleotide sequence comprising a sequence encoding the amino acid sequence shown in any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36, or an enzymatically active fragment or variant thereof. In one embodiment, the polynucleotide is stably incorporated into the genome of the cell. In another embodiment, the polynucleotide is not incorporated into the cell genome and is transiently expressed. In one embodiment, the polynucleotide sequence of the invention is provided in an expression construct of the invention. The transformed cell can be a prokaryotic cell, for example, a bacterial cell such as E. coli or B. subtilis, or the transformed cell can be a eukaryotic cell, for example, a plant cell, including protoplasts, or an animal cell. Plant cells include, but are not limited to, dicotyledonous, monocotyledonous, and conifer cells. Animal cells include human cells, mammalian cells, avian cells, and insect cells. Mammalian cells include, but are not limited to, COS, 3T3, and CHO cells. Cells of the invention can be grown in vitro, e.g., in a bioreactor or in tissue culture. Cells of the invention can also be grown in vivo, e.g., as ascites in a mammal, in a seed of a plant (such as corn or soybean seeds), etc.

[0099] Single letter amino acid abbreviations are defined in Table 5.

TABLE-US-00005 TABLE 5 Letter Symbol Amino Acid A Alanine B Asparagine or aspartic acid C Cysteine D Aspartic Acid E Glutamic Acid F Phenylalanine G Glycine H Histidine I Isoleucine K Lysine L Leucine M Methionine N Asparagine P Proline Q Glutamine R Arginine S Serine T Threonine V Valine W Tryptophan Y Tyrosine Z Glutamine or glutamic acid

[0100] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0101] Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

EXAMPLE 1

Produce SGSH and SGSH-Lectin Fusion Proteins

[0102] Construct design and plant-based expression. Sixteen gene constructs encoding SGSH and SGSH fusions with RTB and NBB (Table 6) were developed and expressed transiently in N. benthamiana leaves. Variants assessing signal peptides (human SGSH vs. plant-derived signal peptide), codon usage (SGSH sequence vs tobacco codon optimized), and fusion orientation were compared for product yield and quality (FIG. 1). Constructs were introduced into Agrobacterium tumefaciens, and induced cultures were vacuum infiltrated into leaves of intact plants and incubated for 2 to 5 days prior to harvest (Medrano et al., 2009). All constructs produced recombinant products of the expected sizes (56 kDa for SGSH; .about.91 kDa for lectin-SGSH fusions) that cross-reacted with anti-RTB, anti-His-tag, and anti-SGSH antibodies as appropriate (e.g., see FIG. 1). All constructs that used the native human signal peptide showed significantly lower product than those using the BioStrategies' plant signal peptide (PoSP). Expression kinetics in planta indicated abundant product at 48 and 72 h post-infiltration indicating product stability. FIG. 1 compares protein yields of selected constructs. For lectin-SGSH fusions (S5-S16), PoSP and lectin fused at the C-terminus (S12 for RTB and S16 for NBB) gave better protein yields (although some cleavage between the domains was observed with this orientation, the amount of full length protein is higher than lectin fused at the N-terminus). Based on these results, we selected a construct harboring SGSH (S4), SGSH-RTB fusion (S12) and SGSH-NBB fusion (S16) for further studies in Examples 2 and 3.

TABLE-US-00006 TABLE 6 Sulfamidase and lectin fusion constructs Signal SGSH peptide N-term C-term RTBtr NBB His Construct Abbr. SGSH PoSP Nat Opt Nat Opt N-term C-term N-term C-term tag hSP:SGSH.sup.NAT:His S1 X X X (nucleotide: SEQ ID NO: 38) (amino acid: SEQ ID NO: 39) hSP:SGSH.sup.OPT:His S2 X X X (nucleotide: SEQ ID NO: 40) (amino acid: SEQ ID NO: 41) PoSP:SGSH.sup.NAT:His S3 X X X (nucleotide: SEQ ID NO: 42) (amino acid: SEQ ID NO: 43) PoSP:SGSH.sup.OPT:His S4 X X X (nucleotide: SEQ ID NO: 44) (amino acid: SEQ ID NO: 45) PoSP:RTBtr:SGSH.sup.NAT:His S5 X X X X (nucleotide: SEQ ID NO: 46) (amino acid: SEQ ID NO: 47) PoSP:RTBtr:SGSH.sup.OPT:His S6 X X X X (nucleotide: SEQ ID NO: 48) (amino acid: SEQ ID NO: 49) PoSP:NBB:SGSH.sup.NAT:His S7 X X X X (nucleotide: SEQ ID NO: 50) (amino acid: SEQ ID NO: 51) PoSP:NBB:SGSH.sup.OPT:His S8 X X X X (nucleotide: SEQ ID NO: 52) (amino acid: SEQ ID NO: 53) hSP:SGSH.sup.NAT:RTBtr:His S9 X X X X (nucleotide: SEQ ID NO: 54) (amino acid: SEQ ID NO: 55) hSP:SGSH.sup.OPT:RTBtr:His S10 X X X X (nucleotide: SEQ ID NO: 56) (amino acid: SEQ ID NO: 57) PoSP:SGSH.sup.NAT:RTBtr:His S11 X X X X (nucleotide: SEQ ID NO: 58) (amino acid: SEQ ID NO: 59) PoSP:SGSH.sup.OPT:RTBtr:His S12 X X X X (nucleotide: SEQ ID NO: 60) (amino acid: SEQ ID NO: 61) hSP:SGSH.sup.NAT:NBB:His S13 X X X X (nucleotide: SEQ ID NO: 62) (amino acid: SEQ ID NO: 63) hSP:SGSH.sup.OPT:NBB:His S14 X X X X (nucleotide: SEQ ID NO: 64) (amino acid: SEQ ID NO: 65) PoSP:SGSH.sup.NAT:NBB:His S15 X X X X (nucleotide: SEQ ID NO: 66) (amino acid: SEQ ID NO: 67) PoSP:SGSH.sup.OPT:NBB:His S16 X X X X (nucleotide: SEQ ID NO: 68) (amino acid: SEQ ID NO: 69) Constructs harboring only SGSH were considered as located at the N-term in this table. PoSP, Patatin Optimized Signal Peptide/Nat, native sequence/Opt, codon optimized sequence based on Nicotiana tabacum/N-term, N terminus/C-term, C terminus/His tag, 6x histidine tag

TABLE-US-00007 TABLE 7 Sulfatase modifying factor 1 (FGE) Signal peptide SUMF1 His Construct Abbr. SUMF1 PoSP Nat Opt tag KDEL hSP:SUMF1.sup.NAT:His F1 X X X (nucleotide: SEQ ID NO: 70) (amino acid: SEQ ID NO: 71) hSP:SUMF1.sup.OPT:His F2 X X X (nucleotide: SEQ ID NO: 72) (amino acid: SEQ ID NO: 73) PoSP:SUMF1.sup.NAT:His F3 X X X (nucleotide: SEQ ID NO: 74) (amino acid: SEQ ID NO: 75) PoSP:SUMF1.sup.OPT:His F4 X X X (nucleotide: SEQ ID NO: 76) (amino acid: SEQ ID NO: 77) PoSP:SUMF1.sup.NAT:His:KDEL F5 X X X X (nucleotide: SEQ ID NO: 78) (amino acid: SEQ ID NO: 79) PoSP:SUMF1.sup.OPT:His:KDEL F6 X X X X (nucleotide: SEQ ID NO: 80) (amino acid: SEQ ID NO: 81) PoSP, Patatin Optimized Signal Peptide Nat, native sequence Opt, codon optimized sequence based on Nicotiana tabacum His tag, 6x histidine tag KDEL, KDEL retrieval sequence

EXAMPLE 2

Assess SGSH Enzyme and Carbohydrate-Binding Activity of Plant-Made SGSH and SGSH-Lectin Fusions

[0103] Assessment of SGSH activity. Plant tissues expressing S4, S12 and S16 constructs were used for extraction and initial purification of the SGSH and SGSH-fusion proteins. Several extraction buffers and clarification strategies were tested with the goal to obtain initial test material to assess activity. Leaf extracts were subjected to an initial affinity chromatography enrichment step (Nickel IMAC was used for the His-tagged S4; lactose resin for the S12 RTB fusion, and N-acetyl-galactosamine resin for the S16 NBB fusion). Recovery of the S12 and S16 products on selective sugar affinity columns confirmed lectin activity of the products. These proteins were quantified and used to assess SGSH activity based on the standard 2-step fluorometric assay as described (Karpova et. al., 1996) and using recombinant human SGSH (Novoprotein; made in HEK293 cells) as control proteins. No sulfamidase activity was detected in the plant-derived products.

[0104] SUMF1. Sulfatases carry a unique amino acid in their active site, C.alpha.-formylglycine (FGly), which is required for their catalytic activity. In this reaction, a specific cysteine is oxidized to FGly by the formylglycine-generating enzyme (FGE), as a post/co-translational modification that happens in nascent sulfatase polypeptides within the endoplasmic reticulum in mammalian cells. FGE is encoded by the sulfatase modifying factor 1 (SUMF1) gene. Phylogenetic studies have not identified SUMF1 homologs in plants and plants do not contain sulfatases that contain this modification. To support co-expression studies, we developed six new constructs for expression of human SUMF1 (Table 7). Native cDNA sequence encoding human SUMF1 (NCBI NM_182760) and tobacco-codon optimized SUMF1 cDNA were synthesized (GENEART) to include a C-term hexahistidine tag. Two signal peptides were tested (SUMF1 SP vs our plant PoSP). In addition, constructs adding a C-terminal KDEL ER retrieval sequence were developed. SUMF1 acts on SGSH in the ER; its ER-localization is mediated by a region within the N-terminus (residues 34-68; Malalyalam et al., 2008). This retention mechanism does not appear highly effective in animal cells (significant amounts of SUMF1 are secreted) and the ability of plants to "read" this ER signal was unknown. We therefore produced a KDEL-modified version to ensure ER retention of SUMF1 in plants. SUMF1 constructs (Table 7) were expressed transiently in N. benthamiana leaves and yields were assessed at 48, 72, and 96 hr post-infiltration. All constructs produced recombinant products of the expected sizes (42 kDa) that cross-reacted with anti-SUMF1 (FIG. 2) and anti-His antibodies. The highest expression of SUMF1 was at 72 h post-infiltration; codon optimization and signal peptide did not have significant impact on protein yield. However, the KDEL signal appears to enhance protein stability; SUMF1-KDEL remained at high levels at both 72 and 96 hr. F6 was selected for initial co-expression studies.

[0105] SUMF1/SGSH co-expression yields active sulfamidase. In order to determine if SUMF1 mediated formylglycine modification of SGSH in plants leading to production of an enzymatically active sulfatase, leaves were infiltrated with a 1:1 mixed culture of Agrobacterium tumefaciens ("Agro") harboring SUMF1 (F6) and SGSH (S4 or S12). Leaves were harvested at 72 h post-infiltration and purified by affinity chromatography, as described above for S4 and S12 constructs. Mammalian cell-derived SGSH and plant-derived SGSH (S4) and SGSH-RTB (S12) that were expressed in the presence or absence of SUMF1 (F6) were tested for sulfamidase enzymatic activity (FIG. 3) and shown as units/.mu.mol to encompass differences in molecular size of each protein. As shown in FIG. 3, plant-made SGSH (S4 and S12) were enzymatically active only when SUMF1 was co-expressed, and were more active than SGSH made in HEK293 human cells. SGSH:NBB (S16) showed analogous SGSH activity when expressed with SUMF1 (not shown). For the S12 product, protein identity (both SGSH and RTB) and FGly modification were confirmed through peptide sequencing by mass spectrometry (MS/MS; UAMS Biomedical Research Center). FGly modification was only found when SGSH was co-expressed with SUMF1. Our results demonstrate plants can produce fully active SGSH when co-expressed with SUMF1 and that the lectin fusion partner does not inhibit enzyme activity. Interestingly, co-expression with SUMF1-KDEL provided greater SGSH product yields than un-modified forms (not shown) suggesting broader applications using other production platforms or for gene therapy approaches for the entire sulfatase family.

EXAMPLE 3

Demonstrate Uptake, Lysosomal Delivery, and Reduction of "Disease Substrate" in MPS IIIA Cultured Cells Treated with SGSH and SGSH-Lectin Fusions

[0106] MPS IIIA patients are deficient in SGSH activity leading to pathological accumulation of sulfated glucosaminoglycans (GAGs) with cellular phenotypes including elevated GAGs and increased lysosomal volume per cell. As a further demonstration that the plant-produced SGSH was fully functional following modification by SUMF1, MPS IIIA patient fibroblasts (GM01881) were treated with plant-produced SGSH (S4) or SGSH-RTB (S12) that were expressed in the presence and absence of co-expressed SUMF1 (FIG. 4). S12 (SGSH:RTB) produced in the presence of SUMF1 effectively reduced GAG content and lysosomal volume to "normal" levels. SGSH alone (S4+/-SUMF1) was not corrective indicating that lectin-based delivery as well as FGly activation are critical in phenotype correction. These results indicate that RTB effectively delivers active SGSH to the site of GAG disease substrate accumulation resulting in disease phenotype correction at the cellular level. Analogous results have been demonstrated with S16 (SGSH:NBB; co-expressed with SUMF1; data not shown) indicating that multiple plant lectins can facilitate cellular uptake and lysosomal delivery of plant-made sulfatases.

EXAMPLE 4

Increase Sulfatase Activity by Modifying Co-Expression Parameters of SGSH and SUMF1

[0107] SUMF1 is localized to the ER and acts on mammalian sulfatases as they are co-translationally inserted into rough ER. The strategy for plant based SGSH and SUMF1 production in Example 2 and Example 3 involved co-expression where the kinetics of expression were the same and demonstrated that the SGSH enzymatic activity directly reflects the FGly modification mediated by SUMF1. Strategies that differentially change the kinetics of either SGSH or SUMF1 production such that SUMF1 is present in the plant ER prior and during the production phase for SGSH may result in a greater efficiency of SGSH modification and provide a higher specific activity product. Two strategies were selected for testing this (among many that could be used including expressing SGSH and SUMF1 under control of differentially expressed promoters, transiently expressing SGSH in a stable transgenic plant engineered to constitutively express the SUMF1 transgene, and other strategies providing SUMF1 activity prior and during production of the sulfatase). First, the S12 (SGSH:RTB) gene was introduced into a plant Agro/viral vectoring system (pBYR) (Huang et al., 2009) which is typically infiltrated at lower levels with a delayed initiation of high-level expression. Agro cultures bearing SUMF1 in the pBK (NCBI GU982971) vector were co-infiltrated with Agro strains bearing either S12 (SGSH:RTB) in pBK or in the Agro/viral vector pBYR. SGSH activity was then assessed in protein purified from leaf extracts and compared to the recombinant human SGSH produced in human HEK293 cells. The specific activity of plant-derived S12 product produced using the mixed Agro (SUMF1) and Agro/viral (S12 SGSH:RTB) co-expression parameters was 3-5 fold higher than S12 produced using a 1:1 ratio of the same genes both expressed using the pBK Agro vectoring system (shown in FIG. 5). The specific activity of the product was also 6-9 fold more active than human cell-derived rhSGSH indicating higher levels of FGly modification. A second demonstration that directed expression such that onset of SUMF1 production occurs earlier than SGSH increases the yield of active SGSH was also shown. In this example, a culture of Agro bearing the SUMF1 gene construct (F6) were induced by treatment with acetosyringone for 24 hours. Acetosyringone speeds activation of bacterial virulence leading to faster expression of transfected recombinant proteins. The induced culture was then mixed with Agro cultures bearing the S12 (SGSH:RTB) construct that was not induced. The mixed culture was then vacuum infiltrated into leaves of intact N. benthamiana plants and the plants were incubated for 3 to 5 days and harvested. The S12 sulfatase enzyme activity was 2-fold higher under conditions where the SUMF1-bearing Agro was selectively pre-induced by acetosyringone compared to previous infiltrations where both the SUMF1 and S12 strains were simultaneously activated by acetosyrongone. These results indicate that having plant cells "pre-loaded" with the SUMF1 modifying protein yields S12 wherein a significantly greater proportion of the SGSH product is modified to its fully functional form. By modifying the temporal parameters for expression (through either induction or viral vectoring systems), we demonstrated that the plant-based system yields sulfatase product with significantly greater specific activity (higher FGly modification) than the commercially available products produced in human cells (as much as 9-fold greater).

EXAMPLE 5

Demonstrate In Vivo Efficacy of SUMF1-Activated Sulfatase Enzyme Replacement Therapeutics by Treating Sulfatase-Deficient Mice

[0108] The biochemical and behavioral aspects of disease development have been well-characterized in the SGSH-deficient MPS-IIIA mouse model. These mice show elevated heparan sulfate levels detected at birth, lysosomal vacuolarization evident by 3-6 weeks of age and progressively worsening of behavioral/cognitive problems (altered activity, aggression, gait dysfunction, learning deficits, leading to lethargy and death) (Crawley et al., 2006). To assess in vivo efficacy of the S12 (SGSH:RTB) and S16 (SGSH:NBB) these fusion products are synthesized in plants that are co-expressing SUMF1 or SUMF1 modified with KDEL and purified to at least 95% purity of sulfatase enzyme activity with endotoxin levels below that recommended for mouse trials. MPS IIIA mice (e.g., 6-8 week old mice) are treated with the plant-derived S12 or S16 fusion product by i.v.-administration in doses ranging from 1 to 5 mg/kg in MPS-IIIA mice and analysis is done by methods similar to those described previously for this disease model (Rozaklis et al., 2011) and compared with wild type and untreated MPS IIIA control mice. For short-term biodistribution analyses, genotype-confirmed MPS-IIIA mice and unaffected -/+ or +/+ are treated (i.v., tail vein) with 100-150 .mu.l `vehicle` (PBS), S12, or S16. At 1, 2, and 3 hr, serum is collected by orbital bleed from 3 mice/group to determine serum clearance of the product. At 4, 12, and 24 hr after injection, 3 mice/time point (MPS-IIIA and WT mice) are euthanized, serum collected (heart puncture) and liver, spleen, and brain tissues are either formalin fixed or snap-frozen in liquid nitrogen for subsequent analyses. SGSH levels and enzyme activity is measured in tissues and serum as described (Rozaklis et al., 2011). Presence of the S12 and S16 products in specific tissues is confirmed by immunohistochemistry of fixed tissue.

[0109] To demonstrate efficacy in reducing GAG levels (the MPS IIIA disease substrate) and correcting the tissue pathology (e.g., cellular vacuolization; accumulation of associated gangliosides), MPS IIIA mice are treated 1-2 times per week with doses ranging from 0.5 to 5 mg/kg body weight for 4-6 weeks and the mice are harvested to assess SGSH levels, GAG levels and cellular morphology in selected tissues (e.g., liver, kidney, and multiple tissues of the brain). To demonstrate impacts on behavior of this neurodegenerative disease, weekly treatment can be extended to a total of 12-16 weeks and assessment of behavioral aspects are performed by open-field tests measuring activity and rearing behaviors (MPS-IIIA mice display reduced activity/gait) and memory/learning tests (e.g., using a Morris water maze). At study endpoint (72 hr after final injection), mice are euthanized and blood collected by heart puncture. Some animals from each group are fixation-perfused and processed for histological analyses. For biochemical analyses, livers, spleens and brains of non-perfused animals are sliced and frozen for heparan sulfate analyses. Immunohistological analyses include assessment of neuronal pathology in the cerebral cortex and hippocampus (e.g., using LIMP-II and GM3 as markers which are significantly elevated in untreated MPS IIIA mice). Extended administration of the S12 and S16 fusions is expected to lead to increased sulfatase activity, decreased GAG levels, and improvement in cellular phenotype and behavior in the MPS IIIA mice.

EXAMPLE 6

Demonstrate In Vivo Efficacy of SUMF1 Enzyme Replacement Therapeutics in Treating the SUMF1.sup.-/- Mouse Model for Multiple Sulfatase Deficiency

[0110] Similar to Example 5, plant-made SUMF1 fusions are used as an enzyme replacement therapy for treating SUMF1.sup.-/- mice. This mouse model shows similar disease development as multiple sulfatase deficiency patients (Settembre et al., 2007). Specifically, SUMF1.sup.-/- mice show growth retardation and skeletal abnormalities, neurological defects, and early mortality. At the cellular level, there is significant vacuolization, lysosomal storage of glycosaminoglycans, and inflammatory responses characterized by abundant highly vacuolated macrophages. For these studies, SUMF1 fusions are produced in plants and purified to greater than 95% enzyme purity with acceptable endotoxin levels. These products may include: RTB:SUMF1, NBB:SUMF1, RTB:SUMF1-KDEL, NBB:SUMF1-KDEL, SUMF1:RTB-KDEL or SUMF1:NBB-KDEL with the lectin providing uptake and the KDEL or SUMF1 domains directing subcellular trafficking to the ER. SUMF1 fusions are administered to mice and serum and tissues processed as previously described in Example 5. In addition, tissues are assayed for sulfatase activity (which is totally lacking in this mutant mouse strain due to absence of SUMF1). Extended administration of the SUMF1-lectin fusions results in increased sulfatase activity, decreased GAG levels, and improvement in macrophage morphology and disease phenotype.

[0111] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

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Sequence CWU 1

1

8112380DNAHomo sapiens 1aggccccgcc ccgcagccca gccggaaggg ccggcggacg ctcgctaggt cggctcgctg 60gccggggctc cgcggctccc gtggttgcca tggcggcggt tgtcgcggcg acgaggtggt 120ggcagctgtt gctggtgctc agcgccgcgg ggatgggggc ctcgggcgcc ccgcagcccc 180ccaacatcct gctcctgctc atggacgaca tgggatgggg tgacctcggg gtgtatggag 240agccctccag agagaccccg aatttggacc ggatggctgc agaagggctg cttttcccaa 300acttctattc tgccaaccct ctgtgctcgc catcgagggc ggcactgctc acaggacggc 360tacccatccg caatggcttc tacaccacca acgcccatgc cagaaacgcc tacacaccgc 420aggagattgt gggcggcatc ccagactcgg agcagctcct gccggagctt ctgaagaagg 480ccggctacgt cagcaagatt gtcggcaagt ggcatctggg tcacaggccc cagttccacc 540ccctgaagca cggatttgat gagtggtttg gatcccccaa ctgccacttt ggaccttatg 600acaacaaggc caggcccaac atccctgtgt acagggactg ggagatggtt ggcagatatt 660atgaagaatt tcctattaat ctgaagacgg gggaagccaa cctcacccag atctacctgc 720aggaagccct ggacttcatt aagagacagg cacggcacca cccctttttc ctctactggg 780ctgtcgacgc cacgcacgca cccgtctatg cctccaaacc cttcttgggc accagtcagc 840gagggcggta tggagacgcc gtccgggaga ttgatgacag cattgggaag atactggagc 900tcctccaaga cctgcacgtc gcggacaaca ccttcgtctt cttcacgtcg gacaacggcg 960ctgccctcat ttccgccccc gaacaaggtg gcagcaacgg cccctttctg tgtgggaagc 1020agaccacgtt tgaaggaggg atgagggagc ctgccctcgc atggtggcca gggcacgtca 1080ctgcaggcca ggtgagccac cagctgggca gcatcatgga cctcttcacc accagcctgg 1140cccttgcggg cctgacgccg cccagcgaca gggccattga tggcctcaac ctcctcccca 1200ccctcctgca gggccggctg atggacaggc ctatcttcta ttaccgtggc gacacgctga 1260tggcggccac cctcgggcag cacaaggctc acttctggac ctggaccaac tcctgggaga 1320acttcagaca gggcattgat ttctgccctg ggcagaacgt ttcaggggtc acaactcaca 1380atctggaaga ccacacgaag ctgcccctga tcttccacct gggacgggac ccaggggaga 1440ggttccccct cagctttgcc agcgccgagt accaggaggc cctcagcagg atcacctcgg 1500tcgtccagca gcaccaggag gccttggtcc ccgcgcagcc ccagctcaac gtgtgcaact 1560gggcggtcat gaactgggca cctccgggct gtgaaaagtt agggaagtgt ctgacacctc 1620cagaatccat tcccaagaag tgcctctggt cccactagca cctgcgcaga ctcaggccag 1680gcctagaatc tccggttggc cctgcaagtg cctggaggaa ggatggctct ggcctcggtc 1740ctcccccaac cctgcccaag ccagacagac agcacctgca gacgcagggg gactgcacaa 1800ttccacctgc ccaggacctg accctggcgt gtgcttggcc ctcctcctcg cccacggcgc 1860ctcagatttc aggaccctcc tcctcgccca cggcgcctca gacctcagga ccctgccgtc 1920tcacgccttt gtgaacccca aatatctgag accagtctca gtttattttg ccaaggttaa 1980ggatgcacct gtgacagcct caggaggtcc tgacaacagg tgcctgaggt ggctggggat 2040acagtttgcc tttatacatc ttagggagac acaagatcag tatgtgtatg gcgtacattg 2100gttcagtcag ccttccactg aatacacgat tgagtctggc ccagtgaatc cgcattttta 2160tgtaaacagt aagggaacgg ggcaatcata taagcgtttg tctcagggga gccccagagg 2220gatgacttcc agttccgtct gtcctttgtc cacaaggaat ttccctggac gctaattatg 2280agggaggcgt gtagcttctt atcattgtaa ctatgttatt tagaaataaa acgggaggca 2340ggtttgccta attcccagct tgaaaaaaaa aaaaaaaaaa 23802522PRTHomo sapiens 2Met Ala Ala Val Val Ala Ala Thr Arg Trp Trp Gln Leu Leu Leu Val 1 5 10 15 Leu Ser Ala Ala Gly Met Gly Ala Ser Gly Ala Pro Gln Pro Pro Asn 20 25 30 Ile Leu Leu Leu Leu Met Asp Asp Met Gly Trp Gly Asp Leu Gly Val 35 40 45 Tyr Gly Glu Pro Ser Arg Glu Thr Pro Asn Leu Asp Arg Met Ala Ala 50 55 60 Glu Gly Leu Leu Phe Pro Asn Phe Tyr Ser Ala Asn Pro Leu Cys Ser 65 70 75 80 Pro Ser Arg Ala Ala Leu Leu Thr Gly Arg Leu Pro Ile Arg Asn Gly 85 90 95 Phe Tyr Thr Thr Asn Ala His Ala Arg Asn Ala Tyr Thr Pro Gln Glu 100 105 110 Ile Val Gly Gly Ile Pro Asp Ser Glu Gln Leu Leu Pro Glu Leu Leu 115 120 125 Lys Lys Ala Gly Tyr Val Ser Lys Ile Val Gly Lys Trp His Leu Gly 130 135 140 His Arg Pro Gln Phe His Pro Leu Lys His Gly Phe Asp Glu Trp Phe 145 150 155 160 Gly Ser Pro Asn Cys His Phe Gly Pro Tyr Asp Asn Lys Ala Arg Pro 165 170 175 Asn Ile Pro Val Tyr Arg Asp Trp Glu Met Val Gly Arg Tyr Tyr Glu 180 185 190 Glu Phe Pro Ile Asn Leu Lys Thr Gly Glu Ala Asn Leu Thr Gln Ile 195 200 205 Tyr Leu Gln Glu Ala Leu Asp Phe Ile Lys Arg Gln Ala Arg His His 210 215 220 Pro Phe Phe Leu Tyr Trp Ala Val Asp Ala Thr His Ala Pro Val Tyr 225 230 235 240 Ala Ser Lys Pro Phe Leu Gly Thr Ser Gln Arg Gly Arg Tyr Gly Asp 245 250 255 Ala Val Arg Glu Ile Asp Asp Ser Ile Gly Lys Ile Leu Glu Leu Leu 260 265 270 Gln Asp Leu His Val Ala Asp Asn Thr Phe Val Phe Phe Thr Ser Asp 275 280 285 Asn Gly Ala Ala Leu Ile Ser Ala Pro Glu Gln Gly Gly Ser Asn Gly 290 295 300 Pro Phe Leu Cys Gly Lys Gln Thr Thr Phe Glu Gly Gly Met Arg Glu 305 310 315 320 Pro Ala Leu Ala Trp Trp Pro Gly His Val Thr Ala Gly Gln Val Ser 325 330 335 His Gln Leu Gly Ser Ile Met Asp Leu Phe Thr Thr Ser Leu Ala Leu 340 345 350 Ala Gly Leu Thr Pro Pro Ser Asp Arg Ala Ile Asp Gly Leu Asn Leu 355 360 365 Leu Pro Thr Leu Leu Gln Gly Arg Leu Met Asp Arg Pro Ile Phe Tyr 370 375 380 Tyr Arg Gly Asp Thr Leu Met Ala Ala Thr Leu Gly Gln His Lys Ala 385 390 395 400 His Phe Trp Thr Trp Thr Asn Ser Trp Glu Asn Phe Arg Gln Gly Ile 405 410 415 Asp Phe Cys Pro Gly Gln Asn Val Ser Gly Val Thr Thr His Asn Leu 420 425 430 Glu Asp His Thr Lys Leu Pro Leu Ile Phe His Leu Gly Arg Asp Pro 435 440 445 Gly Glu Arg Phe Pro Leu Ser Phe Ala Ser Ala Glu Tyr Gln Glu Ala 450 455 460 Leu Ser Arg Ile Thr Ser Val Val Gln Gln His Gln Glu Ala Leu Val 465 470 475 480 Pro Ala Gln Pro Gln Leu Asn Val Cys Asn Trp Ala Val Met Asn Trp 485 490 495 Ala Pro Pro Gly Cys Glu Lys Leu Gly Lys Cys Leu Thr Pro Pro Glu 500 505 510 Ser Ile Pro Lys Lys Cys Leu Trp Ser His 515 520 35144DNAHomo sapiens 3ccctgtccct ggctcacgtg atcgcgccta gggagaaaac gtctgactcc agccaccggc 60cttcaaggca cggcttttta ttccttcggc tggtcggcct ctcgcccttc agctacctgt 120gcgtccctcc gtcccgtccc gtcccggggt caccccggag cctgtccgct atgcggctcc 180tgcctctagc cccaggtcgg ctccggcggg gcagcccccg ccacctgccc tcctgcagcc 240cagcgctgct actgctggtg ctgggcggct gcctgggggt cttcggggtg gctgcgggaa 300cccggaggcc caacgtggtg ctgctcctca cggacgacca ggacgaagtg ctcggcggca 360tgacaccgct aaagaaaacc aaagctctca tcggagagat ggggatgact ttttccagtg 420cttatgtgcc aagtgctctc tgctgcccca gcagagccag tatcctgaca ggaaagtacc 480cacataatca tcacgttgtg aacaacactc tggaggggaa ctgcagtagt aagtcctggc 540agaagatcca agaaccaaat actttcccag caattctcag atcaatgtgt ggttatcaga 600ccttttttgc agggaaatat ttaaatgagt acggagcccc agatgcaggt ggactagaac 660acgttcctct gggttggagt tactggtatg ccttggaaaa gaattctaag tattataatt 720acaccctgtc tatcaatggg aaggcacgga agcatggtga aaactatagt gtggactacc 780tgacagatgt tttggctaat gtctccttgg actttctgga ctacaagtcc aactttgagc 840ccttcttcat gatgatcgcc actccagcgc ctcattcgcc ttggacagct gcacctcagt 900accagaaggc tttccagaat gtctttgcac caagaaacaa gaacttcaac atccatggaa 960cgaacaagca ctggttaatt aggcaagcca agactccaat gactaattct tcaatacagt 1020ttttagataa tgcatttagg aaaaggtggc aaactctcct ctcagttgat gaccttgtgg 1080agaaactggt caagaggctg gagttcactg gggagctcaa caacacttac atcttctata 1140cctcagacaa tggctatcac acaggacagt tttccttgcc aatagacaag agacagctgt 1200atgagtttga tatcaaagtt ccactgttgg ttcgaggacc tgggatcaaa ccaaatcaga 1260caagcaagat gctggttgcc aacattgact tgggtcctac tattttggac attgctggct 1320acgacctaaa taagacacag atggatggga tgtccttatt gcccattttg agaggtgcca 1380gtaacttgac ctggcgatca gatgtcctgg tggaatacca aggagaaggc cgtaacgtca 1440ctgacccaac atgcccttcc ctgagtcctg gcgtatctca atgcttccca gactgtgtat 1500gtgaagatgc ttataacaat acctatgcct gtgtgaggac aatgtcagca ttgtggaatt 1560tgcagtattg cgagtttgat gaccaggagg tgtttgtaga agtctataat ctgactgcag 1620acccagacca gatcactaac attgctaaaa ccatagaccc agagctttta ggaaagatga 1680actatcggtt aatgatgtta cagtcctgtt ctgggccaac ctgtcgcact ccaggggttt 1740ttgaccccgg atacaggttt gacccccgtc tcatgttcag caatcgcggc agtgtcagga 1800ctcgaagatt ttccaaacat cttctgtagc gacctcacac agcctctgca gatggatccc 1860tgcacgcctc tttctgatga agtgattgta gtaggtgtct gtagctagtc ttcaagacca 1920cacctggaag agtttctggg ctggctttaa gtcctgtttg aaaaagcaac ccagtcagct 1980gacttcctcg tgcaatgtgt taaactgtga actctgccca tgtgtcagga gtggctgtct 2040ctggtctctt cctttagctg acaaggacac tcctgaggtc tttgttctca ctgtattctt 2100tttatcctgg ggccacagtt cttgattatt cctcttgtgg ttaaagactg aatttgtaaa 2160cccattcaga taaatggcag tactttagga cacacacaaa cacacagaca caccttttga 2220tatgtaagct tgacctaaag tcaaaggacc tgtgtagcat ttcagattga gcacttcact 2280atcaaaaata ctaacatcac atggcttgaa gagtaaccat cagagctgaa tcatccaagt 2340aagaacaagt accattgttg attgataagt agagatacat tttttatgat gttcatcaca 2400gtgtggtaag gttgcaaatt caaaacatgt cacccaagct ctgttcatgt ttttgtgaat 2460tctaggctgg tgctgcactg aaatagagca gtaagcttgt gataaaggcc aattccaggt 2520agctcttgaa ggtgatagcc atctactttc cagtggctgc caaccacagg gagtgccagt 2580taacactgga aggattaagg caaggtccct tctcttgaga ctcccctctg agatctgaaa 2640aatgaagtgg cttaggaaca tcagcagtga agaactgcca agagttggtg aaggttgtct 2700cttccgaggg ccttctgaag acagggctct tgaacagaca agtggaaggg ctgtaccagg 2760gataaaggaa agaagtgcct gtccagcagg gagcttgaat ttaagttcca tgtatgaagt 2820cattggctct atctgcattt ttctgtcatt ctcttcattt gttttaaggt ggaaaatttt 2880cttacagttg atgcaaagta tcaactactt taccctacct tctccccttt tagatgggtt 2940cttcctgagt tttggagtct tgtatgatta tcagtattcc cctgtcaaaa tcaaatctat 3000tcaggtttct tcactgttga gaacacctaa atgtttttat ttttgagaag tggggacaga 3060gtctcactat gtcacccagg ctggagtgca atggcatgat ctcagctcac tgcaaccttc 3120gcctcctggg ttcaagcgat tctcctgcct ccgcctcctg agtagctggg attataggca 3180cgcaccacca cgcccagcta attttttgta tttttagtag agacagagtt tcaccatgtt 3240ggccaggctg gtcttgaact cctgaccttg tgatccaccc acctcggcct cccagagtgc 3300tgggattaca ggcatgagcc accacgcttg gctaagaaca cctaaatttt tatgtttctt 3360ggctcaaaaa ccagttccat ttctaatgtt gtcctcacaa gaaggctaat tggtggtgag 3420acagcagggg aggaggaaga gctgtggttt gtaacttgtt caactcaggc aataagcgat 3480tttagcttta tttaaagtct tctgtccagc tttaagcact ttgtaagaca tggctgaaag 3540tagcttttct atcagaattg cagatagtca tgttgggcta acagtcaatt ggatatattc 3600ctttacctca catgacccca gcaactgtgg tggtatctag aggtgaaaca ggcaagtgaa 3660atggacacct ctgctgtgaa tgttttagag aaggaaattc aaaaaatgtt gtaactgaaa 3720gcactgttga atatgggtat cggctttctt tttcactttg actcttaaca ttatcagtca 3780acttccacat taatgaaagt tgaccatagt tatttccaaa taaaaagaaa ccaactctta 3840ccaggtcttg gactgtgatg tcatattatt cagttttatg cttgttcctg agcagaactc 3900ataagagtga catagtcagc tgctgacggc acctcagcca cgccactctt actcagttca 3960gtgggtgtgc ttgcgtggta ggatgtggtg cagccctctc tacgctcttc tatttttggt 4020atatttccta tctaaccttc aaatagcttc caattctttt tttcttggac tggcttcatt 4080ctgaatttgt gctaaaataa tctttcataa agagacctca gtttatagcg taacagacta 4140cacaatgcac tgatgttttc ataatgttta agggacccac tgcaagaagc ttgctgcctc 4200cttttaattg tattcattta gattttgatt ttccatgtta agaaggtgag gtccatgttg 4260gtgcccttca gagtagagaa ccatgtaaac attaggaatg aacagaggcc ttaggaatga 4320atagagagtt tgccttatac aatttcctgt tacaaagctc tccctctcat gcaaagtagg 4380gaacaccttt tgagcatctt tgaatttgac aaatggtgct gttgcaaaca cttttttttt 4440gagatgaagt ctcgcggttg tcacccgggc tggagtgcag tggcgtgatc tcggctcact 4500gcaacttcca cctcctgggt tccagcagtt ctcctgcctc agcctcccaa gtagctgaga 4560ttacaggcgc ctgccacccc acctggctga tttttgtaat tttagtagag acggggtttc 4620accatgttgg ccaggctgat taactcctga cctcaggtga tccacctttc tcggcctccc 4680aaagtgctgg gattacgggt gtgagccacc gtgcccggcc tgcaaacaca ttttaattga 4740caacactagg gctgttgtac aaaatagtaa tgatagccat ggaagtttta ccttattctg 4800tgagaagtgt tcttaaactt attaagtgtc taaactaagg tttagtgctt ttttaaagga 4860aagttgtccc aggattcatc ctaaagaaag caaaagttaa ttcaactgat ccaccaatgg 4920aattagatgg gtagagttgg gttcttgagt tttaccacca cttagttccc actgaatttt 4980gtaacttcct gtgtttgcat cctctgttcc tattctgccc ttgctctgtg tcatctcagt 5040catttgactt agaaagtgcc cttcaaaagg accctgttca ctgctgcact tttcaatgaa 5100ttaaaattta tttctgttct agtgggaaaa aaaaaaaaaa aaaa 51444552PRTHomo sapiens 4Met Arg Leu Leu Pro Leu Ala Pro Gly Arg Leu Arg Arg Gly Ser Pro 1 5 10 15 Arg His Leu Pro Ser Cys Ser Pro Ala Leu Leu Leu Leu Val Leu Gly 20 25 30 Gly Cys Leu Gly Val Phe Gly Val Ala Ala Gly Thr Arg Arg Pro Asn 35 40 45 Val Val Leu Leu Leu Thr Asp Asp Gln Asp Glu Val Leu Gly Gly Met 50 55 60 Thr Pro Leu Lys Lys Thr Lys Ala Leu Ile Gly Glu Met Gly Met Thr 65 70 75 80 Phe Ser Ser Ala Tyr Val Pro Ser Ala Leu Cys Cys Pro Ser Arg Ala 85 90 95 Ser Ile Leu Thr Gly Lys Tyr Pro His Asn His His Val Val Asn Asn 100 105 110 Thr Leu Glu Gly Asn Cys Ser Ser Lys Ser Trp Gln Lys Ile Gln Glu 115 120 125 Pro Asn Thr Phe Pro Ala Ile Leu Arg Ser Met Cys Gly Tyr Gln Thr 130 135 140 Phe Phe Ala Gly Lys Tyr Leu Asn Glu Tyr Gly Ala Pro Asp Ala Gly 145 150 155 160 Gly Leu Glu His Val Pro Leu Gly Trp Ser Tyr Trp Tyr Ala Leu Glu 165 170 175 Lys Asn Ser Lys Tyr Tyr Asn Tyr Thr Leu Ser Ile Asn Gly Lys Ala 180 185 190 Arg Lys His Gly Glu Asn Tyr Ser Val Asp Tyr Leu Thr Asp Val Leu 195 200 205 Ala Asn Val Ser Leu Asp Phe Leu Asp Tyr Lys Ser Asn Phe Glu Pro 210 215 220 Phe Phe Met Met Ile Ala Thr Pro Ala Pro His Ser Pro Trp Thr Ala 225 230 235 240 Ala Pro Gln Tyr Gln Lys Ala Phe Gln Asn Val Phe Ala Pro Arg Asn 245 250 255 Lys Asn Phe Asn Ile His Gly Thr Asn Lys His Trp Leu Ile Arg Gln 260 265 270 Ala Lys Thr Pro Met Thr Asn Ser Ser Ile Gln Phe Leu Asp Asn Ala 275 280 285 Phe Arg Lys Arg Trp Gln Thr Leu Leu Ser Val Asp Asp Leu Val Glu 290 295 300 Lys Leu Val Lys Arg Leu Glu Phe Thr Gly Glu Leu Asn Asn Thr Tyr 305 310 315 320 Ile Phe Tyr Thr Ser Asp Asn Gly Tyr His Thr Gly Gln Phe Ser Leu 325 330 335 Pro Ile Asp Lys Arg Gln Leu Tyr Glu Phe Asp Ile Lys Val Pro Leu 340 345 350 Leu Val Arg Gly Pro Gly Ile Lys Pro Asn Gln Thr Ser Lys Met Leu 355 360 365 Val Ala Asn Ile Asp Leu Gly Pro Thr Ile Leu Asp Ile Ala Gly Tyr 370 375 380 Asp Leu Asn Lys Thr Gln Met Asp Gly Met Ser Leu Leu Pro Ile Leu 385 390 395 400 Arg Gly Ala Ser Asn Leu Thr Trp Arg Ser Asp Val Leu Val Glu Tyr 405 410 415 Gln Gly Glu Gly Arg Asn Val Thr Asp Pro Thr Cys Pro Ser Leu Ser 420 425 430 Pro Gly Val Ser Gln Cys Phe Pro Asp Cys Val Cys Glu Asp Ala Tyr 435 440 445 Asn Asn Thr Tyr Ala Cys Val Arg Thr Met Ser Ala Leu Trp Asn Leu 450 455 460 Gln Tyr Cys Glu Phe Asp Asp Gln Glu Val Phe Val Glu Val Tyr Asn 465 470 475 480 Leu Thr Ala Asp Pro Asp Gln Ile Thr Asn Ile Ala Lys Thr Ile Asp 485 490 495 Pro Glu Leu Leu Gly Lys Met Asn Tyr Arg Leu Met Met Leu Gln Ser 500 505 510 Cys Ser Gly Pro Thr Cys Arg Thr Pro Gly Val Phe Asp Pro Gly Tyr 515 520 525 Arg Phe Asp Pro Arg Leu Met Phe Ser Asn Arg Gly Ser Val Arg Thr 530 535 540 Arg Arg Phe Ser Lys His Leu Leu 545 550 52770DNAHomo sapiens 5gaccggggtc ggggcagggg gcggggccga gcgggagacc agagagccgg agccggatcc 60cgatcccgag tccgagccgc cgccgccatg agctgccccg tgcccgcctg ctgcgcgctg 120ctgctagtcc tggggctctg ccgggcgcgt ccccggaacg cactgctgct cctcgcggat 180gacggaggct ttgagagtgg cgcgtacaac aacagcgcca tcgccacccc gcacctggac 240gccttggccc gccgcagcct cctctttcgc aatgccttca cctcggtcag cagctgctct 300cccagccgcg ccagcctcct cactggcctg ccccagcatc agaatgggat gtacgggctg 360caccaggacg tgcaccactt caactccttc gacaaggtgc

ggagcctgcc gctgctgctc 420agccaagctg gtgtgcgcac aggcatcatc gggaagaagc acgtggggcc ggagaccgtg 480tacccgtttg actttgcgta cacggaggag aatggctccg tcctccaggt ggggcggaac 540atcactagaa ttaagctgct cgtccggaaa ttcctgcaga ctcaggatga ccggcctttc 600ttcctctacg tcgccttcca cgacccccac cgctgtgggc actcccagcc ccagtacgga 660accttctgtg agaagtttgg caacggagag agcggcatgg gtcgtatccc agactggacc 720ccccaggcct acgacccact ggacgtgctg gtgccttact tcgtccccaa caccccggca 780gcccgagccg acctggccgc tcagtacacc accgtcggcc gcatggacca aggagttgga 840ctggtgctcc aggagctgcg tgacgccggt gtcctgaacg acacactggt gatcttcacg 900tccgacaacg ggatcccctt ccccagcggc aggaccaacc tgtactggcc gggcactgct 960gaacccttac tggtgtcatc cccggagcac ccaaaacgct ggggccaagt cagcgaggcc 1020tacgtgagcc tcctagacct cacgcccacc atcttggatt ggttctcgat cccgtacccc 1080agctacgcca tctttggctc gaagaccatc cacctcactg gccggtccct cctgccggcg 1140ctggaggccg agcccctctg ggccaccgtc tttggcagcc agagccacca cgaggtcacc 1200atgtcctacc ccatgcgctc cgtgcagcac cggcacttcc gcctcgtgca caacctcaac 1260ttcaagatgc cctttcccat cgaccaggac ttctacgtct cacccacctt ccaggacctc 1320ctgaaccgca ccacagctgg tcagcccacg ggctggtaca aggacctccg tcattactac 1380taccgggcgc gctgggagct ctacgaccgg agccgggacc cccacgagac ccagaacctg 1440gccaccgacc cgcgctttgc tcagcttctg gagatgcttc gggaccagct ggccaagtgg 1500cagtgggaga cccacgaccc ctgggtgtgc gcccccgacg gcgtcctgga ggagaagctc 1560tctccccagt gccagcccct ccacaatgag ctgtgaccat cccaggaggc ctgtgcacac 1620atcccaggca tgtcccagac acatcccaca cgtgtccgtg tggccggcca gcctggggag 1680tagtggcaac agcccttccg tccacactcc catccaagga gggttcttcc ttcctgtggg 1740gtcactcttg ccattgcctg gagggggacc agagcatgtg accagagcat gtgcccagcc 1800cctccaccac caggggcact gccgtcatgg caggggacac agttgtcctt gtgtctgaac 1860catgtcccag cacgggaatt ctagacatac gtggtctgcg gacagggcag cgcccccagc 1920ccatgacaag ggagtcttgt tttctggctt ggtttgggga cctgcaaatg ggaggcctga 1980ggccctcttc aggctttggc agccacagat acttctgaac ccttcacaga gagcaggcag 2040gggcttcggt gccgcgtggg cagtacgcag gtcccaccga cactcacctg ggagcacggc 2100gcctggctct taccagcgtc tggcctagag gaagcctttg agcgaccttt gggcaggttt 2160ctgcttcttc tgttttgccc catggtcaag tccctgttcc ccaggcaggt ttcagctgat 2220tggcagcagg ctccctgagt gatgagcttg aacctgtggt gtttctgggc agaagcttat 2280cttttttgag agtgtccgaa gatgaaggca tggcgatgcc cgtcctctgg cttgggttaa 2340ttcttcggtg acactggcat tgctgggtgg tgatgcccgt cctctggctt gggttaattc 2400ttcggtgaca ctggcgttgc tgggtggcaa tgcccatcct ctgccttggg ttaattcttc 2460ggtgacactg gcgttgctgg gtggcgatgc ccgtcctctg gcttgggtta attcttggat 2520gacgtcggcg ttgctgggag aatgtgccgt tcctgccctg cctccaccca cctcgggagc 2580agaagcccgg cctggacacc cctcggcctg gacacccctc gaaggagagg gcgcttcctt 2640gagtaggtgg gctccccttg cccttccctc cctatcactc catactgggg tgggctggag 2700gaggccacag gccagctatt gtaaaagctt tttattttag taaaatatac agaagttctt 2760tttctgaaaa 27706502PRTHomo sapiens 6Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu 500 75710DNAHomo sapiens 7aggttacttg actgggagtt ctcagacctc cagtttcagc cctgccctca gcctccaatc 60cgtaagagac acccagcccc agcaattgga ttgggcagcc cgtcttgaca caccactgtg 120ctgagtgctt gaggacgtgt ttcaacagat ggttggggtt agtgtgtgtc atcacattcg 180agtggggatt aagagaagga aggctgcctt gctggagctg tgtggtcttc tccaagtgag 240agtcgcaggc aatagaacta ctttgctttt ggaggaaaag gaggaattca ttttcagcag 300acacaagaaa agcagttttt ttttcaggga ttcttcactt ctcttgaaca aggaactcac 360tcagagacta acacaaagga agtaatttct tacctggtca ttatttagtc tacaataagt 420tcatccttct tcagtgtgac cagtaaattc ttcccatact cttgaagaga gcataattgg 480aatggagagg tgctgacggc cacccaccat catctaaaga agataaactt ggcaaatgac 540atgcaggttc ttcaaggcag aataattgca gaaaatcttc aaaggaccct atctgcagat 600gttctgaata cctctgagaa tagagattga ttattcaacc aggataccta attcaagaac 660tccagaaatc aggagacgga gacattttgt cagttttgca acattggacc aaatacaatg 720aagtattctt gctgtgctct ggttttggct gtcctgggca cagaattgct gggaagcctc 780tgttcgactg tcagatcccc gaggttcaga ggacggatac agcaggaacg aaaaaacatc 840cgacccaaca ttattcttgt gcttaccgat gatcaagatg tggagctggg gtccctgcaa 900gtcatgaaca aaacgagaaa gattatggaa catggggggg ccaccttcat caatgccttt 960gtgactacac ccatgtgctg cccgtcacgg tcctccatgc tcaccgggaa gtatgtgcac 1020aatcacaatg tctacaccaa caacgagaac tgctcttccc cctcgtggca ggccatgcat 1080gagcctcgga cttttgctgt atatcttaac aacactggct acagaacagc cttttttgga 1140aaatacctca atgaatataa tggcagctac atcccccctg ggtggcgaga atggcttgga 1200ttaatcaaga attctcgctt ctataattac actgtttgtc gcaatggcat caaagaaaag 1260catggatttg attatgcaaa ggactacttc acagacttaa tcactaacga gagcattaat 1320tacttcaaaa tgtctaagag aatgtatccc cataggcccg ttatgatggt gatcagccac 1380gctgcgcccc acggccccga ggactcagcc ccacagtttt ctaaactgta ccccaatgct 1440tcccaacaca taactcctag ttataactat gcaccaaata tggataaaca ctggattatg 1500cagtacacag gaccaatgct gcccatccac atggaattta caaacattct acagcgcaaa 1560aggctccaga ctttgatgtc agtggatgat tctgtggaga ggctgtataa catgctcgtg 1620gagacggggg agctggagaa tacttacatc atttacaccg ccgaccatgg ttaccatatt 1680gggcagtttg gactggtcaa ggggaaatcc atgccatatg actttgatat tcgtgtgcct 1740ttttttattc gtggtccaag tgtagaacca ggatcaatag tcccacagat cgttctcaac 1800attgacttgg cccccacgat cctggatatt gctgggctcg acacacctcc tgatgtggac 1860ggcaagtctg tcctcaaact tctggaccca gaaaagccag gtaacaggtt tcgaacaaac 1920aagaaggcca aaatttggcg tgatacattc ctagtggaaa gaggcaaatt tctacgtaag 1980aaggaagaat ccagcaagaa tatccaacag tcaaatcact tgcccaaata tgaacgggtc 2040aaagaactat gccagcaggc caggtaccag acagcctgtg aacaaccggg gcagaagtgg 2100caatgcattg aggatacatc tggcaagctt cgaattcaca agtgtaaagg acccagtgac 2160ctgctcacag tccggcagag cacgcggaac ctctacgctc gcggcttcca tgacaaagac 2220aaagagtgca gttgtaggga gtctggttac cgtgccagca gaagccaaag aaagagtcaa 2280cggcaattct tgagaaacca ggggactcca aagtacaagc ccagatttgt ccatactcgg 2340cagacacgtt ccttgtccgt cgaatttgaa ggtgaaatat atgacataaa tctggaagaa 2400gaagaagaat tgcaagtgtt gcaaccaaga aacattgcta agcgtcatga tgaaggccac 2460aaggggccaa gagatctcca ggcttccagt ggtggcaaca ggggcaggat gctggcagat 2520agcagcaacg ccgtgggccc acctaccact gtccgagtga cacacaagtg ttttattctt 2580cccaatgact ctatccattg tgagagagaa ctgtaccaat cggccagagc gtggaaggac 2640cataaggcat acattgacaa agagattgaa gctctgcaag ataaaattaa gaatttaaga 2700gaagtgagag gacatctgaa gagaaggaag cctgaggaat gtagctgcag taaacaaagc 2760tattacaata aagagaaagg tgtaaaaaag caagagaaat taaagagcca tcttcaccca 2820ttcaaggagg ctgctcagga agtagatagc aaactgcaac ttttcaagga gaacaaccgt 2880aggaggaaga aggagaggaa ggagaagaga cggcagagga agggggaaga gtgcagcctg 2940cctggcctca cttgcttcac gcatgacaac aaccactggc agacagcccc gttctggaac 3000ctgggatctt tctgtgcttg cacgagttct aacaataaca cctactggtg tttgcgtaca 3060gttaatgaga cgcataattt tcttttctgt gagtttgcta ctggcttttt ggagtatttt 3120gatatgaata cagatcctta tcagctcaca aatacagtgc acacggtaga acgaggcatt 3180ttgaatcagc tacacgtaca actaatggag ctcagaagct gtcaaggata taagcagtgc 3240aacccaagac ctaagaatct tgatgttgga aataaagatg gaggaagcta tgacctacac 3300agaggacagt tatgggatgg atgggaaggt taatcagccc cgtctcactg cagacatcaa 3360ctggcaaggc ctagaggagc tacacagtgt gaatgaaaac atctatgagt acagacaaaa 3420ctacagactt agtctggtgg actggactaa ttacttgaag gatttagata gagtatttgc 3480actgctgaag agtcactatg agcaaaataa aacaaataag actcaaactg ctcaaagtga 3540cgggttcttg gttgtctctg ctgagcacgc tgtgtcaatg gagatggcct ctgctgactc 3600agatgaagac ccaaggcata aggttgggaa aacacctcat ttgaccttgc cagctgacct 3660tcaaaccctg catttgaacc gaccaacatt aagtccagag agtaaacttg aatggaataa 3720cgacattcca gaagttaatc atttgaattc tgaacactgg agaaaaaccg aaaaatggac 3780ggggcatgaa gagactaatc atctggaaac cgatttcagt ggcgatggca tgacagagct 3840agagctcggg cccagcccca ggctgcagcc cattcgcagg cacccgaaag aacttcccca 3900gtatggtggt cctggaaagg acatttttga agatcaacta tatcttcctg tgcattccga 3960tggaatttca gttcatcaga tgttcaccat ggccaccgca gaacaccgaa gtaattccag 4020catagcgggg aagatgttga ccaaggtgga gaagaatcac gaaaaggaga agtcacagca 4080cctagaaggc agcgcctcct cttcactctc ctctgattag atgaaactgt taccttaccc 4140taaacacagt atttcttttt aactttttta tttgtaaact aataaaggta atcacagcca 4200ccaacattcc aagctaccct gggtaccttt gtgcagtaga agctagtgag catgtgagca 4260agcggtgtgc acacggagac tcatcgttat aatttactat ctgccaagag tagaaagaaa 4320ggctggggat atttgggttg gcttggtttt gattttttgc ttgtttgttt gttttgtact 4380aaaacagtat tatcttttga atatcgtagg gacataagta tatacatgtt atccaatcaa 4440gatggctaga atggtgcctt tctgagtgtc taaaacttga cacccctggt aaatctttca 4500acacacttcc actgcctgcg taatgaagtt ttgattcatt tttaaccact ggaatttttc 4560aatgccgtca ttttcagtta gatgattttg cactttgaga ttaaaatgcc atgtctattt 4620gattagtctt atttttttat ttttacaggc ttatcagtct cactgttggc tgtcattgtg 4680acaaagtcaa ataaaccccc aaggacgaca cacagtatgg atcacatatt gtttgacatt 4740aagcttttgc cagaaaatgt tgcatgtgtt ttacctcgac ttgctaaaat cgattagcag 4800aaaggcatgg ctaataatgt tggtggtgaa aataaataaa taagtaaaca aaatgaagat 4860tgcctgctct ctctgtgcct agcctcaaag cgttcatcat acatcatacc tttaagattg 4920ctatattttg ggttattttc ttgacaggag aaaaagatct aaagatcttt tattttcatc 4980ttttttggtt ttcttggcat gactaagaag cttaaatgtt gataaaatat gactagtttt 5040gaatttacac caagaacttc tcaataaaag aaaatcatga atgctccaca atttcaacat 5100accacaagag aagttaattt cttaacattg tgttctatga ttatttgtaa gaccttcacc 5160aagttctgat atcttttaaa gacatagttc aaaattgctt ttgaaaatct gtattcttga 5220aaatatcctt gttgtgtatt aggtttttaa ataccagcta aaggattacc tcactgagtc 5280atcagtaccc tcctattcag ctccccaaga tgatgtgttt ttgcttaccc taagagaggt 5340tttcttctta tttttagata attcaagtgc ttagataaat tatgttttct ttaagtgttt 5400atggtaaact cttttaaaga aaatttaata tgttatagct gaatcttttt ggtaacttta 5460aatctttatc atagactctg tacatatgtt caaattagct gcttgcctga tgtgtgtatc 5520atcggtggga tgacagaaca aacatattta tgatcatgaa taatgtgctt tgtaaaaaga 5580tttcaagtta ttaggaagca tactctgttt tttaatcatg tataatattc catgatactt 5640ttatagaaca attctggctt caggaaagtc tagaagcaat atttcttcaa ataaaaggtg 5700tttaaacttt 57108871PRTHomo sapiens 8Met Lys Tyr Ser Cys Cys Ala Leu Val Leu Ala Val Leu Gly Thr Glu 1 5 10 15 Leu Leu Gly Ser Leu Cys Ser Thr Val Arg Ser Pro Arg Phe Arg Gly 20 25 30 Arg Ile Gln Gln Glu Arg Lys Asn Ile Arg Pro Asn Ile Ile Leu Val 35 40 45 Leu Thr Asp Asp Gln Asp Val Glu Leu Gly Ser Leu Gln Val Met Asn 50 55 60 Lys Thr Arg Lys Ile Met Glu His Gly Gly Ala Thr Phe Ile Asn Ala 65 70 75 80 Phe Val Thr Thr Pro Met Cys Cys Pro Ser Arg Ser Ser Met Leu Thr 85 90 95 Gly Lys Tyr Val His Asn His Asn Val Tyr Thr Asn Asn Glu Asn Cys 100 105 110 Ser Ser Pro Ser Trp Gln Ala Met His Glu Pro Arg Thr Phe Ala Val 115 120 125 Tyr Leu Asn Asn Thr Gly Tyr Arg Thr Ala Phe Phe Gly Lys Tyr Leu 130 135 140 Asn Glu Tyr Asn Gly Ser Tyr Ile Pro Pro Gly Trp Arg Glu Trp Leu 145 150 155 160 Gly Leu Ile Lys Asn Ser Arg Phe Tyr Asn Tyr Thr Val Cys Arg Asn 165 170 175 Gly Ile Lys Glu Lys His Gly Phe Asp Tyr Ala Lys Asp Tyr Phe Thr 180 185 190 Asp Leu Ile Thr Asn Glu Ser Ile Asn Tyr Phe Lys Met Ser Lys Arg 195 200 205 Met Tyr Pro His Arg Pro Val Met Met Val Ile Ser His Ala Ala Pro 210 215 220 His Gly Pro Glu Asp Ser Ala Pro Gln Phe Ser Lys Leu Tyr Pro Asn 225 230 235 240 Ala Ser Gln His Ile Thr Pro Ser Tyr Asn Tyr Ala Pro Asn Met Asp 245 250 255 Lys His Trp Ile Met Gln Tyr Thr Gly Pro Met Leu Pro Ile His Met 260 265 270 Glu Phe Thr Asn Ile Leu Gln Arg Lys Arg Leu Gln Thr Leu Met Ser 275 280 285 Val Asp Asp Ser Val Glu Arg Leu Tyr Asn Met Leu Val Glu Thr Gly 290 295 300 Glu Leu Glu Asn Thr Tyr Ile Ile Tyr Thr Ala Asp His Gly Tyr His 305 310 315 320 Ile Gly Gln Phe Gly Leu Val Lys Gly Lys Ser Met Pro Tyr Asp Phe 325 330 335 Asp Ile Arg Val Pro Phe Phe Ile Arg Gly Pro Ser Val Glu Pro Gly 340 345 350 Ser Ile Val Pro Gln Ile Val Leu Asn Ile Asp Leu Ala Pro Thr Ile 355 360 365 Leu Asp Ile Ala Gly Leu Asp Thr Pro Pro Asp Val Asp Gly Lys Ser 370 375 380 Val Leu Lys Leu Leu Asp Pro Glu Lys Pro Gly Asn Arg Phe Arg Thr 385 390 395 400 Asn Lys Lys Ala Lys Ile Trp Arg Asp Thr Phe Leu Val Glu Arg Gly 405 410 415 Lys Phe Leu Arg Lys Lys Glu Glu Ser Ser Lys Asn Ile Gln Gln Ser 420 425 430 Asn His Leu Pro Lys Tyr Glu Arg Val Lys Glu Leu Cys Gln Gln Ala 435 440 445 Arg Tyr Gln Thr Ala Cys Glu Gln Pro Gly Gln Lys Trp Gln Cys Ile 450 455 460 Glu Asp Thr Ser Gly Lys Leu Arg Ile His Lys Cys Lys Gly Pro Ser 465 470 475 480 Asp Leu Leu Thr Val Arg Gln Ser Thr Arg Asn Leu Tyr Ala Arg Gly 485 490 495 Phe His Asp Lys Asp Lys Glu Cys Ser Cys Arg Glu Ser Gly Tyr Arg 500 505 510 Ala Ser Arg Ser Gln Arg Lys Ser Gln Arg Gln Phe Leu Arg Asn Gln 515 520 525 Gly Thr Pro Lys Tyr Lys Pro Arg Phe Val His Thr Arg Gln Thr Arg 530 535 540

Ser Leu Ser Val Glu Phe Glu Gly Glu Ile Tyr Asp Ile Asn Leu Glu 545 550 555 560 Glu Glu Glu Glu Leu Gln Val Leu Gln Pro Arg Asn Ile Ala Lys Arg 565 570 575 His Asp Glu Gly His Lys Gly Pro Arg Asp Leu Gln Ala Ser Ser Gly 580 585 590 Gly Asn Arg Gly Arg Met Leu Ala Asp Ser Ser Asn Ala Val Gly Pro 595 600 605 Pro Thr Thr Val Arg Val Thr His Lys Cys Phe Ile Leu Pro Asn Asp 610 615 620 Ser Ile His Cys Glu Arg Glu Leu Tyr Gln Ser Ala Arg Ala Trp Lys 625 630 635 640 Asp His Lys Ala Tyr Ile Asp Lys Glu Ile Glu Ala Leu Gln Asp Lys 645 650 655 Ile Lys Asn Leu Arg Glu Val Arg Gly His Leu Lys Arg Arg Lys Pro 660 665 670 Glu Glu Cys Ser Cys Ser Lys Gln Ser Tyr Tyr Asn Lys Glu Lys Gly 675 680 685 Val Lys Lys Gln Glu Lys Leu Lys Ser His Leu His Pro Phe Lys Glu 690 695 700 Ala Ala Gln Glu Val Asp Ser Lys Leu Gln Leu Phe Lys Glu Asn Asn 705 710 715 720 Arg Arg Arg Lys Lys Glu Arg Lys Glu Lys Arg Arg Gln Arg Lys Gly 725 730 735 Glu Glu Cys Ser Leu Pro Gly Leu Thr Cys Phe Thr His Asp Asn Asn 740 745 750 His Trp Gln Thr Ala Pro Phe Trp Asn Leu Gly Ser Phe Cys Ala Cys 755 760 765 Thr Ser Ser Asn Asn Asn Thr Tyr Trp Cys Leu Arg Thr Val Asn Glu 770 775 780 Thr His Asn Phe Leu Phe Cys Glu Phe Ala Thr Gly Phe Leu Glu Tyr 785 790 795 800 Phe Asp Met Asn Thr Asp Pro Tyr Gln Leu Thr Asn Thr Val His Thr 805 810 815 Val Glu Arg Gly Ile Leu Asn Gln Leu His Val Gln Leu Met Glu Leu 820 825 830 Arg Ser Cys Gln Gly Tyr Lys Gln Cys Asn Pro Arg Pro Lys Asn Leu 835 840 845 Asp Val Gly Asn Lys Asp Gly Gly Ser Tyr Asp Leu His Arg Gly Gln 850 855 860 Leu Trp Asp Gly Trp Glu Gly 865 870 93909DNAHomo sapiens 9gagcgagagt gtgtcgagtg agtgtgcgtc tgtgtgtccc ggcgagggtg cgcgctcggc 60gccgggagcg cggccagccg agtccggagg catcgggagg tcgagagccg ccgggacccc 120agctctgcgt tcactgcccc gtccggagct ggacttcggg gccggggccg gggccgtgcg 180ccggggacag gcagggccgg gtcgcgggcc gcgcgtcccc caggccggag atctgcgagt 240gaagagggac gagggaaaag aaacaaagcc acagacgcaa cttgagactc ccgcatccca 300aaagaagcac cagatcagca aaaaaagaag atgggccccc cgagcctcgt gctgtgcttg 360ctgtccgcaa ctgtgttctc cctgctgggt ggaagctcgg ccttcctgtc gcaccaccgc 420ctgaaaggca ggtttcagag ggaccgcagg aacatccgcc ccaacatcat cctggtgctg 480acggacgacc aggatgtgga gctgggttcc atgcaggtga tgaacaagac ccggcgcatc 540atggagcagg gcggggcgca cttcatcaac gccttcgtga ccacacccat gtgctgcccc 600tcacgctcct ccatcctcac tggcaagtac gtccacaacc acaacaccta caccaacaat 660gagaactgct cctcgccctc ctggcaggca cagcacgaga gccgcacctt tgccgtgtac 720ctcaatagca ctggctaccg gacagctttc ttcgggaagt atcttaatga atacaacggc 780tcctacgtgc cacccggctg gaaggagtgg gtcggactcc ttaaaaactc ccgcttttat 840aactacacgc tgtgtcggaa cggggtgaaa gagaagcacg gctccgacta ctccaaggat 900tacctcacag acctcatcac caatgacagc gtgagcttct tccgcacgtc caagaagatg 960tacccgcaca ggccagtcct catggtcatc agccatgcag ccccccacgg ccctgaggat 1020tcagccccac aatattcacg cctcttccca aacgcatctc agcacatcac gccgagctac 1080aactacgcgc ccaacccgga caaacactgg atcatgcgct acacggggcc catgaagccc 1140atccacatgg aattcaccaa catgctccag cggaagcgct tgcagaccct catgtcggtg 1200gacgactcca tggagacgat ttacaacatg ctggttgaga cgggcgagct ggacaacacg 1260tacatcgtat acaccgccga ccacggttac cacatcggcc agtttggcct ggtgaaaggg 1320aaatccatgc catatgagtt tgacatcagg gtcccgttct acgtgagggg ccccaacgtg 1380gaagccggct gtctgaatcc ccacatcgtc ctcaacattg acctggcccc caccatcctg 1440gacattgcag gcctggacat acctgcggat atggacggga aatccatcct caagctgctg 1500gacacggagc ggccggtgaa tcggtttcac ttgaaaaaga agatgagggt ctggcgggac 1560tccttcttgg tggagagagg caagctgcta cacaagagag acaatgacaa ggtggacgcc 1620caggaggaga actttctgcc caagtaccag cgtgtgaagg acctgtgtca gcgtgctgag 1680taccagacgg cgtgtgagca gctgggacag aagtggcagt gtgtggagga cgccacgggg 1740aagctgaagc tgcataagtg caagggcccc atgcggctgg gcggcagcag agccctctcc 1800aacctcgtgc ccaagtacta cgggcagggc agcgaggcct gcacctgtga cagcggggac 1860tacaagctca gcctggccgg acgccggaaa aaactcttca agaagaagta caaggccagc 1920tatgtccgca gtcgctccat ccgctcagtg gccatcgagg tggacggcag ggtgtaccac 1980gtaggcctgg gtgatgccgc ccagccccga aacctcacca agcggcactg gccaggggcc 2040cctgaggacc aagatgacaa ggatggtggg gacttcagtg gcactggagg ccttcccgac 2100tactcagccg ccaaccccat taaagtgaca catcggtgct acatcctaga gaacgacaca 2160gtccagtgtg acctggacct gtacaagtcc ctgcaggcct ggaaagacca caagctgcac 2220atcgaccacg agattgaaac cctgcagaac aaaattaaga acctgaggga agtccgaggt 2280cacctgaaga aaaagcggcc agaagaatgt gactgtcaca aaatcagcta ccacacccag 2340cacaaaggcc gcctcaagca cagaggctcc agtctgcatc ctttcaggaa gggcctgcaa 2400gagaaggaca aggtgtggct gttgcgggag cagaagcgca agaagaaact ccgcaagctg 2460ctcaagcgcc tgcagaacaa cgacacgtgc agcatgccag gcctcacgtg cttcacccac 2520gacaaccagc actggcagac ggcgcctttc tggacactgg ggcctttctg tgcctgcacc 2580agcgccaaca ataacacgta ctggtgcatg aggaccatca atgagactca caatttcctc 2640ttctgtgaat ttgcaactgg cttcctagag tactttgatc tcaacacaga cccctaccag 2700ctgatgaatg cagtgaacac actggacagg gatgtcctca accagctaca cgtacagctc 2760atggagctga ggagctgcaa gggttacaag cagtgtaacc cccggactcg aaacatggac 2820ctgggactta aagatggagg aagctatgag caatacaggc agtttcagcg tcgaaagtgg 2880ccagaaatga agagaccttc ttccaaatca ctgggacaac tgtgggaagg ctgggaaggt 2940taagaaacaa cagaggtgga cctccaaaaa catagaggca tcacctgact gcacaggcaa 3000tgaaaaacca tgtgggtgat ttccagcaga cctgtggtat tggccaggag gcctgagaaa 3060gcaagcacgc actctcagtc aacatgacag attctggagg ataaccagca ggagcagaga 3120taacttcagg aagtccattt ttgcccctgc ttttgctttg gattatacct caccagctgc 3180acaaaatgca ttttttcgta tcaaaaagtc accactaacc ctcccccaga agctcacaaa 3240ggaaaacgga gagagcgagc gagagagatt tccttggaaa tttctcccaa gggcgaaagt 3300cattggaatt tttaaatcat aggggaaaag cagtcctgtt ctaaatcctc ttattctttt 3360ggtttgtcac aaagaaggaa ctaagaagca ggacagaggc aacgtggaga ggctgaaaac 3420agtgcagaga cgtttgacaa tgagtcagta gcacaaaaga gatgacattt acctagcact 3480ataaaccctg gttgcctctg aagaaactgc cttcattgta tatatgtgac tatttacatg 3540taatcaacat gggaactttt aggggaacct aataagaaat cccaattttc aggagtggtg 3600gtgtcaataa acgctctgtg gccagtgtaa aagaaaatcc ctcgcagttg tggacatttc 3660tgttcctgtc cagataccat ttctcctagt atttctttgt tatgtcccag aactgatgtt 3720ttttttttaa ggtactgaaa agaaatgaag ttgatgtatg tcccaagttt tgatgaaact 3780gtatttgtaa aaaaaatttt gtagtttaag tattgtcata cagtgttcaa aaccccagcc 3840aatgaccagc agttggtatg aagaaccttt gacattttgt aaaaggccat ttcttgggaa 3900aaaaaaaaa 390910870PRTHomo sapiens 10Met Gly Pro Pro Ser Leu Val Leu Cys Leu Leu Ser Ala Thr Val Phe 1 5 10 15 Ser Leu Leu Gly Gly Ser Ser Ala Phe Leu Ser His His Arg Leu Lys 20 25 30 Gly Arg Phe Gln Arg Asp Arg Arg Asn Ile Arg Pro Asn Ile Ile Leu 35 40 45 Val Leu Thr Asp Asp Gln Asp Val Glu Leu Gly Ser Met Gln Val Met 50 55 60 Asn Lys Thr Arg Arg Ile Met Glu Gln Gly Gly Ala His Phe Ile Asn 65 70 75 80 Ala Phe Val Thr Thr Pro Met Cys Cys Pro Ser Arg Ser Ser Ile Leu 85 90 95 Thr Gly Lys Tyr Val His Asn His Asn Thr Tyr Thr Asn Asn Glu Asn 100 105 110 Cys Ser Ser Pro Ser Trp Gln Ala Gln His Glu Ser Arg Thr Phe Ala 115 120 125 Val Tyr Leu Asn Ser Thr Gly Tyr Arg Thr Ala Phe Phe Gly Lys Tyr 130 135 140 Leu Asn Glu Tyr Asn Gly Ser Tyr Val Pro Pro Gly Trp Lys Glu Trp 145 150 155 160 Val Gly Leu Leu Lys Asn Ser Arg Phe Tyr Asn Tyr Thr Leu Cys Arg 165 170 175 Asn Gly Val Lys Glu Lys His Gly Ser Asp Tyr Ser Lys Asp Tyr Leu 180 185 190 Thr Asp Leu Ile Thr Asn Asp Ser Val Ser Phe Phe Arg Thr Ser Lys 195 200 205 Lys Met Tyr Pro His Arg Pro Val Leu Met Val Ile Ser His Ala Ala 210 215 220 Pro His Gly Pro Glu Asp Ser Ala Pro Gln Tyr Ser Arg Leu Phe Pro 225 230 235 240 Asn Ala Ser Gln His Ile Thr Pro Ser Tyr Asn Tyr Ala Pro Asn Pro 245 250 255 Asp Lys His Trp Ile Met Arg Tyr Thr Gly Pro Met Lys Pro Ile His 260 265 270 Met Glu Phe Thr Asn Met Leu Gln Arg Lys Arg Leu Gln Thr Leu Met 275 280 285 Ser Val Asp Asp Ser Met Glu Thr Ile Tyr Asn Met Leu Val Glu Thr 290 295 300 Gly Glu Leu Asp Asn Thr Tyr Ile Val Tyr Thr Ala Asp His Gly Tyr 305 310 315 320 His Ile Gly Gln Phe Gly Leu Val Lys Gly Lys Ser Met Pro Tyr Glu 325 330 335 Phe Asp Ile Arg Val Pro Phe Tyr Val Arg Gly Pro Asn Val Glu Ala 340 345 350 Gly Cys Leu Asn Pro His Ile Val Leu Asn Ile Asp Leu Ala Pro Thr 355 360 365 Ile Leu Asp Ile Ala Gly Leu Asp Ile Pro Ala Asp Met Asp Gly Lys 370 375 380 Ser Ile Leu Lys Leu Leu Asp Thr Glu Arg Pro Val Asn Arg Phe His 385 390 395 400 Leu Lys Lys Lys Met Arg Val Trp Arg Asp Ser Phe Leu Val Glu Arg 405 410 415 Gly Lys Leu Leu His Lys Arg Asp Asn Asp Lys Val Asp Ala Gln Glu 420 425 430 Glu Asn Phe Leu Pro Lys Tyr Gln Arg Val Lys Asp Leu Cys Gln Arg 435 440 445 Ala Glu Tyr Gln Thr Ala Cys Glu Gln Leu Gly Gln Lys Trp Gln Cys 450 455 460 Val Glu Asp Ala Thr Gly Lys Leu Lys Leu His Lys Cys Lys Gly Pro 465 470 475 480 Met Arg Leu Gly Gly Ser Arg Ala Leu Ser Asn Leu Val Pro Lys Tyr 485 490 495 Tyr Gly Gln Gly Ser Glu Ala Cys Thr Cys Asp Ser Gly Asp Tyr Lys 500 505 510 Leu Ser Leu Ala Gly Arg Arg Lys Lys Leu Phe Lys Lys Lys Tyr Lys 515 520 525 Ala Ser Tyr Val Arg Ser Arg Ser Ile Arg Ser Val Ala Ile Glu Val 530 535 540 Asp Gly Arg Val Tyr His Val Gly Leu Gly Asp Ala Ala Gln Pro Arg 545 550 555 560 Asn Leu Thr Lys Arg His Trp Pro Gly Ala Pro Glu Asp Gln Asp Asp 565 570 575 Lys Asp Gly Gly Asp Phe Ser Gly Thr Gly Gly Leu Pro Asp Tyr Ser 580 585 590 Ala Ala Asn Pro Ile Lys Val Thr His Arg Cys Tyr Ile Leu Glu Asn 595 600 605 Asp Thr Val Gln Cys Asp Leu Asp Leu Tyr Lys Ser Leu Gln Ala Trp 610 615 620 Lys Asp His Lys Leu His Ile Asp His Glu Ile Glu Thr Leu Gln Asn 625 630 635 640 Lys Ile Lys Asn Leu Arg Glu Val Arg Gly His Leu Lys Lys Lys Arg 645 650 655 Pro Glu Glu Cys Asp Cys His Lys Ile Ser Tyr His Thr Gln His Lys 660 665 670 Gly Arg Leu Lys His Arg Gly Ser Ser Leu His Pro Phe Arg Lys Gly 675 680 685 Leu Gln Glu Lys Asp Lys Val Trp Leu Leu Arg Glu Gln Lys Arg Lys 690 695 700 Lys Lys Leu Arg Lys Leu Leu Lys Arg Leu Gln Asn Asn Asp Thr Cys 705 710 715 720 Ser Met Pro Gly Leu Thr Cys Phe Thr His Asp Asn Gln His Trp Gln 725 730 735 Thr Ala Pro Phe Trp Thr Leu Gly Pro Phe Cys Ala Cys Thr Ser Ala 740 745 750 Asn Asn Asn Thr Tyr Trp Cys Met Arg Thr Ile Asn Glu Thr His Asn 755 760 765 Phe Leu Phe Cys Glu Phe Ala Thr Gly Phe Leu Glu Tyr Phe Asp Leu 770 775 780 Asn Thr Asp Pro Tyr Gln Leu Met Asn Ala Val Asn Thr Leu Asp Arg 785 790 795 800 Asp Val Leu Asn Gln Leu His Val Gln Leu Met Glu Leu Arg Ser Cys 805 810 815 Lys Gly Tyr Lys Gln Cys Asn Pro Arg Thr Arg Asn Met Asp Leu Gly 820 825 830 Leu Lys Asp Gly Gly Ser Tyr Glu Gln Tyr Arg Gln Phe Gln Arg Arg 835 840 845 Lys Trp Pro Glu Met Lys Arg Pro Ser Ser Lys Ser Leu Gly Gln Leu 850 855 860 Trp Glu Gly Trp Glu Gly 865 870 115876DNAHomo sapiens 11agaacccgcc ccggagggga gggacgcagg gaagagtcgc acggacgcac tcgcgctgcg 60gccagcgccc gggcctgcgg gcccgggcgg cggctgtgtt gcgcagtctt catgggttcc 120cgacgaggag gtctctgtgg ctgcggcggc ggctgctaac tgcgccacct gctgcagcct 180gtccccgccg ctctgaagcg gccgcgtcga agccgaaatg ccgccacccc ggaccggccg 240aggccttctc tggctgggtc tggttctgag ctccgtctgc gtcgccctcg gatccgaaac 300gcaggccaac tcgaccacag atgctctgaa cgttcttctc atcatcgtgg atgacctgcg 360cccctccctg ggctgttatg gggataagct ggtgaggtcc ccaaatattg accaactggc 420atcccacagc ctcctcttcc agaatgcctt tgcgcagcaa gcagtgtgcg ccccgagccg 480cgtttctttc ctcactggca ggagacctga caccacccgc ctgtacgact tcaactccta 540ctggagggtg cacgctggaa acttctccac catcccccag tacttcaagg agaatggcta 600tgtgaccatg tcggtgggaa aagtctttca ccctgggata tcttctaacc ataccgatga 660ttctccgtat agctggtctt ttccacctta tcatccttcc tctgagaagt atgaaaacac 720taagacatgt cgagggccag atggagaact ccatgccaac ctgctttgcc ctgtggatgt 780gctggatgtt cccgagggca ccttgcctga caaacagagc actgagcaag ccatacagtt 840gttggaaaag atgaaaacgt cagccagtcc tttcttcctg gccgttgggt atcataagcc 900acacatcccc ttcagatacc ccaaggaatt tcagaagttg tatcccttgg agaacatcac 960cctggccccc gatcccgagg tccctgatgg cctaccccct gtggcctaca acccctggat 1020ggacatcagg caacgggaag acgtccaagc cttaaacatc agtgtgccgt atggtccaat 1080tcctgtggac tttcagcgga aaatccgcca gagctacttt gcctctgtgt catatttgga 1140tacacaggtc ggccgcctct tgagtgcttt ggacgatctt cagctggcca acagcaccat 1200cattgcattt acctcggatc atgggtgggc tctaggtgaa catggagaat gggccaaata 1260cagcaatttt gatgttgcta cccatgttcc cctgatattc tatgttcctg gaaggacggc 1320ttcacttccg gaggcaggcg agaagctttt cccttacctc gacccttttg attccgcctc 1380acagttgatg gagccaggca ggcaatccat ggaccttgtg gaacttgtgt ctctttttcc 1440cacgctggct ggacttgcag gactgcaggt tccacctcgc tgccccgttc cttcatttca 1500cgttgagctg tgcagagaag gcaagaacct tctgaagcat tttcgattcc gtgacttgga 1560agaggatccg tacctccctg gtaatccccg tgaactgatt gcctatagcc agtatccccg 1620gccttcagac atccctcagt ggaattctga caagccgagt ttaaaagata taaagatcat 1680gggctattcc atacgcacca tagactatag gtatactgtg tgggttggct tcaatcctga 1740tgaatttcta gctaactttt ctgacatcca tgcaggggaa ctgtattttg tggattctga 1800cccattgcag gatcacaata tgtataatga ttcccaaggt ggagatcttt tccagttgtt 1860gatgccttga gttttgccaa ccatggatgg caaatgtgat gtgctccctt ccagctggtg 1920agaggaggag ttagagctgg tcgttttgtg attacccata atattggaag cagcctgagg 1980gctagttaat ccaaacatgc atcaacaatt tggcctgaga atatgtaaca gccaaacctt 2040ttcgtttagt ctttattaaa atttataatt ggtaattgga ccagtttttt ttttaatttc 2100cctcttttta aaacagttac ggcttattta ctgaataaat acaaagcaaa caaactcaag 2160ttatgtcata cctttggata cgaagaccat acataataac caaacataac attatacaca 2220aagaatactt tcattatttg tggaatttag tgcatttcaa aaagtaatca tatatcaaac 2280taggcaccac actaagttcc tgattatttt gtttataatt taataatata tcttatgagc 2340cctatatatt caaaatatta tgttaacatg taatccatgt ttctttttca aatctaaagt 2400taaaaaaaaa tagcagaagc cagtgtctta aagtctatct tttgtttcta agaccatggg 2460atttcataat ctcaagataa aatatgtatg aagtaattaa tgtagaattt ttacaccaaa 2520taataaataa tgcttaataa actagagata tgagatgtgt aggaaatttg gttaaacttt 2580tttcagatac tttctggccc aaataataat ttgttagcaa ataatatgac ccttgaactc 2640aatggccatc tattaaaaga ctgttgttca cactggaaaa catttaaaga tgtgactata 2700tccatgggtg gattgaatca ctcaaaatat attagtatcc ttctttaggg atggttggtt 2760acagacatgt atttattcag gaggcagaaa atattccatt ttaattgctt attaaagaaa 2820acattaaatt ctaaattatt ttgaggactg tgaagacttt tcattagtgt aatattaggt 2880cattgtcaat ctcccagaat gtagttctat attctctaaa tatgaaagta tccagaaagg 2940ccagtggtag taaaaagctt agtgtatata atctcaaaag ggatggaata tttacaactc 3000atatttataa catgttgaat cttctcagtt atcagtagtc atcagaagtg tcaatagctt 3060tctaaataaa tattaaatat ctactgtcct gtagtgaagg agtaattttt agtaattttc 3120tctttacaaa gtctccagtg tttccaggta aatatttgtg aaacaaaata cagcaaacta 3180cattgttact tcagtgtatt gttgccaaaa atgacaagat attatattaa

aatcagtaaa 3240ttttagacag attttaaaaa ttaattagcc tacaatagag gttatatggt aacacggtga 3300tcttctaagc agttaagtga ctgactgttc tggcaacaac gacttctccg tgactgaagg 3360gccctgttca tttcctgatc ctgaagctcg tctctctttt gagcctccgc ttgctttggt 3420cgatggtttc cctcagcttt ttctttgctg ttcttcatcc tcgttgttgc tgtcatcatg 3480ttcactgtgg cttttacaat acagcctgta aattccttat gacatagttc agtgcatttg 3540gctttattgc ctgctccaca gttctttacc tttacttggc ttagagaaac tgtatctttg 3600ttgcttcata taacctttcc ccaaccccac taagctggac ataacttatt agtggtcctc 3660ccgtcacttt atttgtagaa atctctcttt cacatgagca ggggttcttt catgtggttt 3720agctgacagc agaactagtg attctagaca ttttgcatgg ccctcattca gtggctcaca 3780aacatgaggg agcatcagaa ctacttgagg ggcttgttaa aacccagtgc gttagaagtc 3840ggatgcggtg gctcacacct gtaatcccag cactttggga ggcccaggca ggcggatcac 3900ttgaggttag gagttcaaga ccagcctggc caacatggtg aaaccccgtc tctactaaaa 3960atacaaaagt tagccgggtg tggtggtgca tgcctgtaat cccagcttct tgggaggcca 4020aggcacaaga atcgcttgaa ccaggagacg gaggtttcag tgaatgaaga tcgtgccatt 4080gtattccagc ctcggcaaca cagcaggact gtgattttct ttggagactc ctagattttc 4140tgtggttttg aactgaattt gttggatgtt ggcaagtgcc tcttatgagc tgtttcttta 4200tcctgcattt gccccacaaa gacttatctg gaggtgagca aagtatgttt ggtagtgagg 4260tcacaaaggc aatcagcccc ttcctcccca ctcccattgc catcttctca gtccttctcc 4320ctttctttcc aagtagttta cccacccctc ctctttcctc ccctgtccct aaaataatcc 4380acgtgtcttc ctaaaatctc tctttgatcc tgtcctttga taacaccgtc agtgcctact 4440actgggtcta gacagacctc tgttgagcag tcagagtctt ccctgactcc acaatgcccc 4500tttccttggc tgaccagtat gactactggt ccccaccttt cccttgccta tccctacctc 4560cctcctacta ggttgtccca tccctctctt cacccattca ttcatgacca tttttcacta 4620ccaagctccc cccctcccga aggaggctga ggtttttgtg actctctaga ctctattgtg 4680ggatggaatg aacattgcta aagaatcttg tgttcgcttt actttaaaaa ggtatttttt 4740tcctaattat aaaactgatg tgtcagttac ggaaaaatta gaaatgcagc acaaatacat 4800gaatatttta ccacaaaatt gccatataat atcttgtctt ttttgggggt gtgaattttt 4860tgcattgttc tggtcatatt ctttatcatg taatttatgt tcttttttac taagtattat 4920gtgtggttat tatagatttt cacaaagata tattgctggt aatatatttt attgtgtagt 4980cttataattt acttaacctt ctttcaattg ttagaaattt aggctatttc cagattttca 5040gtattgtaaa taatgctgtg atgaccaatt ttgtgaataa aatgttttta tgtatttcag 5100attattccct taggatagtc tctcagtgcc aagttgtcaa aaacatctct attttgctta 5160tcttcctgct ctcttgctgc cttagggggt agtaaactga aacataaagt aaacatgcat 5220acaaataaaa aacataaaac aaaaataagc aacctgatgg taataggtga aagtggtaac 5280ctgttttaac tttgaattct tgccgggcgc ggtggctcac gcctgtaatc ccagcacttt 5340gggaggctga ggcgggtgga tcacgaggtc aggagttcaa aaccagcctg gccaagatgg 5400tgaaatcccg tctctactaa aaatacaaaa attagccggg cgtggtggcg ggcgcctgta 5460atcccagcta cttgggaggc tgaggcagag aattgcttga acccaggagg cggaggttgc 5520agtgagccaa gatcgcgcca ctgcactcca gcctgggtga cagagcgaga ctccgtctca 5580aataaaaaac aacaaaaaac aaaaaaaact taaaattctt tgcttgttag tgaccttgat 5640catggttctc tttgtacgat agttgggcat ctgtatttcc acttgtgtga atttgccttt 5700aaattttggt tatgggtttc accttttaaa ataatcaaac atatttatct tttcctgtgt 5760gataggtttt tttctgtatc ttttcctgtt aaacacacag acccctcccc aatctggaca 5820ttgaataaat attcattttc ctttgcattg ttaaaaaaaa aaaaaaaaaa aaaaaa 587612550PRTHomo sapiens 12Met Pro Pro Pro Arg Thr Gly Arg Gly Leu Leu Trp Leu Gly Leu Val 1 5 10 15 Leu Ser Ser Val Cys Val Ala Leu Gly Ser Glu Thr Gln Ala Asn Ser 20 25 30 Thr Thr Asp Ala Leu Asn Val Leu Leu Ile Ile Val Asp Asp Leu Arg 35 40 45 Pro Ser Leu Gly Cys Tyr Gly Asp Lys Leu Val Arg Ser Pro Asn Ile 50 55 60 Asp Gln Leu Ala Ser His Ser Leu Leu Phe Gln Asn Ala Phe Ala Gln 65 70 75 80 Gln Ala Val Cys Ala Pro Ser Arg Val Ser Phe Leu Thr Gly Arg Arg 85 90 95 Pro Asp Thr Thr Arg Leu Tyr Asp Phe Asn Ser Tyr Trp Arg Val His 100 105 110 Ala Gly Asn Phe Ser Thr Ile Pro Gln Tyr Phe Lys Glu Asn Gly Tyr 115 120 125 Val Thr Met Ser Val Gly Lys Val Phe His Pro Gly Ile Ser Ser Asn 130 135 140 His Thr Asp Asp Ser Pro Tyr Ser Trp Ser Phe Pro Pro Tyr His Pro 145 150 155 160 Ser Ser Glu Lys Tyr Glu Asn Thr Lys Thr Cys Arg Gly Pro Asp Gly 165 170 175 Glu Leu His Ala Asn Leu Leu Cys Pro Val Asp Val Leu Asp Val Pro 180 185 190 Glu Gly Thr Leu Pro Asp Lys Gln Ser Thr Glu Gln Ala Ile Gln Leu 195 200 205 Leu Glu Lys Met Lys Thr Ser Ala Ser Pro Phe Phe Leu Ala Val Gly 210 215 220 Tyr His Lys Pro His Ile Pro Phe Arg Tyr Pro Lys Glu Phe Gln Lys 225 230 235 240 Leu Tyr Pro Leu Glu Asn Ile Thr Leu Ala Pro Asp Pro Glu Val Pro 245 250 255 Asp Gly Leu Pro Pro Val Ala Tyr Asn Pro Trp Met Asp Ile Arg Gln 260 265 270 Arg Glu Asp Val Gln Ala Leu Asn Ile Ser Val Pro Tyr Gly Pro Ile 275 280 285 Pro Val Asp Phe Gln Arg Lys Ile Arg Gln Ser Tyr Phe Ala Ser Val 290 295 300 Ser Tyr Leu Asp Thr Gln Val Gly Arg Leu Leu Ser Ala Leu Asp Asp 305 310 315 320 Leu Gln Leu Ala Asn Ser Thr Ile Ile Ala Phe Thr Ser Asp His Gly 325 330 335 Trp Ala Leu Gly Glu His Gly Glu Trp Ala Lys Tyr Ser Asn Phe Asp 340 345 350 Val Ala Thr His Val Pro Leu Ile Phe Tyr Val Pro Gly Arg Thr Ala 355 360 365 Ser Leu Pro Glu Ala Gly Glu Lys Leu Phe Pro Tyr Leu Asp Pro Phe 370 375 380 Asp Ser Ala Ser Gln Leu Met Glu Pro Gly Arg Gln Ser Met Asp Leu 385 390 395 400 Val Glu Leu Val Ser Leu Phe Pro Thr Leu Ala Gly Leu Ala Gly Leu 405 410 415 Gln Val Pro Pro Arg Cys Pro Val Pro Ser Phe His Val Glu Leu Cys 420 425 430 Arg Glu Gly Lys Asn Leu Leu Lys His Phe Arg Phe Arg Asp Leu Glu 435 440 445 Glu Asp Pro Tyr Leu Pro Gly Asn Pro Arg Glu Leu Ile Ala Tyr Ser 450 455 460 Gln Tyr Pro Arg Pro Ser Asp Ile Pro Gln Trp Asn Ser Asp Lys Pro 465 470 475 480 Ser Leu Lys Asp Ile Lys Ile Met Gly Tyr Ser Ile Arg Thr Ile Asp 485 490 495 Tyr Arg Tyr Thr Val Trp Val Gly Phe Asn Pro Asp Glu Phe Leu Ala 500 505 510 Asn Phe Ser Asp Ile His Ala Gly Glu Leu Tyr Phe Val Asp Ser Asp 515 520 525 Pro Leu Gln Asp His Asn Met Tyr Asn Asp Ser Gln Gly Gly Asp Leu 530 535 540 Phe Gln Leu Leu Met Pro 545 550 134325DNAHomo sapiens 13cacaggtcac ggggcggggc cgaggcggaa gcgcccgcag cccggtaccg gctcctcctg 60ggctccctct agcgccttcc ccccggcccg actccgctgg tcagcgccaa gtgacttacg 120cccccgaccc tgagcccgga ccgctaggcg aggaggatca gatctccgct cgagaatctg 180aaggtgccct ggtcctggag gagttccgtc ccagcccgcg gtctcccggt actgtcgggc 240cccggccctc tggagcttca ggaggcggcc gtcagggtcg gggagtattt gggtccgggg 300tctcagggaa gggcggcgcc tgggtctgcg gtatcggaaa gagcctgctg gagccaagta 360gccctccctc tcttgggaca gacccctcgg tcccatgtcc atgggggcac cgcggtccct 420cctcctggcc ctggctgctg gcctggccgt tgcccgtccg cccaacatcg tgctgatctt 480tgccgacgac ctcggctatg gggacctggg ctgctatggg caccccagct ctaccactcc 540caacctggac cagctggcgg cgggagggct gcggttcaca gacttctacg tgcctgtgtc 600tctgtgcaca ccctctaggg ccgccctcct gaccggccgg ctcccggttc ggatgggcat 660gtaccctggc gtcctggtgc ccagctcccg ggggggcctg cccctggagg aggtgaccgt 720ggccgaagtc ctggctgccc gaggctacct cacaggaatg gccggcaagt ggcaccttgg 780ggtggggcct gagggggcct tcctgccccc ccatcagggc ttccatcgat ttctaggcat 840cccgtactcc cacgaccagg gcccctgcca gaacctgacc tgcttcccgc cggccactcc 900ttgcgacggt ggctgtgacc agggcctggt ccccatccca ctgttggcca acctgtccgt 960ggaggcgcag cccccctggc tgcccggact agaggcccgc tacatggctt tcgcccatga 1020cctcatggcc gacgcccagc gccaggatcg ccccttcttc ctgtactatg cctctcacca 1080cacccactac cctcagttca gtgggcagag ctttgcagag cgttcaggcc gcgggccatt 1140tggggactcc ctgatggagc tggatgcagc tgtggggacc ctgatgacag ccatagggga 1200cctggggctg cttgaagaga cgctggtcat cttcactgca gacaatggac ctgagaccat 1260gcgtatgtcc cgaggcggct gctccggtct cttgcggtgt ggaaagggaa cgacctacga 1320gggcggtgtc cgagagcctg ccttggcctt ctggccaggt catatcgctc ccggcgtgac 1380ccacgagctg gccagctccc tggacctgct gcctaccctg gcagccctgg ctggggcccc 1440actgcccaat gtcaccttgg atggctttga cctcagcccc ctgctgctgg gcacaggcaa 1500gagccctcgg cagtctctct tcttctaccc gtcctaccca gacgaggtcc gtggggtttt 1560tgctgtgcgg actggaaagt acaaggctca cttcttcacc cagggctctg cccacagtga 1620taccactgca gaccctgcct gccacgcctc cagctctctg actgctcatg agcccccgct 1680gctctatgac ctgtccaagg accctggtga gaactacaac ctgctggggg gtgtggccgg 1740ggccacccca gaggtgctgc aagccctgaa acagcttcag ctgctcaagg cccagttaga 1800cgcagctgtg accttcggcc ccagccaggt ggcccggggc gaggaccccg ccctgcagat 1860ctgctgtcat cctggctgca ccccccgccc agcttgctgc cattgcccag atccccatgc 1920ctgagggccc ctcggctggc ctgggcatgt gatggctcct cactgggagc ctgtggggga 1980ggctcaggtg tctggagggg gtttgtgcct gataacgtaa taacaccagt ggagacttgc 2040agatgtgaca attcgtccaa tcctggggta atgctgtgtg ctggtgccgg tcccctgtgg 2100tacgaatgag gaaactgagg tgcagagagg ttcaggactt gtacaagatc acccagccag 2160aaagaggttg ggctgggatt tgaaccctgg tgtcgtggct ctggaagctg ccctggcgcc 2220ttggtgatct gcgtgggtca gtgcacacag gcacacgtca gcctcaagga catgggcaca 2280tctgttcaca ggagcagcgc cacgtgcctt tgagtgccag gaacggggtg ggagggtggg 2340agggtgtgag ggccagaaga ctcagaagat gcaaagtgcc tgagagagac gggatattcc 2400cccagaagaa gcattcttag agacacaggc actggacctc cttggttctt ataagaaacc 2460tgtctgaagc tgggtgatga gttgcacact ccaggtgggg ctaaggggcc tggagcccct 2520gctggctcct aggaaggcac agcagcaggc cctgagacgg ctcctctggg gcccctccac 2580cctcccaggc ctctgcattt cacctgtgcc cacacttctg tctcctgcct tcaccttttg 2640acccactact aacgattctc cacccagcag acaaagtgat ctcttaaaaa tatctgttgg 2700ctgggcacgg tggctcacgc ctgtaatccc agcactttag gaagccgagg cgggtggatc 2760acctgaggtc gggagttcga gaccagcctg accaacatgg agaaacccca tctctactaa 2820aaatacaaaa ttagccaggt gtagtggtgc atccctgtaa tcccagctac ttgggagtct 2880gaggctggag aatcacttga acctgggagg cggtggttgc agtgagccga gatcgcacca 2940ttgcactcca gcctgggcaa caagagaaaa actctgtctc aaaaaacaaa aaatctgtta 3000ggctgcacac ggcgattcac tcctgtattc ccagtgcttt gggaggctga ggtgagagga 3060tgcctgaggc caggaattca gaccagcctg ggcaacatag tgagacccca gctctaaaga 3120tttgtttttg tttttttttt tttttttttt tttttttttt tttttttttt gagacggagt 3180ctcgctctgt cgcccaggct agagtgcagt ggtaccatct ccgctcactg caacctccgc 3240ctcccgggtt ccagggattc tcctgcctca gcctccctag tagctggaac tacaggtgtg 3300tgctgccatg cccagctaat ttttttttat ttaatagaga caagatttca ccatgttggc 3360caggctggtc tcaaactcct gacctcaggt gatccacccg cctcagcctc ccaaagtgct 3420gggattacag gtgtgaacca ccacacctgg ccaacaatat ttgttttaat tagccaggcg 3480tggtagcatt tgtcctagca atttgggagg ttgaggtggg agaatcactt cagcccacta 3540ggtcgaggct gtagtgagct ataattgtac cactgcactc cagcctcggg gacagagtga 3600gaccctgtct gcaaataaac aaataaaaca tcaggctggg cttgagcatc tattcctgct 3660caaaatttcg caggcttctc agaagaaaat ccaaacccct tacagtgacc cagtttgccc 3720ttgaggcctc cacccacacc cccttccccc cagtcttagg gggtggcctg gctgttccct 3780tcaacggcaa cgctctgcct ccattgttgg cctcctctgc agggagggac tgtctgagca 3840cctgcccgtg tctgtgcagc atggcacact gacgtcaggc ccacgtgcat gcccaggtgg 3900ccagtcacac gccaggtgct ccctcagtgt tggccaagtg agaggagcac accttccggg 3960cgttcagaca cctccccgtg gcagacaccg ttcgttgcta ccaaacagcc acctccttcc 4020taatgggctc ccatttttca gtgctgggca aaggtccctt gatcttggag ttgcagcctc 4080tttctctcca aggagggcgg tgaccagcct gagccagtca atccagtgat tggttcagga 4140gtagcctgtg accaggagtc ctggtagtga acgactgggg cagccctggg ggtgaggacc 4200ttgcgcagcc gtcacaggcc ctgattggac actgggcagc tgctaaccca gtgtctccag 4260ctgcctacct ggagagctcc aagcgtaaga aaataaaccc tgcctgttga agccaaaaaa 4320aaaaa 432514509PRTHomo sapiens 14Met Ser Met Gly Ala Pro Arg Ser Leu Leu Leu Ala Leu Ala Ala Gly 1 5 10 15 Leu Ala Val Ala Arg Pro Pro Asn Ile Val Leu Ile Phe Ala Asp Asp 20 25 30 Leu Gly Tyr Gly Asp Leu Gly Cys Tyr Gly His Pro Ser Ser Thr Thr 35 40 45 Pro Asn Leu Asp Gln Leu Ala Ala Gly Gly Leu Arg Phe Thr Asp Phe 50 55 60 Tyr Val Pro Val Ser Leu Cys Thr Pro Ser Arg Ala Ala Leu Leu Thr 65 70 75 80 Gly Arg Leu Pro Val Arg Met Gly Met Tyr Pro Gly Val Leu Val Pro 85 90 95 Ser Ser Arg Gly Gly Leu Pro Leu Glu Glu Val Thr Val Ala Glu Val 100 105 110 Leu Ala Ala Arg Gly Tyr Leu Thr Gly Met Ala Gly Lys Trp His Leu 115 120 125 Gly Val Gly Pro Glu Gly Ala Phe Leu Pro Pro His Gln Gly Phe His 130 135 140 Arg Phe Leu Gly Ile Pro Tyr Ser His Asp Gln Gly Pro Cys Gln Asn 145 150 155 160 Leu Thr Cys Phe Pro Pro Ala Thr Pro Cys Asp Gly Gly Cys Asp Gln 165 170 175 Gly Leu Val Pro Ile Pro Leu Leu Ala Asn Leu Ser Val Glu Ala Gln 180 185 190 Pro Pro Trp Leu Pro Gly Leu Glu Ala Arg Tyr Met Ala Phe Ala His 195 200 205 Asp Leu Met Ala Asp Ala Gln Arg Gln Asp Arg Pro Phe Phe Leu Tyr 210 215 220 Tyr Ala Ser His His Thr His Tyr Pro Gln Phe Ser Gly Gln Ser Phe 225 230 235 240 Ala Glu Arg Ser Gly Arg Gly Pro Phe Gly Asp Ser Leu Met Glu Leu 245 250 255 Asp Ala Ala Val Gly Thr Leu Met Thr Ala Ile Gly Asp Leu Gly Leu 260 265 270 Leu Glu Glu Thr Leu Val Ile Phe Thr Ala Asp Asn Gly Pro Glu Thr 275 280 285 Met Arg Met Ser Arg Gly Gly Cys Ser Gly Leu Leu Arg Cys Gly Lys 290 295 300 Gly Thr Thr Tyr Glu Gly Gly Val Arg Glu Pro Ala Leu Ala Phe Trp 305 310 315 320 Pro Gly His Ile Ala Pro Gly Val Thr His Glu Leu Ala Ser Ser Leu 325 330 335 Asp Leu Leu Pro Thr Leu Ala Ala Leu Ala Gly Ala Pro Leu Pro Asn 340 345 350 Val Thr Leu Asp Gly Phe Asp Leu Ser Pro Leu Leu Leu Gly Thr Gly 355 360 365 Lys Ser Pro Arg Gln Ser Leu Phe Phe Tyr Pro Ser Tyr Pro Asp Glu 370 375 380 Val Arg Gly Val Phe Ala Val Arg Thr Gly Lys Tyr Lys Ala His Phe 385 390 395 400 Phe Thr Gln Gly Ser Ala His Ser Asp Thr Thr Ala Asp Pro Ala Cys 405 410 415 His Ala Ser Ser Ser Leu Thr Ala His Glu Pro Pro Leu Leu Tyr Asp 420 425 430 Leu Ser Lys Asp Pro Gly Glu Asn Tyr Asn Leu Leu Gly Gly Val Ala 435 440 445 Gly Ala Thr Pro Glu Val Leu Gln Ala Leu Lys Gln Leu Gln Leu Leu 450 455 460 Lys Ala Gln Leu Asp Ala Ala Val Thr Phe Gly Pro Ser Gln Val Ala 465 470 475 480 Arg Gly Glu Asp Pro Ala Leu Gln Ile Cys Cys His Pro Gly Cys Thr 485 490 495 Pro Arg Pro Ala Cys Cys His Cys Pro Asp Pro His Ala 500 505 156076DNAHomo sapiens 15aaaagtgaat acatgatttt atttaactca ttaataagga aattggtaag gtgttaaaac 60caattcaaag gacaatccaa agaacagatc aggaatacta aaataaatat gcaagcggag 120gtgaaactgt tttccttggt agtggtggag gggaaggatt gctactccgc tggataaagt 180tcatttgtgt atatataaat aagaattatt ttccattgtt atttatctat aacttataaa 240gttgtaaaca acttccacgg aatcagactc aacctggaag ggtatggtct ctaggcaatg 300caaaaatttt cccctacacc tgttaacaac tataatatct ccagacagag tagacagaaa 360gtctggatgg caacgggaat ctactggtca tacggctaac ttcctaattc aataagcacg 420tgactaaagg attttttcct tccactcaga tatttcaggc taactagata ctgtgtgctt 480cttagtgtca ctgcttagtg ggggagccag ctctgagtgg ggtcatatcc ggacaagcga 540atgagctatt tattcaatga ccacgcaaca ctccaaatcc tcccagggca acttgaaagt 600aaccgcacct tccaaagggc accgtgcaat cagactgtgt gtttggcctc ctgtttgcta 660gtggggagga agcggcttca tgggtgtaca ctacgcataa atgaatgtga aaggctattt 720agacctctgc cttttcaccg tcctcccacc tgccacaggc tgggctcttg tgctagaaat 780gacttgctag ctagacatca tggttcagga tctgagtcag aggtttaacc atttataagc 840ttttttctta tgaaaaattg gcactaatta taatgtctaa ctgtcagagt tgttgcaggc 900tttacaggag acgcgggctg tgaagatgct ttgtaaattg tgaagcgtta ttaaagaaca 960catctttttt ttttaggaaa ccacagtgca aatttaattg ccggggaaga taacgggcct 1020tggtgccctc caagcgtcag

ctgagtttcc aagaagccgg gcagcgggcg cccgcgggtt 1080cgtctctggc tcctcctccg ccacagcagc cgggggcccg ggtcggaggc ggcgggggcc 1140gagcgcccgg cctcgcaagc ccacggcccg ctgggggtgc cgtcccgcgc cggggcggag 1200caggccccgg cagcccagtt cctcattcta tcagcggtac aaggggctgg tggcgccaca 1260ggcgctggga ccgcgggcgg acaaggatgg gtccgcgcgg cgcggcgagc ttgccccgag 1320gccccggacc tcggcggctg ctcctccccg tcgtcctccc gctgctgctg ctgctgttgt 1380tggcgccgcc gggctcgggc gccggggcca gccggccgcc ccacctggtc ttcttgctgg 1440cagacgacct aggctggaac gacgtcggct tccacggctc ccgcatccgc acgccgcacc 1500tggacgcgct ggcggccggc ggggtgctcc tggacaacta ctacacgcag ccgctgtgca 1560cgccgtcgcg gagccagctg ctcactggcc gctaccagat ccgtacaggt ttacagcacc 1620aaataatctg gccctgtcag cccagctgtg ttcctctgga tgaaaaactc ctgccccagc 1680tcctaaaaga agcaggttat actacccata tggtcggaaa atggcacctg ggaatgtacc 1740ggaaagaatg ccttccaacc cgccgaggat ttgataccta ctttggatat ctcctgggta 1800gtgaagatta ttattcccat gaacgctgta cattaattga cgctctgaat gtcacacgat 1860gtgctcttga ttttcgagat ggcgaagaag ttgcaacagg atataaaaat atgtattcaa 1920caaacatatt caccaaaagg gctatagccc tcataactaa ccatccacca gagaagcctc 1980tgtttctcta ccttgctctc cagtctgtgc atgagcccct tcaggtccct gaggaatact 2040tgaagccata tgactttatc caagacaaga acaggcatca ctatgcagga atggtgtccc 2100ttatggatga agcagtagga aatgtcactg cagctttaaa aagcagtggg ctctggaaca 2160acacggtgtt catcttttct acagataacg gagggcagac tttggcaggg ggtaataact 2220ggccccttcg aggaagaaaa tggagcctgt gggaaggagg cgtccgaggg gtgggctttg 2280tggcaagccc cttgctgaag cagaagggcg tgaagaaccg ggagctcatc cacatctctg 2340actggctgcc aacactcgtg aagctggcca ggggacacac caatggcaca aagcctctgg 2400atggcttcga cgtgtggaaa accatcagtg aaggaagccc atcccccaga attgagctgc 2460tgcataatat tgacccgaac ttcgtggact cttcaccgtg tcccaggaac agcatggctc 2520cagcaaagga tgactcttct cttccagaat attcagcctt taacacatct gtccatgctg 2580caattagaca tggaaattgg aaactcctca cgggctaccc aggctgtggt tactggttcc 2640ctccaccgtc tcaatacaat gtttctgaga taccctcatc agacccacca accaagaccc 2700tctggctctt tgatattgat cgggaccctg aagaaagaca tgacctgtcc agagaatatc 2760ctcacatcgt cacaaagctc ctgtcccgcc tacagttcta ccataaacac tcagtccccg 2820tgtacttccc tgcacaggac ccccgctgtg atcccaaggc cactggggtg tggggccctt 2880ggatgtagga tttcagggag gctagaaaac ctttcaattg gaagttggac ctcaggcctt 2940ttctcacgac tcttgtctca tttgttatcc caacctgggt tcacttggcc cttctcttgc 3000tcttaaacca caccgaggtg tctaatttca acccctaatg catttaagaa gctgataaaa 3060tctgcaacac tcctgctgtt ggctggagca tgtgtctaga ggtgggggtg gctgggttta 3120tccccctttc ctaagccttg ggacagctgg gaacttaact tgaaatagga agttctcact 3180gaatcctgga ggctggaaca gctggctctt ttagactcac aagtcagacg ttcgattccc 3240ctctgccaat agccagtttt attggagtga atcacatttc ttacgcaaat gaagggagca 3300gacagtgatt aatggttctg ttggccaagg cttctccctg tcggtgaagg atcatgttca 3360ggcactccaa gtgaaccacc cctcttggtt caccccttac tcacttatct catcacagag 3420cataaggccc attttgttgt tcaggtcaac agcaaaatgc ctgcaccatg actgtggctt 3480ttaaaataaa gaaatgtgtt tttatcgtaa tttatttccc cccagccatt gctcactctg 3540tctagacttc ctgccacttc caattcttct gtggcttttc ctgcctttcc ttttgacctc 3600agtagtccta tccctgggaa ggccactttg cttctctacc tgagcacccc tgatttctgg 3660aacgctgctg agccctgcct tacttttgcc cctagggctg aagctagagg cctccccgta 3720ataggcggtg gagttgctct gtgaggatgt tcatggtaga cactaagagg gctgggtggg 3780agatgcttgg ctctgtggca tctgttcagc gaggcttttc ctatattgca tggagttagt 3840cattgtgatt gtagctttat ttcataatat attaagactt gcactgctat ttactagcag 3900tgagaagaaa cctcaggaaa ggatatgaaa aagcaagtgg ccagtgtctg ggatactggg 3960ccttggtaaa gcagaggagg gcacacccac agtcctctta ttctctgttt tactgcttgt 4020tttgaggttc tggggtctgg caaagaggat gcagtttgac acctgcagcc ctttctcaat 4080cccactaatg tcttactaat gtggaacagt ccatattagc tccagagagt gtcaaaccca 4140gagaaatgtg tgcaaaaatg atactctttt ctgcattagc cccaccattg tgttcaccaa 4200tgcttggaac actgcctgaa ggcactcatt ttttaatttt tattttattt ttaatttttt 4260atatctttat gagacgatct cactctgtca ccaggttgga gtacagtggt acaatcacaa 4320ctcaccgtag cctcaaactc ctgggctcaa gtgattctcc cacctcaggc acccaaatag 4380ctggaactac aggcatatac cgccacaccc agctaatttt attttttgaa aagacaaggt 4440tccctatgtt gcccagctgg tcttaaactc ctgggctcca gcaattatcc cagcttgggc 4500tccaaaagtg ctgggattac aggcatgagt caccatgcct ggcctcattt tttaaaacaa 4560atgaataaat ggacaaatga gtaaatgaga aagtctcaca ccatgaaaga tgctagtcca 4620atgagctgaa tacagaggta atataaatgt cttccagctg ttgcttttct gttctcaagc 4680tgcccctcct ggggtaggag cataatctac atcactgggc agtcacagga cactctatag 4740caaggttgta gcgtcctctc cagtgggggg agaaaaggaa ctgtgcctac caaaggtact 4800ctcttgtcag caatttccat ttctatactt tatgggacac tagaaactaa aagcaacaaa 4860taatctgata taagtccttg tatagtcatc cttcaattca gtagcaatat tttctggtca 4920ctactaacct gtattgtatt aaaatgagac tattggaagg aaatggtgct aaaactaata 4980acatctctta ccaaccttta cccaactcct gggttggcaa acagctgacc aaactgccat 5040cacctcccac ttggaagtgt atggccgaca gcatgaaata gctgagccca gatgttcctt 5100ctgcatcctc cgaatcccag ggctgggtgt aggtagccgt tggaggccat cgctacaggg 5160cacctatctg ttatcgctgc tgtcctccca acagctgtct ccagttctag ttccttggtt 5220ttcaggcaca gtgggggatg ttctgcaccc agtggacttc aaaagagttt tgaagactta 5280attttttgta aaacaagtac ttgagatttt ggtttatcca taatagaatg tatttcatta 5340gattctctga ttctatataa gaatgtgaaa agattgatat attgttgtta gaaataatgt 5400tatttctttc caattttttt tttttttttt tttgagatgg agtctcgctc tgtcacccag 5460gctggagtgc agtggtgtga tctcggctca ctgcagcctc taactcccag gttcaagcta 5520ttctcctgcc tcagcctccc aagtagctgg attacaggca tacaccacca cgcctggcta 5580tgttttgtat ttttcgtaga gatagggttt caccatgttg gccaggctgg tctcaaactc 5640ctgacctcaa gtgatccacc cacttcagct tcccaaagca ctgggattac aggtgtgagc 5700cactgtgccc ggcaaatttt tttaccttta cagaaggttt tgcttattta attgtgagct 5760catttttctt tgttactttt gtccccccag atttggggga caaaataaaa ttaatctttt 5820aaaatgtgtc agccatatgt atggggcttc catttggggt gaggagaaag ttctggaact 5880agatagtggt catggttata caacatcata aatgcaatta ctgccactga attgtatgtt 5940ttaaagtggt taaaatgtta agttttatgt tttattacaa tttttaaatg tgtcaaccaa 6000ctttatagta cataaattat atctcagtaa agctgttaaa taaataaata tagtaaaaat 6060tttagaacta aaaaaa 607616533PRTHomo sapiens 16Met Gly Pro Arg Gly Ala Ala Ser Leu Pro Arg Gly Pro Gly Pro Arg 1 5 10 15 Arg Leu Leu Leu Pro Val Val Leu Pro Leu Leu Leu Leu Leu Leu Leu 20 25 30 Ala Pro Pro Gly Ser Gly Ala Gly Ala Ser Arg Pro Pro His Leu Val 35 40 45 Phe Leu Leu Ala Asp Asp Leu Gly Trp Asn Asp Val Gly Phe His Gly 50 55 60 Ser Arg Ile Arg Thr Pro His Leu Asp Ala Leu Ala Ala Gly Gly Val 65 70 75 80 Leu Leu Asp Asn Tyr Tyr Thr Gln Pro Leu Cys Thr Pro Ser Arg Ser 85 90 95 Gln Leu Leu Thr Gly Arg Tyr Gln Ile Arg Thr Gly Leu Gln His Gln 100 105 110 Ile Ile Trp Pro Cys Gln Pro Ser Cys Val Pro Leu Asp Glu Lys Leu 115 120 125 Leu Pro Gln Leu Leu Lys Glu Ala Gly Tyr Thr Thr His Met Val Gly 130 135 140 Lys Trp His Leu Gly Met Tyr Arg Lys Glu Cys Leu Pro Thr Arg Arg 145 150 155 160 Gly Phe Asp Thr Tyr Phe Gly Tyr Leu Leu Gly Ser Glu Asp Tyr Tyr 165 170 175 Ser His Glu Arg Cys Thr Leu Ile Asp Ala Leu Asn Val Thr Arg Cys 180 185 190 Ala Leu Asp Phe Arg Asp Gly Glu Glu Val Ala Thr Gly Tyr Lys Asn 195 200 205 Met Tyr Ser Thr Asn Ile Phe Thr Lys Arg Ala Ile Ala Leu Ile Thr 210 215 220 Asn His Pro Pro Glu Lys Pro Leu Phe Leu Tyr Leu Ala Leu Gln Ser 225 230 235 240 Val His Glu Pro Leu Gln Val Pro Glu Glu Tyr Leu Lys Pro Tyr Asp 245 250 255 Phe Ile Gln Asp Lys Asn Arg His His Tyr Ala Gly Met Val Ser Leu 260 265 270 Met Asp Glu Ala Val Gly Asn Val Thr Ala Ala Leu Lys Ser Ser Gly 275 280 285 Leu Trp Asn Asn Thr Val Phe Ile Phe Ser Thr Asp Asn Gly Gly Gln 290 295 300 Thr Leu Ala Gly Gly Asn Asn Trp Pro Leu Arg Gly Arg Lys Trp Ser 305 310 315 320 Leu Trp Glu Gly Gly Val Arg Gly Val Gly Phe Val Ala Ser Pro Leu 325 330 335 Leu Lys Gln Lys Gly Val Lys Asn Arg Glu Leu Ile His Ile Ser Asp 340 345 350 Trp Leu Pro Thr Leu Val Lys Leu Ala Arg Gly His Thr Asn Gly Thr 355 360 365 Lys Pro Leu Asp Gly Phe Asp Val Trp Lys Thr Ile Ser Glu Gly Ser 370 375 380 Pro Ser Pro Arg Ile Glu Leu Leu His Asn Ile Asp Pro Asn Phe Val 385 390 395 400 Asp Ser Ser Pro Cys Pro Arg Asn Ser Met Ala Pro Ala Lys Asp Asp 405 410 415 Ser Ser Leu Pro Glu Tyr Ser Ala Phe Asn Thr Ser Val His Ala Ala 420 425 430 Ile Arg His Gly Asn Trp Lys Leu Leu Thr Gly Tyr Pro Gly Cys Gly 435 440 445 Tyr Trp Phe Pro Pro Pro Ser Gln Tyr Asn Val Ser Glu Ile Pro Ser 450 455 460 Ser Asp Pro Pro Thr Lys Thr Leu Trp Leu Phe Asp Ile Asp Arg Asp 465 470 475 480 Pro Glu Glu Arg His Asp Leu Ser Arg Glu Tyr Pro His Ile Val Thr 485 490 495 Lys Leu Leu Ser Arg Leu Gln Phe Tyr His Lys His Ser Val Pro Val 500 505 510 Tyr Phe Pro Ala Gln Asp Pro Arg Cys Asp Pro Lys Ala Thr Gly Val 515 520 525 Trp Gly Pro Trp Met 530 176377DNAHomo sapiens 17tccgcctcac attatctgcc caagcacagt gctgttggcc aagcctccag cagctgacgg 60gacccagctg tagtgaggtt gcagtgattg agtaggattg gcctgcttca aagcagaggt 120ttctcatggg aatatgctta ttaaactccc actggtgcag aaaccatgaa cagaggatga 180acaagtgaag ttgcaatctc ctccatcaca gctcagttcc ccaacaacag gatcacaagc 240tggagatgcc tttaaggaag atgaagatcc ctttcctcct actgttcttt ctgtgggaag 300ccgagagcca cgcagcatca aggccgaaca tcatcctggt gatggctgac gacctcggca 360ttggagatcc tgggtgctat gggaacaaaa ctatcaggac tcccaatatc gaccggttgg 420ccagtggggg agtgaaactc actcagcacc tggcagcatc accgctgtgc acaccaagca 480gggcagcctt catgactggc cggtaccctg tccgatcagg aatggcatct tggtcccgca 540ctggagtttt cctcttcaca gcctcttcgg gaggacttcc caccgatgag attacctttg 600ctaagcttct gaaggatcaa ggttattcaa cagcactgat agggaaatgg caccttggga 660tgagctgtca cagcaagact gacttctgtc accacccttt acatcacggc ttcaattatt 720tctatgggat ctctttgacc aatctgagag actgcaagcc cggagagggc agtgtcttca 780ccacgggctt caagaggctg gtcttcctcc ccctgcagat cgtcggggtc accctcctta 840cccttgctgc actcaattgt ctggggctac tccacgtgcc tctaggcgtt tttttcagcc 900ttctcttcct agcagcccta atcctgaccc ttttcttggg cttccttcat tacttccggc 960ccctgaactg cttcatgatg aggaactacg agatcattca gcagcccatg tcctatgaca 1020atctcaccca gaggctaacg gtggaggcgg cccagttcat acagcggaac actgagactc 1080cgttcctgct tgtcttgtcc tacctccacg tgcacacagc cctgttctcc agcaaagact 1140ttgctggcaa aagtcaacac ggagtctacg gggatgctgt tgaggaaatg gactggagtg 1200tggggcagat cttgaacctt ctggatgagc tgagattggc taatgatacc ctcatctact 1260tcacatcgga ccagggagca catgtagaag aagtgtcttc caaaggagaa attcatggcg 1320gaagtaatgg gatctataaa ggaggaaaag caaacaactg ggaaggaggt atccgggttc 1380caggcatcct tcgttggccc agggtgatac aggctggcca gaagattgat gagcccacta 1440gcaacatgga catatttcct acagtagcca agctggctgg agctcccttg cctgaggaca 1500ggatcattga tggacgtgat ctgatgcccc tgcttgaagg aaaaagccaa cgctccgatc 1560atgagtttct cttccattac tgcaacgcct acttaaatgc tgtgcgctgg caccctcaga 1620acagcacatc catctggaag gcctttttct tcacccccaa cttcaacccc gtgggttcca 1680acggatgctt tgccacacac gtgtgcttct gtttcgggag ttatgtcacc catcacgacc 1740cacctttact ctttgatatt tccaaagatc ccagagagag aaacccacta actccagcat 1800ccgagccccg gttttatgaa atcctcaaag tcatgcagga agctgcggac agacacaccc 1860agaccctgcc agaggtgccc gatcagtttt catggaacaa ctttctttgg aagccctggc 1920ttcagctgtg ctgtccttcc accggcctgt cttgccagtg tgatagagaa aaacaggata 1980agagactgag ccgctagcag cgcctgggga ccagacagac gcatgtggca aagctcacca 2040tcttcactac aaacacgcct gagagtggca ctggggaaac ataactccat ctacaccttg 2100gatttggact gattctccat tttatcacct gaaggcttgg gccagagctc aacagctact 2160caactggagg ggtgaggggg ataaggtctg tagtatacag acaggaagat ggtaggttta 2220tgccttctgt ggccagagtc ttggactcat ggaaatagaa tgaatagagg ggcattcaca 2280aggcacacca gtgcaagcag atgacaaaaa ggtgcagaag gcaatcttaa aacagaaagg 2340tgcaggaggt accttaactc acccctcagc aaatacctat gtcaacagta taagttacca 2400tttactctat aatctgcagt gatgcaataa ccagcataat aaaaaggcaa tcacataaaa 2460aagagtttag tcgtctaaac ataagtaact ttaaggtgaa tgaaagatct tctttaggaa 2520taatagatga tggtaagttc cactttggtt attggaaggc aagtcattat tactggtatt 2580agttaaaaca catatcaaat gcttgctctt catcatatat atagttatgc atacatacac 2640acacacacat acagtatatt ctttcctcaa aagggttaag atgtctaaaa tagggaccta 2700gaagcttaac actatttaag taaatacagt agaagctcac aaatagattt ctttgcacaa 2760tgattttttg caaaatttta cagtaataat aatcccaagg caaatctctc ctgaactgct 2820ttccattcca taatttgtag tataattctt ggattccact gttttctttg gggaatggaa 2880gttctgaatt aaaagcccac tgtggagatg ctgtggttca tggaatctct tccagtgtaa 2940ttcagaatca ttggcctaga aagtctctga tatttggagg ggaacaaaaa tcactcacaa 3000gcaatccatg atctatacac ataagcataa tttcctttag ttctagttag tcatcagaga 3060acagtcatgt atgcaagttt tgtgactgag aaatttctgt gcttccaatc cacaatgaga 3120tgcatgattt tgttttcatc ccatttcccc caagcccctg taaatcaggg aaaatgcgca 3180actgatcgcc taggagaggg cctcgtagtg gcacagctgg agatagtttc aaagtctaaa 3240ccaccagccc atcctgagga aagcctccta tggaatgtaa agtgcaatca tttcttcaga 3300tataagactt tccccaacaa tgtgattgga ttcctttatg gcaaaatcga gagaagctgc 3360catccacctg cttatgcatt tatctctttt gtggacttgt ctgaccacct tctatttgcc 3420cagagtttgc tcaattccaa gacagtgccc atgaatggga cacctgtaat gtaacccaca 3480cagcggtttg cagagaatgt tagccatgac ttgggctttc tgaaagttgg ctataatttc 3540tctatcccta cccacaaccc tgggaagttg gagcaagagg ggcatactat tgggctggga 3600ggatttgaca gcatttcccc agttgccctt taagttcttc tatttcaaac gttaattttg 3660cttctctttc taaaaaaaaa aaaaaaaaag aaagagaaga aagaagtgat tcctaccccc 3720tacctccaga gttgttgaaa gctgaaaagc atacaagatt cttcctttta acttggattt 3780ctcgttccag aaattgtggg ataatctgta ttcttgcttt agaaaacatt cttagagagg 3840gtactagctt actgatgatg tgttaggatt gctactgatg ctgtcatgtg gaaactattt 3900aaaggcacta ttataaattt atcctataag atgacaatgt ttactcaaag tctaacatat 3960tcaatgcaag taagactttc tgaaaacact tgatgatgtg gaaatgctgc aggattaaat 4020aacttgaaga gcctttatag attatatgaa tgcctatttg tgtctagaac cagttattta 4080acctgtaaaa tgtcaatagc aaatgaagga tgaagtatat ctctagatgc aaatacattg 4140agtttaaaag tgcctcaaaa taattgagat cacatttcag gacatttgga aatcaggtcg 4200atttgtggta actgtagtca tcttaaattt caaaccattt accatctgaa agttttgatt 4260tgaatgtaaa acaggaaatt ggaattcctt tgtccaggag aaacctcaca aaccttcttt 4320aaggcatagt tttgttgttt gtttgcttgt ttgttgcagg ctgtaaggca tggctgcttg 4380tttacaaagc atctcattca tattacctgt ggagttgcat atccaaacct tagtgagttt 4440tgaagcttta agcaaattct tttaaaaaat tcttgtattt ctagcattac tagatattaa 4500aagttaagca aatagattaa tgacgtatac ataggcatca tttcacaagg tcagtaatgc 4560tgcaggaaaa gcaaaattgc aatctacgta tctatggtac taaggaagtc ctgtttttca 4620aaaatggaag cccacttctc agatttttct gaagggcata caatgaaaag tgaaggggaa 4680acacacacac acaaaaaaac aagtatttgg cttgtcacag gaatctgatt gcattaagtg 4740aaaggattat ttagaatatg ttaatgcaaa gctaaaataa aattttcctt ggcaattaaa 4800aatgctgtgc gctaataccc tgctttctat cgtgactcaa ttcaacaatg tggggaatgt 4860ttactacatt tccaacttga tgtcaagcaa tggggaatac aagttccagt tctgcaaaga 4920ttcgtcaact ttcttagctc aagagagagg ctgagaaatg cagagaagaa taagacataa 4980aatagctccg acctccatga tccgagagtg ggaaaaggcc cgattattac ccataaggca 5040cactctctaa ggccttttaa ggggcctaca aaaatgtttt attttataat cagaagaaaa 5100ggaaatgaac attggggatt gaaaatcata ttggtatttg caccaacata gtcataaaat 5160agtatgttaa tatgttttta ctttatatat ttatatatta aaatatattt aatatgtttt 5220gcctttgtgg cccatgaaag tcttactggg ccctggggaa ggtatcctac cctggtgaag 5280cagctgcttt gctctacaaa tacctggggc agaaatttga tttgaaaagt attattctct 5340cttctctttg tttcaactgg attcctttgg aaaaccaaac tagtatcaga acaaaccccg 5400aaacagtaag aaattggagt gagaagggca tggtattggg actaggatcg gctctcattc 5460gatcgagcta ttctcttaaa atgacaaaaa gtgtccataa agaggctgct ggagagtgcg 5520tggccatagg gagccgacat gcccgggagg aaaggtgttg attacatgga tacttctaaa 5580agctaaagcc ttgttgcctt ctctttaatg cctagagaat gggatgtgtg atgcaaatgc 5640tcaaaacctc ttaaatcata gctgtctgac ctctacggac ctcacatcca tctgaggctt 5700catggacaaa gattctccac ttggccaaac tttagccaag ctcctcaacc ttctcccagg 5760cccaatctgg gcacttcctt gtaaaatcta gttttggcaa gaagtctatt aggtcagttt 5820agcaagaaca cctaaccccc ccatatctgt tcaacctcag tatctgatca ggctcctcag 5880cctccaccat cccccaggtg atgtctggtc aactggcctg ccttcagcta gaatcctgtt 5940aggtcggttt agatgaatgc tccctgatat ttcctcttgg taatcttcca tccactgccc 6000ctgaccctgt tccctgtcta taaatcccca gttttccatg gtgtattcag agctgagtcc 6060agtctctctc ccctactaca agtccccatt gctgtggtcc ccgtacctgt catgatggtc 6120ctaaataaag tcttactgtg ctttaatagg tagcattgaa aaattttttt ctttgacatc 6180attcatgaca acatgaaacc tattgggaca gcatgactgt gcagggtctt tagagctcag 6240ctttctgagg ccctgagcat tcttggtttt ccgacatcgt gaacctgttc tgtgttgcaa 6300gatatcactc aagccagtgt tgcttaatac catctctttg tgtaatagat ctgaataaag 6360taattgtaat acaccaa 637718583PRTHomo sapiens 18Met Pro Leu Arg Lys Met

Lys Ile Pro Phe Leu Leu Leu Phe Phe Leu 1 5 10 15 Trp Glu Ala Glu Ser His Ala Ala Ser Arg Pro Asn Ile Ile Leu Val 20 25 30 Met Ala Asp Asp Leu Gly Ile Gly Asp Pro Gly Cys Tyr Gly Asn Lys 35 40 45 Thr Ile Arg Thr Pro Asn Ile Asp Arg Leu Ala Ser Gly Gly Val Lys 50 55 60 Leu Thr Gln His Leu Ala Ala Ser Pro Leu Cys Thr Pro Ser Arg Ala 65 70 75 80 Ala Phe Met Thr Gly Arg Tyr Pro Val Arg Ser Gly Met Ala Ser Trp 85 90 95 Ser Arg Thr Gly Val Phe Leu Phe Thr Ala Ser Ser Gly Gly Leu Pro 100 105 110 Thr Asp Glu Ile Thr Phe Ala Lys Leu Leu Lys Asp Gln Gly Tyr Ser 115 120 125 Thr Ala Leu Ile Gly Lys Trp His Leu Gly Met Ser Cys His Ser Lys 130 135 140 Thr Asp Phe Cys His His Pro Leu His His Gly Phe Asn Tyr Phe Tyr 145 150 155 160 Gly Ile Ser Leu Thr Asn Leu Arg Asp Cys Lys Pro Gly Glu Gly Ser 165 170 175 Val Phe Thr Thr Gly Phe Lys Arg Leu Val Phe Leu Pro Leu Gln Ile 180 185 190 Val Gly Val Thr Leu Leu Thr Leu Ala Ala Leu Asn Cys Leu Gly Leu 195 200 205 Leu His Val Pro Leu Gly Val Phe Phe Ser Leu Leu Phe Leu Ala Ala 210 215 220 Leu Ile Leu Thr Leu Phe Leu Gly Phe Leu His Tyr Phe Arg Pro Leu 225 230 235 240 Asn Cys Phe Met Met Arg Asn Tyr Glu Ile Ile Gln Gln Pro Met Ser 245 250 255 Tyr Asp Asn Leu Thr Gln Arg Leu Thr Val Glu Ala Ala Gln Phe Ile 260 265 270 Gln Arg Asn Thr Glu Thr Pro Phe Leu Leu Val Leu Ser Tyr Leu His 275 280 285 Val His Thr Ala Leu Phe Ser Ser Lys Asp Phe Ala Gly Lys Ser Gln 290 295 300 His Gly Val Tyr Gly Asp Ala Val Glu Glu Met Asp Trp Ser Val Gly 305 310 315 320 Gln Ile Leu Asn Leu Leu Asp Glu Leu Arg Leu Ala Asn Asp Thr Leu 325 330 335 Ile Tyr Phe Thr Ser Asp Gln Gly Ala His Val Glu Glu Val Ser Ser 340 345 350 Lys Gly Glu Ile His Gly Gly Ser Asn Gly Ile Tyr Lys Gly Gly Lys 355 360 365 Ala Asn Asn Trp Glu Gly Gly Ile Arg Val Pro Gly Ile Leu Arg Trp 370 375 380 Pro Arg Val Ile Gln Ala Gly Gln Lys Ile Asp Glu Pro Thr Ser Asn 385 390 395 400 Met Asp Ile Phe Pro Thr Val Ala Lys Leu Ala Gly Ala Pro Leu Pro 405 410 415 Glu Asp Arg Ile Ile Asp Gly Arg Asp Leu Met Pro Leu Leu Glu Gly 420 425 430 Lys Ser Gln Arg Ser Asp His Glu Phe Leu Phe His Tyr Cys Asn Ala 435 440 445 Tyr Leu Asn Ala Val Arg Trp His Pro Gln Asn Ser Thr Ser Ile Trp 450 455 460 Lys Ala Phe Phe Phe Thr Pro Asn Phe Asn Pro Val Gly Ser Asn Gly 465 470 475 480 Cys Phe Ala Thr His Val Cys Phe Cys Phe Gly Ser Tyr Val Thr His 485 490 495 His Asp Pro Pro Leu Leu Phe Asp Ile Ser Lys Asp Pro Arg Glu Arg 500 505 510 Asn Pro Leu Thr Pro Ala Ser Glu Pro Arg Phe Tyr Glu Ile Leu Lys 515 520 525 Val Met Gln Glu Ala Ala Asp Arg His Thr Gln Thr Leu Pro Glu Val 530 535 540 Pro Asp Gln Phe Ser Trp Asn Asn Phe Leu Trp Lys Pro Trp Leu Gln 545 550 555 560 Leu Cys Cys Pro Ser Thr Gly Leu Ser Cys Gln Cys Asp Arg Glu Lys 565 570 575 Gln Asp Lys Arg Leu Ser Arg 580 195199DNAHomo sapiens 19cccagatccc gcagctgaga gggcggaagc cttggcacta gcggcgcccg ggcgcggagt 60gcgcagggca aggtcctgcg ctctgggcca gcgctcggcc atgcgatccg ccgcgcggag 120gggacgcgcc gcgcccgccg ccagggactc tttgccggtg ctactgtttt tatgcttgct 180tctgaagacg tgtgaaccta aaactgcaaa tgcctttaaa ccaaatatcc tactgatcat 240ggcggatgat ctaggcactg gggatctcgg ttgctacggg aacaatacac tgagaacgcc 300gaatattgac cagcttgcag aggaaggtgt gaggctcact cagcacctgg cggccgcccc 360gctctgcacc ccaagccgag ctgcattcct cacagggaga cattccttca gatcaggcat 420ggacgccagc aatggatacc gggcccttca gtggaacgca ggctcaggtg gactccctga 480gaacgaaacc acttttgcaa gaatcttgca gcagcatggc tatgcaaccg gcctcatagg 540aaaatggcac cagggtgtga attgtgcatc ccgcggggat cactgccacc accccctgaa 600ccacggattt gactatttct acggcatgcc cttcacgctc acaaacgact gtgacccagg 660caggcccccc gaagtggacg ccgccctgag ggcgcagctc tggggttaca cccagttcct 720ggcgctgggg attctcaccc tggctgccgg ccagacctgc ggtttcttct ctgtctccgc 780gagagcagtc accggcatgg ccggcgtggg ctgcctgttt ttcatctctt ggtactcctc 840cttcgggttt gtgcgacgct ggaactgtat cctgatgaga aaccatgacg tcacggagca 900acccatggtt ctggagaaaa cagcgagtct tatgctaaag gaagctgttt cctatattga 960aagacacaag catgggccat ttctcctctt cctttctttg ctgcatgtgc acattcccct 1020tgtgaccacg agtgcattcc tggggaaaag tcagcatggc ttatatggtg ataatgtgga 1080ggagatggac tggctcatag gtaaggttct taatgccatc gaagacaatg gtttaaagaa 1140ctcaacattc acgtatttca cctctgacca tggaggacat ttagaggcaa gagatggaca 1200cagccagtta gggggatgga acggaattta caaaggtggg aagggcatgg gaggatggga 1260aggtgggatc cgcgtgcccg ggatcttcca ctggccgggg gtgctcccgg ccggccgagt 1320gattggagag cccacgagcc tgatggacgt gttccctact gtggtccagc tggtgggtgg 1380cgaggtgccc caggacaggg tgattgatgg ccacagcctg gtacccttgc tgcagggagc 1440tgaggcacgc tcggcacatg agttcctgtt tcattactgt gggcagcatc ttcacgcagc 1500acgctggcac cagaaggaca gtggaagcgt ctggaaggtt cattacacga ccccgcagtt 1560ccaccccgag ggagcggggg cctgctacgg ccgaggcgtc tgcccatgct ccggggaggg 1620cgtgacccat cacagacccc ctttgctctt tgacctctcc agggacccct ccgaggcacg 1680gcccctgacc cccgactccg agcccctgta ccacgccgtg atagcaaggg taggtgccgc 1740ggtgtcggag catcggcaga ccctgagtcc tgtgccccag cagttttcca tgagcaacat 1800cctgtggaag ccgtggctgc agccgtgctg cggacatttc ccgttctgtt catgccacga 1860ggatggggat ggcaccccct gaatgccagg actgtgagag aggatccagg agagcctgac 1920tgcgttgcaa acaaaattct ccaagcttgg ttctatcttc agcttccctt tttgcaagga 1980acatgccctg gactgagagt gggtccccac tttctttctt tctttctttc ttttttgaga 2040cagagtgtcg ctctgtccct caggctggaa tgcaatggca cgatctctgc tcactgcaac 2100ctccgcctcc cgggttcaag cgattttcct gcctcagcct cctgagtacc caggattaca 2160ggcaccaggc acctgccacc atgcctagct aatttttgta gttttagtag agacagggtt 2220tcaccatgtt gcccaggctg gtctcgcact cctgacctca agtcatccac ctgcctcagc 2280ctcccaaagt gctgggatta caggcacgag ccactgcgcc catgtagggt ttccctttcc 2340tgatttgtga aataagactg tcccagtagg cacccactga tgcctcctct tcctcttcta 2400aatctcaggg ttcgtcattg tgccaatgcc cgatgttttc acccctccgt cttaaagcat 2460tgttgcaatt tcatcaccta gatgacataa cagccttaca aaaggacagg gaggagtgtc 2520tgttcctact ctcacatagc ggaggaaagt tagagcctct cagtctctgt ttatgaggac 2580tcattaatct caaataattg atgcattttt catacattag ggtctctgtc catgtgtctt 2640cctgatattg ttatagaaat ggcttcaggc tgctggtaac agatgctgcg gaaaaagaat 2700gccttaaaca aagccaggca cggtgactca cacctgtaat cccagcactt tgggaggcta 2760aggtgggagg atcacttgag cctaggagtt agacacctac ccagcctgag caacacagtg 2820agacctcatc tctacaaaaa acaaataatt agctagatgt cgtggcgcac agctgtagtc 2880tcagctactt aggaggctga ggcgggagga ttatttgagc ctgggaggtc aaaactgcaa 2940tgagctaaga ttgcactact gcactccggg ctgggagaca gagtaagacc ctgccttaaa 3000aaaaaaaaaa aaaaaatgcc ttaaagaaaa taataagaga agggtgtgtt ctcttccaag 3060taatgagccg atcaagggga agcaacccaa ggctagcagg ctcttttcaa ttcccagctc 3120tgccactctt agcatggcag agagttggcc tcattatgcc agtatggctg ccacagtgtc 3180agacatcaca ttccaggcag tggaaaggag aaagaaccaa agggcatccc tttctcttga 3240agcagtccct gtgagggggg attatctgga agccccaacc caatttctgc ttccaaccat 3300tatccataga aacaactgga agttgagaag tgcagtcttt taggtgggca cctggctgcc 3360ctgtatgaaa ccagaattag gttggtcagc aggaaaacaa gaaaacactt actgtgttga 3420ctgaggtttt tgacgcatcg ctttattgtc aaattaaaca actctatctc attctgcact 3480gaaacacgta ctaccattgc ctataattgg aaaatgatcc tcagaggcac agaagatgcc 3540ctgatggaaa gtttgcccct tgggcaaaga gacagccatg ggaaccttca gacatagaga 3600gagaaggtgg cttttctccc tacattcctc aaatagctaa gatttggcca gtgtgttttc 3660taagtcaatt ctagtgtgtt tcatcctcac ctcttccctc tgtggctttg atgatggaag 3720tgtagtccta acctactgca cagctgggac cccctgcccc tagatcccaa tactggggat 3780gggaggacct tgcactattc ccctcagtcc atctatcgag gtctttgcag gaagcatact 3840gggaattgaa acgagagcct aaatgacatc taagaaaggc agtgttcaat accaggtatt 3900aggtgaggat gggattctaa ggacatcagt gggaggcagg gagccacctt cagacctcag 3960catggaagct tccaagatcc agaggaagag gcaacagcac tgagagtcat aggtagaaga 4020atcatcacag ccctgctaac caggcagctg atgcccctct cccctggctc cctgtgtcca 4080aatcctacag gggcatctgt tggctgaact caacctgaag ccaaagagaa gatgagtgga 4140gagaggcaac atttatagag ctcaggtttc tagggctgga gagggatctg gagggacaca 4200caggagacac ctggcataac caaaaaatga ttaaaaaaaa aaaaaaaaag aaacatctat 4260ggagcatggg acacggggag tggaggcagc taaaagccat ctcatctttc accgtattca 4320acaagcccat tataacaagt ctttcacgct caaccattca aacaatccca acaatcccag 4380cctaagaatt tcctggcatt tgatgaaaat ggctgtgggt tttgctatct ttaagctccc 4440tgggaagcag gatataagcc cagggctggc aggctctttc tagctacctg ctcttgcaca 4500tagagtttgc ctcatggttg caagaaggct gccatagctc cagatggcac atagacattc 4560caggcagcag gaaaaaggaa ggagcactta accgaaggag gtcagggagt tggttagtct 4620ccacctgaag aagagagcca tgaaccagct tcagttgact aacgggctcc tgtgagtgca 4680tctttggact tttctggagg ttgaaatcta gatgtggtat gtgtcttaaa gcagccacca 4740actcctccca ttaccttcca agtgagccca actacacgat ggagcctctt ccctgccctt 4800ggatctgggc tgagcctctg acttgcgttg accaacagaa tgcagtgaaa gtgatgccga 4860tactaccctc cctgccctag acttgggata cctggcagct atattcttcc attcctcagg 4920acttgcaaaa acgggtctca gcatgccttc ccagagccat gaggtgtttc tttgcccatt 4980cattgatctg agaagtgagt gtaaggagtt taaatcaacc tctgttctgt gctagttaag 5040gtaataaagt tgctgcagtc cagggggtag gtacctgtgg acggctctgc gaataggaca 5100gttgcatttc ttgggaatca agtgcatccc taggctggca gtgcagcaga aatactgaat 5160aaaatgtgac aaatctccct ggaaaaaaaa aaaaaaaaa 519920593PRTHomo sapiens 20Met Arg Ser Ala Ala Arg Arg Gly Arg Ala Ala Pro Ala Ala Arg Asp 1 5 10 15 Ser Leu Pro Val Leu Leu Phe Leu Cys Leu Leu Leu Lys Thr Cys Glu 20 25 30 Pro Lys Thr Ala Asn Ala Phe Lys Pro Asn Ile Leu Leu Ile Met Ala 35 40 45 Asp Asp Leu Gly Thr Gly Asp Leu Gly Cys Tyr Gly Asn Asn Thr Leu 50 55 60 Arg Thr Pro Asn Ile Asp Gln Leu Ala Glu Glu Gly Val Arg Leu Thr 65 70 75 80 Gln His Leu Ala Ala Ala Pro Leu Cys Thr Pro Ser Arg Ala Ala Phe 85 90 95 Leu Thr Gly Arg His Ser Phe Arg Ser Gly Met Asp Ala Ser Asn Gly 100 105 110 Tyr Arg Ala Leu Gln Trp Asn Ala Gly Ser Gly Gly Leu Pro Glu Asn 115 120 125 Glu Thr Thr Phe Ala Arg Ile Leu Gln Gln His Gly Tyr Ala Thr Gly 130 135 140 Leu Ile Gly Lys Trp His Gln Gly Val Asn Cys Ala Ser Arg Gly Asp 145 150 155 160 His Cys His His Pro Leu Asn His Gly Phe Asp Tyr Phe Tyr Gly Met 165 170 175 Pro Phe Thr Leu Thr Asn Asp Cys Asp Pro Gly Arg Pro Pro Glu Val 180 185 190 Asp Ala Ala Leu Arg Ala Gln Leu Trp Gly Tyr Thr Gln Phe Leu Ala 195 200 205 Leu Gly Ile Leu Thr Leu Ala Ala Gly Gln Thr Cys Gly Phe Phe Ser 210 215 220 Val Ser Ala Arg Ala Val Thr Gly Met Ala Gly Val Gly Cys Leu Phe 225 230 235 240 Phe Ile Ser Trp Tyr Ser Ser Phe Gly Phe Val Arg Arg Trp Asn Cys 245 250 255 Ile Leu Met Arg Asn His Asp Val Thr Glu Gln Pro Met Val Leu Glu 260 265 270 Lys Thr Ala Ser Leu Met Leu Lys Glu Ala Val Ser Tyr Ile Glu Arg 275 280 285 His Lys His Gly Pro Phe Leu Leu Phe Leu Ser Leu Leu His Val His 290 295 300 Ile Pro Leu Val Thr Thr Ser Ala Phe Leu Gly Lys Ser Gln His Gly 305 310 315 320 Leu Tyr Gly Asp Asn Val Glu Glu Met Asp Trp Leu Ile Gly Lys Val 325 330 335 Leu Asn Ala Ile Glu Asp Asn Gly Leu Lys Asn Ser Thr Phe Thr Tyr 340 345 350 Phe Thr Ser Asp His Gly Gly His Leu Glu Ala Arg Asp Gly His Ser 355 360 365 Gln Leu Gly Gly Trp Asn Gly Ile Tyr Lys Gly Gly Lys Gly Met Gly 370 375 380 Gly Trp Glu Gly Gly Ile Arg Val Pro Gly Ile Phe His Trp Pro Gly 385 390 395 400 Val Leu Pro Ala Gly Arg Val Ile Gly Glu Pro Thr Ser Leu Met Asp 405 410 415 Val Phe Pro Thr Val Val Gln Leu Val Gly Gly Glu Val Pro Gln Asp 420 425 430 Arg Val Ile Asp Gly His Ser Leu Val Pro Leu Leu Gln Gly Ala Glu 435 440 445 Ala Arg Ser Ala His Glu Phe Leu Phe His Tyr Cys Gly Gln His Leu 450 455 460 His Ala Ala Arg Trp His Gln Lys Asp Ser Gly Ser Val Trp Lys Val 465 470 475 480 His Tyr Thr Thr Pro Gln Phe His Pro Glu Gly Ala Gly Ala Cys Tyr 485 490 495 Gly Arg Gly Val Cys Pro Cys Ser Gly Glu Gly Val Thr His His Arg 500 505 510 Pro Pro Leu Leu Phe Asp Leu Ser Arg Asp Pro Ser Glu Ala Arg Pro 515 520 525 Leu Thr Pro Asp Ser Glu Pro Leu Tyr His Ala Val Ile Ala Arg Val 530 535 540 Gly Ala Ala Val Ser Glu His Arg Gln Thr Leu Ser Pro Val Pro Gln 545 550 555 560 Gln Phe Ser Met Ser Asn Ile Leu Trp Lys Pro Trp Leu Gln Pro Cys 565 570 575 Cys Gly His Phe Pro Phe Cys Ser Cys His Glu Asp Gly Asp Gly Thr 580 585 590 Pro 212220DNAHomo sapiens 21ttggtagacg tgggcgtggc tttgagattc ccccatgctg cgatgtgggg ggagtctgct 60ctgtctgtcc taactctctc tgatcttctg acttgggaaa aacaaactcg aagttaatca 120ttcccagctc aaagccttgt gcaagtgctc tctgccttca cgcttgcttc ctttgggaga 180gaaccttcct cttcttgatc ggggattcag gaaggagccc aggagcagag gaagtagaga 240gagagacaac atgttacatc tgcaccattc ttgtttgtgt ttcaggagct ggctgccagc 300gatgctcgct gtactgctaa gtttggcacc atcagcttcc agcgacattt ccgcctcccg 360accgaacatc cttcttctga tggcggacga ccttggcatt ggggacattg gctgctatgg 420caacaacacc atgaggactc cgaatattga ccgccttgca gaggacggcg tgaagctgac 480ccaacacatc tctgccgcat ctttgtgcac cccaagcaga gccgccttcc tcacgggcag 540ataccctgtg cgatcaggga tggtttccag cattggttac cgtgttcttc agtggaccgg 600agcatctgga ggtcttccaa caaatgagac aacttttgca aaaatactga aagagaaagg 660ctatgccact ggactcattg gaaaatggca tctgggtctc aactgtgagt cagccagtga 720tcattgccac caccctctcc atcatggctt tgaccatttc tacggaatgc ctttctcctt 780gatgggtgat tgcgcccgct gggaactctc agagaagcgt gtcaacctgg aacaaaaact 840caacttcctc ttccaagtcc tggccttggt tgccctcaca ctggtagcag ggaagctcac 900acacctgata cccgtctcgt ggatgccggt catctggtca gccctttcgg ccgtcctcct 960cctcgcaagc tcctattttg tgggtgctct gattgtccat gccgattgct ttctgatgag 1020aaaccacacc atcacggagc agcccatgtg cttccaaaga acgacacccc ttattctgca 1080ggaggttgcg tcctttctca aaaggaataa gcatgggcct ttcctcctct ttgtttcctt 1140tctacacgtt cacatccctc ttatcactat ggagaacttc ctcgggaaga gtctccacgg 1200gctgtatggg gacaacgtag aggagatgga ctggatggta ggacggatcc ttgacacttt 1260ggacgtggag ggtttgagca acagcaccct catttatttt acgtcggatc acggcggttc 1320cctagagaat caacttggaa acacccagta tggtggctgg aatggaattt ataaaggtgg 1380gaagggcatg ggaggatggg aaggtgggat ccgcgtgccc gggatcttcc gctggcccgg 1440ggtgctcccg gccggccgag tgattggcga gcccacgagt ctgatggacg tgttccccac 1500cgtggtccgg ctggcgggcg gcgaggtgcc ccaggacaga gtgattgacg gccaagacct 1560tctgcccttg ctcctgggga cagcccaaca ctcagaccac gagttcctga tgcattattg 1620tgagaggttt ctgcacgcag ccaggtggca tcaacgggac agaggaacaa tgtggaaagt 1680ccactttgtg acgcctgtgt tccagccaga gggagccggt gcctgctatg gaagaaaggt 1740ctgcccgtgc tttggggaaa aagtagtcca ccacgatcca cctttgctct ttgacctctc 1800aagagaccct tctgagaccc acatcctcac accagcctca gagcccgtgt tctatcaggt 1860gatggaacga gtccagcagg cggtgtggga acaccagcgg acactcagcc cagttcctct 1920gcagctggac aggctgggca acatctggag accgtggctg cagccctgct gtggcccgtt 1980ccccctctgc tggtgcctta gggaagatga cccacaataa atgtctgcag tgaaaagctg 2040gagccccgat tcctaaattt tgtcactcaa attgaaacaa accagctggc catggtggtt 2100gtcatcccag cactttagga ggccaccaca ggaggatcac

tcccgtgatc aaaaccaacc 2160tgggcaacat gatgaaactc tagctctaca aaacaaaaat aaaaaaaaaa ttagcctgca 222022589PRTHomo sapiens 22Met Leu His Leu His His Ser Cys Leu Cys Phe Arg Ser Trp Leu Pro 1 5 10 15 Ala Met Leu Ala Val Leu Leu Ser Leu Ala Pro Ser Ala Ser Ser Asp 20 25 30 Ile Ser Ala Ser Arg Pro Asn Ile Leu Leu Leu Met Ala Asp Asp Leu 35 40 45 Gly Ile Gly Asp Ile Gly Cys Tyr Gly Asn Asn Thr Met Arg Thr Pro 50 55 60 Asn Ile Asp Arg Leu Ala Glu Asp Gly Val Lys Leu Thr Gln His Ile 65 70 75 80 Ser Ala Ala Ser Leu Cys Thr Pro Ser Arg Ala Ala Phe Leu Thr Gly 85 90 95 Arg Tyr Pro Val Arg Ser Gly Met Val Ser Ser Ile Gly Tyr Arg Val 100 105 110 Leu Gln Trp Thr Gly Ala Ser Gly Gly Leu Pro Thr Asn Glu Thr Thr 115 120 125 Phe Ala Lys Ile Leu Lys Glu Lys Gly Tyr Ala Thr Gly Leu Ile Gly 130 135 140 Lys Trp His Leu Gly Leu Asn Cys Glu Ser Ala Ser Asp His Cys His 145 150 155 160 His Pro Leu His His Gly Phe Asp His Phe Tyr Gly Met Pro Phe Ser 165 170 175 Leu Met Gly Asp Cys Ala Arg Trp Glu Leu Ser Glu Lys Arg Val Asn 180 185 190 Leu Glu Gln Lys Leu Asn Phe Leu Phe Gln Val Leu Ala Leu Val Ala 195 200 205 Leu Thr Leu Val Ala Gly Lys Leu Thr His Leu Ile Pro Val Ser Trp 210 215 220 Met Pro Val Ile Trp Ser Ala Leu Ser Ala Val Leu Leu Leu Ala Ser 225 230 235 240 Ser Tyr Phe Val Gly Ala Leu Ile Val His Ala Asp Cys Phe Leu Met 245 250 255 Arg Asn His Thr Ile Thr Glu Gln Pro Met Cys Phe Gln Arg Thr Thr 260 265 270 Pro Leu Ile Leu Gln Glu Val Ala Ser Phe Leu Lys Arg Asn Lys His 275 280 285 Gly Pro Phe Leu Leu Phe Val Ser Phe Leu His Val His Ile Pro Leu 290 295 300 Ile Thr Met Glu Asn Phe Leu Gly Lys Ser Leu His Gly Leu Tyr Gly 305 310 315 320 Asp Asn Val Glu Glu Met Asp Trp Met Val Gly Arg Ile Leu Asp Thr 325 330 335 Leu Asp Val Glu Gly Leu Ser Asn Ser Thr Leu Ile Tyr Phe Thr Ser 340 345 350 Asp His Gly Gly Ser Leu Glu Asn Gln Leu Gly Asn Thr Gln Tyr Gly 355 360 365 Gly Trp Asn Gly Ile Tyr Lys Gly Gly Lys Gly Met Gly Gly Trp Glu 370 375 380 Gly Gly Ile Arg Val Pro Gly Ile Phe Arg Trp Pro Gly Val Leu Pro 385 390 395 400 Ala Gly Arg Val Ile Gly Glu Pro Thr Ser Leu Met Asp Val Phe Pro 405 410 415 Thr Val Val Arg Leu Ala Gly Gly Glu Val Pro Gln Asp Arg Val Ile 420 425 430 Asp Gly Gln Asp Leu Leu Pro Leu Leu Leu Gly Thr Ala Gln His Ser 435 440 445 Asp His Glu Phe Leu Met His Tyr Cys Glu Arg Phe Leu His Ala Ala 450 455 460 Arg Trp His Gln Arg Asp Arg Gly Thr Met Trp Lys Val His Phe Val 465 470 475 480 Thr Pro Val Phe Gln Pro Glu Gly Ala Gly Ala Cys Tyr Gly Arg Lys 485 490 495 Val Cys Pro Cys Phe Gly Glu Lys Val Val His His Asp Pro Pro Leu 500 505 510 Leu Phe Asp Leu Ser Arg Asp Pro Ser Glu Thr His Ile Leu Thr Pro 515 520 525 Ala Ser Glu Pro Val Phe Tyr Gln Val Met Glu Arg Val Gln Gln Ala 530 535 540 Val Trp Glu His Gln Arg Thr Leu Ser Pro Val Pro Leu Gln Leu Asp 545 550 555 560 Arg Leu Gly Asn Ile Trp Arg Pro Trp Leu Gln Pro Cys Cys Gly Pro 565 570 575 Phe Pro Leu Cys Trp Cys Leu Arg Glu Asp Asp Pro Gln 580 585 232048DNAHomo sapiens 23aaaagaggca gagcctttgc agaacagcct gtctgttctg ctcctagaca ttagagagat 60aatacggctg atagacaaca agaaggtatt ccaagctgca caatgaggcc caggagaccc 120ttggtcttca tgtctttggt gtgtgcactc ttgaacacat gccaggcaca cagggtgcat 180gacgacaagc ctaatattgt cctaatcatg gttgatgacc tgggtattgg agatctgggc 240tgctacggca atgacaccat gaggacgcct cacatcgacc gccttgccag ggaaggcgtg 300cgactgactc agcacatctc tgccgcctcc ctctgcagcc caagccggtc cgcgttcttg 360acgggaagat accccatccg atcaggtatg gtttctagtg gtaatagacg tgtcatccaa 420aatcttgcag tccccgcagg cctccctctt aatgagacaa cacttgcagc cttgctaaag 480aagcaaggat acagcacggg gcttataggc aaatggcacc aaggcttgaa ctgcgactcc 540cgaagtgacc agtgccacca tccatataat tatgggtttg actactacta tggcatgccg 600ttcactctcg ttgacagctg ctggccggac ccctctcgta acacggaatt agcctttgag 660agtcagctct ggctctgtgt gcagctagtt gccattgcca tcctcaccct aacctttggg 720aagctgagcg gctgggtctc tgttccctgg ctcctgatct tctccatgat tctgtttatt 780ttcctcttgg gctatgcttg gttctccagc cacacgtccc ctttatactg ggactgcctc 840ctcatgcggg ggcacgagat cacggagcag cccatgaagg ctgaacgagc tggatccatt 900atggtgaagg aagcgatttc ctttttagaa aggcacagta aggaaacttt ccttctcttt 960ttctcctttc ttcacgtgca cacacctctc cccaccacgg acgatttcac tggcaccagc 1020aagcatggct tgtatgggga taatgtggaa gagatggact ccatggtggg caagattctt 1080gatgctatcg atgattttgg cctaaggaac aacacccttg tctactttac atcagatcac 1140ggagggcatt tggaagctag gcgagggcat gcccaacttg gtggatggaa tggaatatac 1200aaaggtggaa aaggcatggg gggctgggaa ggtggaatcc gcgtcccagg aattgtccga 1260tggcctggaa aggtaccagc tggacggttg attaaggaac ctacaagttt aatggatatt 1320ttaccaactg tcgcatcagt gtcaggagga agtctccctc aggacagggt cattgacggc 1380cgagacctca tgcccttgct gcagggcaac gtcaggcact cggagcatga atttcttttc 1440cactactgtg gctcctacct gcacgccgtg cggtggatcc ccaaggacga cagtgggtca 1500gtttggaagg ctcactatgt gaccccggta ttccagccac cagcttctgg tggctgctat 1560gtcacctcat tatgcagatg tttcggagaa caggttacct accacaaccc ccctctgctc 1620ttcgatctct ccagggaccc ctcagagtcc acacccctga cacctgccac agagcccctc 1680catgattttg tgattaaaaa ggtggccaac gccctgaagg aacaccagga aaccatcgtg 1740cctgtgacct accaactctc agaactgaat cagggcagga cgtggctgaa gccttgctgt 1800ggggtgttcc cattttgtct gtgtgacaag gaagaggaag tctctcagcc tcggggtcct 1860aacgagaaga gataattaca atcaggctac cagaggaagc ctttggtcct aacgagaaga 1920gataattaca atcaggctac caaaggaagc actaactttg gtgctttcaa gttggcaagg 1980agtgcattta atagtcaata aattcatcta ccattccaga ttattaaagg cccactggtt 2040gttccact 204824590PRTHomo sapiens 24Met Arg Pro Arg Arg Pro Leu Val Phe Met Ser Leu Val Cys Ala Leu 1 5 10 15 Leu Asn Thr Cys Gln Ala His Arg Val His Asp Asp Lys Pro Asn Ile 20 25 30 Val Leu Ile Met Val Asp Asp Leu Gly Ile Gly Asp Leu Gly Cys Tyr 35 40 45 Gly Asn Asp Thr Met Arg Thr Pro His Ile Asp Arg Leu Ala Arg Glu 50 55 60 Gly Val Arg Leu Thr Gln His Ile Ser Ala Ala Ser Leu Cys Ser Pro 65 70 75 80 Ser Arg Ser Ala Phe Leu Thr Gly Arg Tyr Pro Ile Arg Ser Gly Met 85 90 95 Val Ser Ser Gly Asn Arg Arg Val Ile Gln Asn Leu Ala Val Pro Ala 100 105 110 Gly Leu Pro Leu Asn Glu Thr Thr Leu Ala Ala Leu Leu Lys Lys Gln 115 120 125 Gly Tyr Ser Thr Gly Leu Ile Gly Lys Trp His Gln Gly Leu Asn Cys 130 135 140 Asp Ser Arg Ser Asp Gln Cys His His Pro Tyr Asn Tyr Gly Phe Asp 145 150 155 160 Tyr Tyr Tyr Gly Met Pro Phe Thr Leu Val Asp Ser Cys Trp Pro Asp 165 170 175 Pro Ser Arg Asn Thr Glu Leu Ala Phe Glu Ser Gln Leu Trp Leu Cys 180 185 190 Val Gln Leu Val Ala Ile Ala Ile Leu Thr Leu Thr Phe Gly Lys Leu 195 200 205 Ser Gly Trp Val Ser Val Pro Trp Leu Leu Ile Phe Ser Met Ile Leu 210 215 220 Phe Ile Phe Leu Leu Gly Tyr Ala Trp Phe Ser Ser His Thr Ser Pro 225 230 235 240 Leu Tyr Trp Asp Cys Leu Leu Met Arg Gly His Glu Ile Thr Glu Gln 245 250 255 Pro Met Lys Ala Glu Arg Ala Gly Ser Ile Met Val Lys Glu Ala Ile 260 265 270 Ser Phe Leu Glu Arg His Ser Lys Glu Thr Phe Leu Leu Phe Phe Ser 275 280 285 Phe Leu His Val His Thr Pro Leu Pro Thr Thr Asp Asp Phe Thr Gly 290 295 300 Thr Ser Lys His Gly Leu Tyr Gly Asp Asn Val Glu Glu Met Asp Ser 305 310 315 320 Met Val Gly Lys Ile Leu Asp Ala Ile Asp Asp Phe Gly Leu Arg Asn 325 330 335 Asn Thr Leu Val Tyr Phe Thr Ser Asp His Gly Gly His Leu Glu Ala 340 345 350 Arg Arg Gly His Ala Gln Leu Gly Gly Trp Asn Gly Ile Tyr Lys Gly 355 360 365 Gly Lys Gly Met Gly Gly Trp Glu Gly Gly Ile Arg Val Pro Gly Ile 370 375 380 Val Arg Trp Pro Gly Lys Val Pro Ala Gly Arg Leu Ile Lys Glu Pro 385 390 395 400 Thr Ser Leu Met Asp Ile Leu Pro Thr Val Ala Ser Val Ser Gly Gly 405 410 415 Ser Leu Pro Gln Asp Arg Val Ile Asp Gly Arg Asp Leu Met Pro Leu 420 425 430 Leu Gln Gly Asn Val Arg His Ser Glu His Glu Phe Leu Phe His Tyr 435 440 445 Cys Gly Ser Tyr Leu His Ala Val Arg Trp Ile Pro Lys Asp Asp Ser 450 455 460 Gly Ser Val Trp Lys Ala His Tyr Val Thr Pro Val Phe Gln Pro Pro 465 470 475 480 Ala Ser Gly Gly Cys Tyr Val Thr Ser Leu Cys Arg Cys Phe Gly Glu 485 490 495 Gln Val Thr Tyr His Asn Pro Pro Leu Leu Phe Asp Leu Ser Arg Asp 500 505 510 Pro Ser Glu Ser Thr Pro Leu Thr Pro Ala Thr Glu Pro Leu His Asp 515 520 525 Phe Val Ile Lys Lys Val Ala Asn Ala Leu Lys Glu His Gln Glu Thr 530 535 540 Ile Val Pro Val Thr Tyr Gln Leu Ser Glu Leu Asn Gln Gly Arg Thr 545 550 555 560 Trp Leu Lys Pro Cys Cys Gly Val Phe Pro Phe Cys Leu Cys Asp Lys 565 570 575 Glu Glu Glu Val Ser Gln Pro Arg Gly Pro Asn Glu Lys Arg 580 585 590 252785DNAHomo sapiens 25ggctgcgccc aggccggcgg gcccagcagc tgcgaaccgc cggcgcacca cctgtttccg 60cgcccgggga cttccccggc ggggctcaga agtgtgggat cggtcgcttg gcttcccctg 120gcgtcagcga cccagggtaa cctcctccac tgctgcgtgc cgtgcaggcc tgcctgtgtg 180agagccacgt gtgccgcgct ctgggcacag ccttggaaag tcaggaccgc gacggcagca 240gagcagaaac cttacagaaa catgaagccc tcaaccatct gctactcagt tattcggggc 300tgacggcggc ttctagaaca tccaggtgtt ctgcagatgc gagaactcat cctgtagtca 360ccagatggag tcccaaacag ccaagcagat gtaaggcctg tgctgtggct ctgaggccct 420gaatacagaa gggtcacttt cttagtggcc aaagagcagt tgttgacatt gatgtctaat 480tattgaacac gaccagtcat tttactgagc tgcggtgagg aaacactgac catagaagat 540caagccaaat gagggattgc aaatttcctg attcttttga attaggattc cagatggggg 600cctcatttct acagccccca acattcctat agccgttatc actgccatca ccactgccac 660cagcatcttc ttgcagattc cacccctgct ccccagagac ttcctgcttt gaaagtgagc 720agaaaggaag ctctcagaaa aatctctagt ggtggctgcc gtcgctccag acaatcggaa 780tcctgccttc accaccatgg gctggctttt tctaaaggtt ttgttggcgg gagtgagttt 840ctcaggattt ctttatcctc ttgtggattt ttgcatcagt gggaaaacaa gaggacagaa 900gccaaacttt gtgattattt tggccgatga catggggtgg ggtgacctgg gagcaaactg 960ggcagaaaca aaggacactg ccaaccttga taagatggct tcggagggaa tgaggtttgt 1020ggatttccat gcagctgcct ccacctgctc accctcccgg gcttccttgc tcaccggccg 1080gcttggcctt cgcaatggag tcacacgcaa ctttgcagtc acttctgtgg gaggccttcc 1140gctcaacgag accaccttgg cagaggtgct gcagcaggcg ggttacgtca ctgggataat 1200aggcaaatgg catcttggac accacggctc ttatcacccc aacttccgtg gttttgatta 1260ctactttgga atcccatata gccatgatat gggctgtact gatactccag gctacaacca 1320ccctccttgt ccagcgtgtc cacagggtga tggaccatca aggaaccttc aaagagactg 1380ttacactgac gtggccctcc ctctttatga aaacctcaac attgtggagc agccggtgaa 1440cttgagcagc cttgcccaga agtatgctga gaaagcaacc cagttcatcc agcgtgcaag 1500caccagcggg aggcccttcc tgctctatgt ggctctggcc cacatgcacg tgcccttacc 1560tgtgactcag ctaccagcag cgccacgggg cagaagcctg tatggtgcag ggctctggga 1620gatggacagt ctggtgggcc agatcaagga caaagttgac cacacagtga aggaaaacac 1680attcctctgg tttacaggag acaatggccc gtgggctcag aagtgtgagc tagcgggcag 1740tgtgggtccc ttcactggat tttggcaaac tcgtcaaggg ggaagtccag ccaagcagac 1800gacctgggaa ggagggcacc gggtcccagc actggcttac tggcctggca gagttccagt 1860taatgtcacc agcactgcct tgttaagcgt gctggacatt tttccaactg tggtagccct 1920ggcccaggcc agcttacctc aaggacggcg ctttgatggt gtggacgtct ccgaggtgct 1980ctttggccgg tcacagcctg ggcacagggt gctgttccac cccaacagcg gggcagctgg 2040agagtttgga gccctgcaga ctgtccgcct ggagcgttac aaggccttct acattaccgg 2100tggagccagg gcgtgtgatg ggagcacggg gcctgagctg cagcataagt ttcctctgat 2160tttcaacctg gaagacgata ccgcagaagc tgtgccccta gaaagaggtg gtgcggagta 2220ccaggctgtg ctgcccgagg tcagaaaggt tcttgcagac gtcctccaag acattgccaa 2280cgacaacatc tccagcgcag attacactca ggacccttca gtaactccct gctgtaatcc 2340ctaccaaatt gcctgccgct gtcaagccgc ataacagacc aatttttatt ccacgaggag 2400gagtacctgg aaattaggca agtttgcttc caaatttcat ttttaccctc tttacaaaca 2460cacgctttag tttagtcttg gagtttagtt ttggagttag ccttgcatat cccttctgta 2520tcctgtccct cctccacgcc gacccgagag cagctgagct gcgctggctc tgggcaggga 2580gtgtgcctta atgggaagca cacgggcttt ggagtcaggc acaggtgcca gctccagctt 2640ttgaacttgg gcaattgttt aacctaacct gcaagttgat tttgagggtt aaataaaggc 2700atacatgaaa atgcctggca aattacctga cacagagcag acattcaata cattttagtt 2760tccttgtttc aaaaaaaaaa aaaaa 278526525PRTHomo sapiens 26Met Gly Trp Leu Phe Leu Lys Val Leu Leu Ala Gly Val Ser Phe Ser 1 5 10 15 Gly Phe Leu Tyr Pro Leu Val Asp Phe Cys Ile Ser Gly Lys Thr Arg 20 25 30 Gly Gln Lys Pro Asn Phe Val Ile Ile Leu Ala Asp Asp Met Gly Trp 35 40 45 Gly Asp Leu Gly Ala Asn Trp Ala Glu Thr Lys Asp Thr Ala Asn Leu 50 55 60 Asp Lys Met Ala Ser Glu Gly Met Arg Phe Val Asp Phe His Ala Ala 65 70 75 80 Ala Ser Thr Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly Arg Leu 85 90 95 Gly Leu Arg Asn Gly Val Thr Arg Asn Phe Ala Val Thr Ser Val Gly 100 105 110 Gly Leu Pro Leu Asn Glu Thr Thr Leu Ala Glu Val Leu Gln Gln Ala 115 120 125 Gly Tyr Val Thr Gly Ile Ile Gly Lys Trp His Leu Gly His His Gly 130 135 140 Ser Tyr His Pro Asn Phe Arg Gly Phe Asp Tyr Tyr Phe Gly Ile Pro 145 150 155 160 Tyr Ser His Asp Met Gly Cys Thr Asp Thr Pro Gly Tyr Asn His Pro 165 170 175 Pro Cys Pro Ala Cys Pro Gln Gly Asp Gly Pro Ser Arg Asn Leu Gln 180 185 190 Arg Asp Cys Tyr Thr Asp Val Ala Leu Pro Leu Tyr Glu Asn Leu Asn 195 200 205 Ile Val Glu Gln Pro Val Asn Leu Ser Ser Leu Ala Gln Lys Tyr Ala 210 215 220 Glu Lys Ala Thr Gln Phe Ile Gln Arg Ala Ser Thr Ser Gly Arg Pro 225 230 235 240 Phe Leu Leu Tyr Val Ala Leu Ala His Met His Val Pro Leu Pro Val 245 250 255 Thr Gln Leu Pro Ala Ala Pro Arg Gly Arg Ser Leu Tyr Gly Ala Gly 260 265 270 Leu Trp Glu Met Asp Ser Leu Val Gly Gln Ile Lys Asp Lys Val Asp 275 280 285 His Thr Val Lys Glu Asn Thr Phe Leu Trp Phe Thr Gly Asp Asn Gly 290 295 300 Pro Trp Ala Gln Lys Cys Glu Leu Ala Gly Ser Val Gly Pro Phe Thr 305 310 315 320 Gly Phe Trp Gln Thr Arg Gln Gly Gly Ser Pro Ala Lys Gln Thr Thr 325 330 335 Trp Glu Gly Gly His Arg Val Pro Ala Leu Ala Tyr Trp Pro Gly Arg 340

345 350 Val Pro Val Asn Val Thr Ser Thr Ala Leu Leu Ser Val Leu Asp Ile 355 360 365 Phe Pro Thr Val Val Ala Leu Ala Gln Ala Ser Leu Pro Gln Gly Arg 370 375 380 Arg Phe Asp Gly Val Asp Val Ser Glu Val Leu Phe Gly Arg Ser Gln 385 390 395 400 Pro Gly His Arg Val Leu Phe His Pro Asn Ser Gly Ala Ala Gly Glu 405 410 415 Phe Gly Ala Leu Gln Thr Val Arg Leu Glu Arg Tyr Lys Ala Phe Tyr 420 425 430 Ile Thr Gly Gly Ala Arg Ala Cys Asp Gly Ser Thr Gly Pro Glu Leu 435 440 445 Gln His Lys Phe Pro Leu Ile Phe Asn Leu Glu Asp Asp Thr Ala Glu 450 455 460 Ala Val Pro Leu Glu Arg Gly Gly Ala Glu Tyr Gln Ala Val Leu Pro 465 470 475 480 Glu Val Arg Lys Val Leu Ala Asp Val Leu Gln Asp Ile Ala Asn Asp 485 490 495 Asn Ile Ser Ser Ala Asp Tyr Thr Gln Asp Pro Ser Val Thr Pro Cys 500 505 510 Cys Asn Pro Tyr Gln Ile Ala Cys Arg Cys Gln Ala Ala 515 520 525 271689DNAHomo sapiens 27atgacaagaa acgccagacc caacattgtc ctgctgatgg cagatgacct tggagtgggg 60gatttgtgct gctacggtaa taactcagtg agcacaccta atattgaccg cctggcaagt 120gaaggagtga ggcttaccca gcatctcgca gctgcttcca tgtgcacccc aagtcgggct 180gccttcctga ccggccggta ccccatcaga tcagggatgg tgtctgccta caacctgaac 240cgtgccttca cgtggcttgg tgggtcaggt ggtcttccca ccaatgaaac gacttttgcc 300aagctgctgc agcaccgtgg ctaccgcacg ggactcatag gcaaatggca cctgggtttg 360agctgcgcct ctcggaatga tcactgttac cacccgctca accatggttt tcactacttt 420tacggggtgc cttttggact tttaagcgac tgccaggcat ccaagacacc agaactgcac 480cgctggctca ggatcaaact gtggatctcc acggtagccc ttgccctggt tccttttctg 540cttctcattc ccaagttcgc ccgctggttc tcagtgccat ggaaggtcat ctttgtcttt 600gctctcctcg cctttctgtt tttcacttcc tggtactcta gttatggatt tactcgacgt 660tggaattgca tccttatgag gaaccatgaa attatccagc agccaatgaa agaggagaaa 720gtagcttccc tcatgctgaa ggaggcactt gctttcattg aaaggtacaa aagggaacct 780tttctcctct ttttttcctt cctgcacgta catactccac tcatctccaa aaagaagttt 840gttgggcgca gtaaatatgg caggtatggg gacaatgtag aagaaatgga ttggatggtg 900ggtaaaatcc tggatgccct ggaccaggag cgcctggcca accacacctt ggtgtacttc 960acctctgaca acgggggcca cctggagccc ctggacgggg ctgttcagct gggtggctgg 1020aacgggatct acaaaggtgg caaaggaatg ggaggatggg aaggaggtat ccgtgtgcca 1080gggatattcc ggtggccgtc agtcttggag gctgggagag tgatcaatga gcccaccagc 1140ttaatggaca tctatccgac gctgtcttat ataggcggag ggatcttgtc ccaggacaga 1200gtgattgacg gccagaacct aatgcccctg ctggaaggaa gggcgtccca ctccgaccac 1260gagttcctct tccactactg tggggtctat ctgcacacgg tcaggtggca tcagaaggac 1320tgtgcaactg tgtggaaagc tcattatgtg actcctaaat tctaccctga aggaacaggt 1380gcctgctatg ggagtggaat atgttcatgt tcgggggatg taacctacca cgacccacca 1440ctcctctttg acatctcaag agacccttca gaagcccttc cactgaaccc tgacaatgag 1500ccattatttg actccgtgat caaaaagatg gaggcagcca taagagagca tcgtaggaca 1560ctaacacctg tcccacagca gttctctgtg ttcaacacaa tttggaaacc atggctgcag 1620ccttgctgtg ggaccttccc cttctgtggg tgtgacaagg aagatgacat ccttcccatg 1680gctccctga 168928562PRTHomo sapiens 28Met Thr Arg Asn Ala Arg Pro Asn Ile Val Leu Leu Met Ala Asp Asp 1 5 10 15 Leu Gly Val Gly Asp Leu Cys Cys Tyr Gly Asn Asn Ser Val Ser Thr 20 25 30 Pro Asn Ile Asp Arg Leu Ala Ser Glu Gly Val Arg Leu Thr Gln His 35 40 45 Leu Ala Ala Ala Ser Met Cys Thr Pro Ser Arg Ala Ala Phe Leu Thr 50 55 60 Gly Arg Tyr Pro Ile Arg Ser Gly Met Val Ser Ala Tyr Asn Leu Asn 65 70 75 80 Arg Ala Phe Thr Trp Leu Gly Gly Ser Gly Gly Leu Pro Thr Asn Glu 85 90 95 Thr Thr Phe Ala Lys Leu Leu Gln His Arg Gly Tyr Arg Thr Gly Leu 100 105 110 Ile Gly Lys Trp His Leu Gly Leu Ser Cys Ala Ser Arg Asn Asp His 115 120 125 Cys Tyr His Pro Leu Asn His Gly Phe His Tyr Phe Tyr Gly Val Pro 130 135 140 Phe Gly Leu Leu Ser Asp Cys Gln Ala Ser Lys Thr Pro Glu Leu His 145 150 155 160 Arg Trp Leu Arg Ile Lys Leu Trp Ile Ser Thr Val Ala Leu Ala Leu 165 170 175 Val Pro Phe Leu Leu Leu Ile Pro Lys Phe Ala Arg Trp Phe Ser Val 180 185 190 Pro Trp Lys Val Ile Phe Val Phe Ala Leu Leu Ala Phe Leu Phe Phe 195 200 205 Thr Ser Trp Tyr Ser Ser Tyr Gly Phe Thr Arg Arg Trp Asn Cys Ile 210 215 220 Leu Met Arg Asn His Glu Ile Ile Gln Gln Pro Met Lys Glu Glu Lys 225 230 235 240 Val Ala Ser Leu Met Leu Lys Glu Ala Leu Ala Phe Ile Glu Arg Tyr 245 250 255 Lys Arg Glu Pro Phe Leu Leu Phe Phe Ser Phe Leu His Val His Thr 260 265 270 Pro Leu Ile Ser Lys Lys Lys Phe Val Gly Arg Ser Lys Tyr Gly Arg 275 280 285 Tyr Gly Asp Asn Val Glu Glu Met Asp Trp Met Val Gly Lys Ile Leu 290 295 300 Asp Ala Leu Asp Gln Glu Arg Leu Ala Asn His Thr Leu Val Tyr Phe 305 310 315 320 Thr Ser Asp Asn Gly Gly His Leu Glu Pro Leu Asp Gly Ala Val Gln 325 330 335 Leu Gly Gly Trp Asn Gly Ile Tyr Lys Gly Gly Lys Gly Met Gly Gly 340 345 350 Trp Glu Gly Gly Ile Arg Val Pro Gly Ile Phe Arg Trp Pro Ser Val 355 360 365 Leu Glu Ala Gly Arg Val Ile Asn Glu Pro Thr Ser Leu Met Asp Ile 370 375 380 Tyr Pro Thr Leu Ser Tyr Ile Gly Gly Gly Ile Leu Ser Gln Asp Arg 385 390 395 400 Val Ile Asp Gly Gln Asn Leu Met Pro Leu Leu Glu Gly Arg Ala Ser 405 410 415 His Ser Asp His Glu Phe Leu Phe His Tyr Cys Gly Val Tyr Leu His 420 425 430 Thr Val Arg Trp His Gln Lys Asp Cys Ala Thr Val Trp Lys Ala His 435 440 445 Tyr Val Thr Pro Lys Phe Tyr Pro Glu Gly Thr Gly Ala Cys Tyr Gly 450 455 460 Ser Gly Ile Cys Ser Cys Ser Gly Asp Val Thr Tyr His Asp Pro Pro 465 470 475 480 Leu Leu Phe Asp Ile Ser Arg Asp Pro Ser Glu Ala Leu Pro Leu Asn 485 490 495 Pro Asp Asn Glu Pro Leu Phe Asp Ser Val Ile Lys Lys Met Glu Ala 500 505 510 Ala Ile Arg Glu His Arg Arg Thr Leu Thr Pro Val Pro Gln Gln Phe 515 520 525 Ser Val Phe Asn Thr Ile Trp Lys Pro Trp Leu Gln Pro Cys Cys Gly 530 535 540 Thr Phe Pro Phe Cys Gly Cys Asp Lys Glu Asp Asp Ile Leu Pro Met 545 550 555 560 Ala Pro 293225DNAHomo sapiens 29gcgtcccgcc cctccacctg gggctcggcc cggcccggca gatgttacaa ctttttcgaa 60ttctctcccg ccgtgtcccc tcgacccgcc caacttgtgc ctccctcccc ttcccctctg 120gggtcctgcc cacctccctg cagggagctg ggctgtttta aggactccgg gtggggcgag 180aggccgggaa agcagaggag agagaaatta ggaggcggga gaaatccagg gcaagaagga 240agaggggagt cagaggatgg tagagagcac tttttggaag ctgccacgcc gcgtctcagg 300ctggccgggc tgagctgggg aagagggagc aaaggcggcg cagggcctgc gcttaggcag 360cgggaggcag ctcggcgcgg gcctgacctc cccagagcgc cccgctgcgg ccgagcagat 420ccggcccagc cgtccggcag ccagtcccgg accagacact ggaccgtccc cggggggcgc 480tgaactccct cgcagcatcc gagccggcgg gccggtggtg cgccctgggc gcgcgaggtg 540gtgaggcccc aggagcccgg cgcgccggga cgcgcgggcc ggcttggcga tgcacaccct 600cactggcttc tccctggtca gcctgctcag cttcggctac ctgtcctggg actgggccaa 660gccgagcttc gtggccgacg ggcccgggga ggctggcgag cagccctcgg ccgctccgcc 720ccagcctccc cacatcatct tcatcctcac ggacgaccaa ggctaccacg acgtgggcta 780ccatggttca gatatcgaga cccctacgct ggacaggctg gcggccaagg gggtcaagtt 840ggagaattat tacatccagc ccatctgcac gccttcgcgg agccagctcc tcactggcag 900gtaccagatc cacacaggac tccagcattc catcatccgc ccacagcagc ccaactgcct 960gcccctggac caggtgacac tgccacagaa gctgcaggag gcaggttatt ccacccatat 1020ggtgggcaag tggcacctgg gcttctaccg gaaggagtgt ctgcccaccc gtcggggctt 1080cgacaccttc ctgggctcgc tcacgggcaa tgtggactat tacacctatg acaactgtga 1140tggcccaggc gtgtgcggct tcgacctgca cgagggtgag aatgtggcct gggggctcag 1200cggccagtac tccactatgc tttatgccca gcgcgccagc catatcctgg ccagccacag 1260ccctcagcgt cccctcttcc tctatgtggc cttccaggca gtacacacac ccctgcagtc 1320ccctcgtgag tacctgtacc gctaccgcac catgggcaat gtggcccggc ggaagtacgc 1380ggccatggtg acctgcatgg atgaggctgt gcgcaacatc acctgggccc tcaagcgcta 1440cggtttctac aacaacagtg tcatcatctt ctccagtgac aatggtggcc agactttctc 1500ggggggcagc aactggccgc tccgaggacg caagggcact tattgggaag gtggcgtgcg 1560gggcctaggc tttgtccaca gtcccctgct caagcgaaag caacggacaa gccgggcact 1620gatgcacatc actgactggt acccgaccct ggtgggtctg gcaggtggta ccacctcagc 1680agccgatggg ctagatggct acgacgtgtg gccggccatc agcgagggcc gggcctcacc 1740acgcacggag atcctgcaca acattgaccc actctacaac catgcccagc atggctccct 1800ggagggcggc tttggcatct ggaacaccgc cgtgcaggct gccatccgcg tgggtgagtg 1860gaagctgctg acaggagacc ccggctatgg cgattggatc ccaccgcaga cactggccac 1920cttcccgggt agctggtgga acctggaacg aatggccagt gtccgccagg ccgtgtggct 1980cttcaacatc agtgctgacc cttatgaacg ggaggacctg gctggccagc ggcctgatgt 2040ggtccgcacc ctgctggctc gcctggccga atataaccgc acagccatcc cggtacgcta 2100cccagctgag aacccccggg ctcatcctga ctttaatggg ggtgcttggg ggccctgggc 2160cagtgatgag gaagaggagg aagaggaagg gagggctcga agcttctccc ggggtcgtcg 2220caagaaaaaa tgcaagattt gcaagcttcg atcctttttc cgtaaactca acaccaggct 2280aatgtcccaa cggatctgat ggtggggagg gagaaaactg tcctttagag gatcttcccc 2340actccggctt ggccctgctg tttctcaggg agaagcctgt cacatctcca tctacaggga 2400gttggagggt gtagagtccc ttggttgaac agggtaggga gcctggatag gagtgggtgg 2460gaataaacca gactgggatg cctgtgtctc agtcctgcct cctcacggac ttgctctgtg 2520acctcaggtg acccacatga gcttttagcc tcagtttcct catctgtaaa atgagctcta 2580atgactttgt gactctttgg tgtggccctg gagcctgggg ccacggtgga gttcctggcc 2640ggccttgcca cttgacaact cctttaaggc ttccccctta acacgggatc cctgtggtgg 2700tgtttgggag ttgcctggag gcaactccaa gcctggcccc cagctgaagc atggcaatct 2760ggctgctctc tacagggacc cccaagcgct gtgggtggag ggcaggggtc gggggggttg 2820accttcttgg gtcttcacat ggcctaggcc agtcctccgg tcagactggt gtcaggcacc 2880gtggtgcaaa attcctcttc tggcccctcc agtacccaga gaaactggct gggccattaa 2940ctgctgcagc accaagggtg gtagaaagag ctgtgaagag cccccaaacc agtaccagga 3000cacctgggtt ctcctgtgac ctggggcaca gttcttgccc tctaggcctt gatttcccca 3060cctgcaagtg gggatgccag ccctggctct gcctccttca tgaggctctg gaagactggc 3120caaggttgtg gaggagcttg tgaacttgat taaagtgtcg taacatgaaa aaaaaaaaaa 3180aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 322530569PRTHomo sapiens 30Met His Thr Leu Thr Gly Phe Ser Leu Val Ser Leu Leu Ser Phe Gly 1 5 10 15 Tyr Leu Ser Trp Asp Trp Ala Lys Pro Ser Phe Val Ala Asp Gly Pro 20 25 30 Gly Glu Ala Gly Glu Gln Pro Ser Ala Ala Pro Pro Gln Pro Pro His 35 40 45 Ile Ile Phe Ile Leu Thr Asp Asp Gln Gly Tyr His Asp Val Gly Tyr 50 55 60 His Gly Ser Asp Ile Glu Thr Pro Thr Leu Asp Arg Leu Ala Ala Lys 65 70 75 80 Gly Val Lys Leu Glu Asn Tyr Tyr Ile Gln Pro Ile Cys Thr Pro Ser 85 90 95 Arg Ser Gln Leu Leu Thr Gly Arg Tyr Gln Ile His Thr Gly Leu Gln 100 105 110 His Ser Ile Ile Arg Pro Gln Gln Pro Asn Cys Leu Pro Leu Asp Gln 115 120 125 Val Thr Leu Pro Gln Lys Leu Gln Glu Ala Gly Tyr Ser Thr His Met 130 135 140 Val Gly Lys Trp His Leu Gly Phe Tyr Arg Lys Glu Cys Leu Pro Thr 145 150 155 160 Arg Arg Gly Phe Asp Thr Phe Leu Gly Ser Leu Thr Gly Asn Val Asp 165 170 175 Tyr Tyr Thr Tyr Asp Asn Cys Asp Gly Pro Gly Val Cys Gly Phe Asp 180 185 190 Leu His Glu Gly Glu Asn Val Ala Trp Gly Leu Ser Gly Gln Tyr Ser 195 200 205 Thr Met Leu Tyr Ala Gln Arg Ala Ser His Ile Leu Ala Ser His Ser 210 215 220 Pro Gln Arg Pro Leu Phe Leu Tyr Val Ala Phe Gln Ala Val His Thr 225 230 235 240 Pro Leu Gln Ser Pro Arg Glu Tyr Leu Tyr Arg Tyr Arg Thr Met Gly 245 250 255 Asn Val Ala Arg Arg Lys Tyr Ala Ala Met Val Thr Cys Met Asp Glu 260 265 270 Ala Val Arg Asn Ile Thr Trp Ala Leu Lys Arg Tyr Gly Phe Tyr Asn 275 280 285 Asn Ser Val Ile Ile Phe Ser Ser Asp Asn Gly Gly Gln Thr Phe Ser 290 295 300 Gly Gly Ser Asn Trp Pro Leu Arg Gly Arg Lys Gly Thr Tyr Trp Glu 305 310 315 320 Gly Gly Val Arg Gly Leu Gly Phe Val His Ser Pro Leu Leu Lys Arg 325 330 335 Lys Gln Arg Thr Ser Arg Ala Leu Met His Ile Thr Asp Trp Tyr Pro 340 345 350 Thr Leu Val Gly Leu Ala Gly Gly Thr Thr Ser Ala Ala Asp Gly Leu 355 360 365 Asp Gly Tyr Asp Val Trp Pro Ala Ile Ser Glu Gly Arg Ala Ser Pro 370 375 380 Arg Thr Glu Ile Leu His Asn Ile Asp Pro Leu Tyr Asn His Ala Gln 385 390 395 400 His Gly Ser Leu Glu Gly Gly Phe Gly Ile Trp Asn Thr Ala Val Gln 405 410 415 Ala Ala Ile Arg Val Gly Glu Trp Lys Leu Leu Thr Gly Asp Pro Gly 420 425 430 Tyr Gly Asp Trp Ile Pro Pro Gln Thr Leu Ala Thr Phe Pro Gly Ser 435 440 445 Trp Trp Asn Leu Glu Arg Met Ala Ser Val Arg Gln Ala Val Trp Leu 450 455 460 Phe Asn Ile Ser Ala Asp Pro Tyr Glu Arg Glu Asp Leu Ala Gly Gln 465 470 475 480 Arg Pro Asp Val Val Arg Thr Leu Leu Ala Arg Leu Ala Glu Tyr Asn 485 490 495 Arg Thr Ala Ile Pro Val Arg Tyr Pro Ala Glu Asn Pro Arg Ala His 500 505 510 Pro Asp Phe Asn Gly Gly Ala Trp Gly Pro Trp Ala Ser Asp Glu Glu 515 520 525 Glu Glu Glu Glu Glu Gly Arg Ala Arg Ser Phe Ser Arg Gly Arg Arg 530 535 540 Lys Lys Lys Cys Lys Ile Cys Lys Leu Arg Ser Phe Phe Arg Lys Leu 545 550 555 560 Asn Thr Arg Leu Met Ser Gln Arg Ile 565 314689DNAHomo sapiens 31ctggagagaa aagagggagg aggcaaaaga actcggagtg ccaaagctaa ataagttagc 60tgagaaaacg cacgcagttt gcagcgcctg cgccgggtgc gccaactacg caaagaccaa 120gcgggctccg cgcggaccgg ccgcggggct agggacccgg ctttggcctt caggctccct 180agcagcgggg aaaaggaatt gctgcccgga gtttctgcgg aggtggaggg agatcaggaa 240acggcttctt cctcacttcg ccgcctggtg agtgtcgggg agattggcaa acgcctagga 300aaggactggg gaaaatagcc ctgggaaagt ggagaaggtg atcaggaggc cggtccacta 360cggcagttta tctgtctgat cagagccaga cgcgacgcgt ccacttcgca gttctttcca 420ggtgtgggga ccgcaggaca gacggccgat cccgccgccc tccgtaccag cactcccagg 480agagtcagcc tcgctcccca acgtcgaggg cgctctggcc acgaaaagtt cctgtccact 540gtgattctca attccttgct tggttttttt ctccagagaa cttttgggtg gagatattaa 600cttttttctt ttttttttcc ttggtggaag ctgctctagg gaggggggag gaggaggaga 660aagtgaaatg tgctggagaa gagcgagccc tccttgttct tccggagtcc catccattaa 720gccatcactt ctggaagatt aaagttgtcg gacatggtga cagctgagag gagaggagga 780tttcttgcca ggtggagagt cttcaccgtc tgttgggtgc atgtgtgcgc ccgcagcggc 840gcggggcgcg tggttctccg cgtggagtct cacctgggac ctgagtgaat ggctcccagg 900ggctgtgcgg ggcatccgcc tccgccttct ccacaggcct gtgtctgtcc tggaaagatg 960ctagcaatgg gggcgctggc aggattctgg atcctctgcc tcctcactta tggttacctg 1020tcctggggcc aggccttaga agaggaggaa gaaggggcct tactagctca agctggagag 1080aaactagagc ccagcacaac ttccacctcc cagccccatc tcattttcat cctagcggat 1140gatcagggat ttagagatgt gggttaccac ggatctgaga ttaaaacacc tactcttgac 1200aagctcgctg ccgaaggagt taaactggag aactactatg tccagcctat ttgcacacca 1260tccaggagtc agtttattac tggaaagtat cagatacaca ccggacttca acattctatc 1320ataagaccta cccaacccaa ctgtttacct ctggacaatg ccaccctacc tcagaaactg 1380aaggaggttg gatattcaac gcatatggtc ggaaaatggc acttgggttt

ttacagaaaa 1440gaatgcatgc ccaccagaag aggatttgat accttttttg gttccctttt gggaagtggg 1500gattactata cacactacaa atgtgacagt cctgggatgt gtggctatga cttgtatgaa 1560aacgacaatg ctgcctggga ctatgacaat ggcatatact ccacacagat gtacactcag 1620agagtacagc aaatcttagc ttcccataac cccacaaagc ctatattttt atatattgcc 1680tatcaagctg ttcattcacc actgcaagct cctggcaggt atttcgaaca ctaccgatcc 1740attatcaaca taaacaggag gagatatgct gccatgcttt cctgcttaga tgaagcaatc 1800aacaacgtga cattggctct aaagacttat ggtttctata acaacagcat tatcatttac 1860tcttcagata atggtggcca gcctacggca ggagggagta actggcctct cagaggtagc 1920aaaggaacat attgggaagg agggatccgg gctgtaggct ttgtgcatag cccacttctg 1980aaaaacaagg gaacagtgtg taaggaactt gtgcacatca ctgactggta ccccactctc 2040atttcactgg ctgaaggaca gattgatgag gacattcaac tagatggcta tgatatctgg 2100gagaccataa gtgagggtct tcgctcaccc cgagtagata ttttgcataa cattgacccc 2160atatacacca aggcaaaaaa tggctcctgg gcagcaggct atgggatctg gaacactgca 2220atccagtcag ccatcagagt gcagcactgg aaattgctta caggaaatcc tggctacagc 2280gactgggtcc cccctcagtc tttcagcaac ctgggaccga accggtggca caatgaacgg 2340atcaccttgt caactggcaa aagtgtatgg cttttcaaca tcacagccga cccatatgag 2400agggtggacc tatctaacag gtatccagga atcgtgaaga agctcctacg gaggctctca 2460cagttcaaca aaactgcagt gccggtcagg tatcccccca aagaccccag aagtaaccct 2520aggctcaatg gaggggtctg gggaccatgg tataaagagg aaaccaagaa aaagaagcca 2580agcaaaaatc aggctgagaa aaagcaaaag aaaagcaaaa aaaagaagaa gaaacagcag 2640aaagcagtct caggttcaac ttgccattca ggtgttactt gtggataagc acaaatattt 2700cctgtttggt taaactttaa tcagttctta tctttcatct gtttcctagg taaaccagca 2760aatttggctc gataatatcg ctggcctaag cgtcaggctt gttttcatgc tgtgccactc 2820cagagacttc tgccacctgg ccgccacact gaaaactgtc ctgctcagtg ccaaggtgct 2880actcttgcaa gccacactta gagagagtgg agatgtttat ttctcttgct cctttagaaa 2940acgtggtgag tcctgagttc cactgctgtg cttcagtcaa ctgaccaaac actgctttga 3000attataggag gagaacaata acctaccatc cgcaagcatg ctaatttgat ggaagttaca 3060gggtatacca tccgcaagca tgctaatttg atggaagtta cagggtagca tgattaaaac 3120tacctttgat aaattacagt caaagattgt gtcacctcaa aggccttgaa gaatatattt 3180tcttggtgaa tttttgtatg tctgtcatat gacacttggg ttttttaatt aattctattt 3240tatatatata tatatgtttc ttttcctgtg aaaagctgtt tttctcacat gtgaacagct 3300tgcacctcat tttaccatgc gtgagggaat ggcaaataag aatgtttgag cacactgccc 3360acaatgaatg taactatttt ctaaacactt tactagaaga acatttcagt ataaaaaacc 3420taatttattt ttacagaaaa atattttgtt gtttttataa aaagttatgc aaatgacttt 3480attttatttt tatttcctgc ataccattag aataatttta tttcatttct tcaaattacc 3540aagcactgta atactataaa ttaatgtaat actgtgtgaa ttcagactat aaaaaacatc 3600attcagaaaa ctttataatc gtcattgttc aaccaagatt ttgaatgtaa taagatgaat 3660atattcctta caaattactt ggaaattcaa tgtttgtgca gagttgagac aactttattg 3720tttctatcat aaactattta tgtatcttaa ttattaaaat gatttacttt atggcactag 3780aaaatttact gtggcttttc tgatctaact tctagctaaa attgtatcat tggtcctaaa 3840aaataaaaat ctttactaat aggcaattga aggaatggtt tgctaacaac cacagtaata 3900taatatgatt ttacagatag atgcttcccc ttggctatga catggagaaa gattttccca 3960taataataac taacatttat attaggttgg tgcaaaacta gttgcggttt ttcccattaa 4020aagtaataaa cttactctta tacaaagtgg acactgtggg gagatacaga gaaatggaag 4080atacggatcc tgcctggagt aggtaacctt gcttggaaac cccacatgca aacgtcatga 4140ggagaattaa aggagtatta tcagtaatga agtttatcat gggtcatcaa tgagcataga 4200ttggtgtgga tcctgtagac cctggtgttt tctttgaagt gccctctcct aatgcagagg 4260ccttgaagct tacagtatac acttgaaaag tcacagatag ctagaattat gatctttgaa 4320gttataactg tgatctgaaa atgtgtgtgg tggtatgaca gcataccatt aaatacattt 4380acatcacagc tcaaaggact gtgatataat ccatttatat cacaactcaa aggactgtga 4440tataatccat ttatatcaca gctcacagtt tctgaaaatg tataaaagaa tctataatct 4500agtactgaaa ttactaaatt gggtaagatg atttaaatga ttttaatttt aacattttat 4560ttctagaata tatggctcca ttttatttta tagtgtaaag ttgtatttcc taaagtttgt 4620gttttgtcga cagtatcttt taaatgagtc ttaaaaataa aggcatattg ttcatgttaa 4680aaaaaaaaa 468932599PRTHomo sapiens 32Met Ala Pro Arg Gly Cys Ala Gly His Pro Pro Pro Pro Ser Pro Gln 1 5 10 15 Ala Cys Val Cys Pro Gly Lys Met Leu Ala Met Gly Ala Leu Ala Gly 20 25 30 Phe Trp Ile Leu Cys Leu Leu Thr Tyr Gly Tyr Leu Ser Trp Gly Gln 35 40 45 Ala Leu Glu Glu Glu Glu Glu Gly Ala Leu Leu Ala Gln Ala Gly Glu 50 55 60 Lys Leu Glu Pro Ser Thr Thr Ser Thr Ser Gln Pro His Leu Ile Phe 65 70 75 80 Ile Leu Ala Asp Asp Gln Gly Phe Arg Asp Val Gly Tyr His Gly Ser 85 90 95 Glu Ile Lys Thr Pro Thr Leu Asp Lys Leu Ala Ala Glu Gly Val Lys 100 105 110 Leu Glu Asn Tyr Tyr Val Gln Pro Ile Cys Thr Pro Ser Arg Ser Gln 115 120 125 Phe Ile Thr Gly Lys Tyr Gln Ile His Thr Gly Leu Gln His Ser Ile 130 135 140 Ile Arg Pro Thr Gln Pro Asn Cys Leu Pro Leu Asp Asn Ala Thr Leu 145 150 155 160 Pro Gln Lys Leu Lys Glu Val Gly Tyr Ser Thr His Met Val Gly Lys 165 170 175 Trp His Leu Gly Phe Tyr Arg Lys Glu Cys Met Pro Thr Arg Arg Gly 180 185 190 Phe Asp Thr Phe Phe Gly Ser Leu Leu Gly Ser Gly Asp Tyr Tyr Thr 195 200 205 His Tyr Lys Cys Asp Ser Pro Gly Met Cys Gly Tyr Asp Leu Tyr Glu 210 215 220 Asn Asp Asn Ala Ala Trp Asp Tyr Asp Asn Gly Ile Tyr Ser Thr Gln 225 230 235 240 Met Tyr Thr Gln Arg Val Gln Gln Ile Leu Ala Ser His Asn Pro Thr 245 250 255 Lys Pro Ile Phe Leu Tyr Ile Ala Tyr Gln Ala Val His Ser Pro Leu 260 265 270 Gln Ala Pro Gly Arg Tyr Phe Glu His Tyr Arg Ser Ile Ile Asn Ile 275 280 285 Asn Arg Arg Arg Tyr Ala Ala Met Leu Ser Cys Leu Asp Glu Ala Ile 290 295 300 Asn Asn Val Thr Leu Ala Leu Lys Thr Tyr Gly Phe Tyr Asn Asn Ser 305 310 315 320 Ile Ile Ile Tyr Ser Ser Asp Asn Gly Gly Gln Pro Thr Ala Gly Gly 325 330 335 Ser Asn Trp Pro Leu Arg Gly Ser Lys Gly Thr Tyr Trp Glu Gly Gly 340 345 350 Ile Arg Ala Val Gly Phe Val His Ser Pro Leu Leu Lys Asn Lys Gly 355 360 365 Thr Val Cys Lys Glu Leu Val His Ile Thr Asp Trp Tyr Pro Thr Leu 370 375 380 Ile Ser Leu Ala Glu Gly Gln Ile Asp Glu Asp Ile Gln Leu Asp Gly 385 390 395 400 Tyr Asp Ile Trp Glu Thr Ile Ser Glu Gly Leu Arg Ser Pro Arg Val 405 410 415 Asp Ile Leu His Asn Ile Asp Pro Ile Tyr Thr Lys Ala Lys Asn Gly 420 425 430 Ser Trp Ala Ala Gly Tyr Gly Ile Trp Asn Thr Ala Ile Gln Ser Ala 435 440 445 Ile Arg Val Gln His Trp Lys Leu Leu Thr Gly Asn Pro Gly Tyr Ser 450 455 460 Asp Trp Val Pro Pro Gln Ser Phe Ser Asn Leu Gly Pro Asn Arg Trp 465 470 475 480 His Asn Glu Arg Ile Thr Leu Ser Thr Gly Lys Ser Val Trp Leu Phe 485 490 495 Asn Ile Thr Ala Asp Pro Tyr Glu Arg Val Asp Leu Ser Asn Arg Tyr 500 505 510 Pro Gly Ile Val Lys Lys Leu Leu Arg Arg Leu Ser Gln Phe Asn Lys 515 520 525 Thr Ala Val Pro Val Arg Tyr Pro Pro Lys Asp Pro Arg Ser Asn Pro 530 535 540 Arg Leu Asn Gly Gly Val Trp Gly Pro Trp Tyr Lys Glu Glu Thr Lys 545 550 555 560 Lys Lys Lys Pro Ser Lys Asn Gln Ala Glu Lys Lys Gln Lys Lys Ser 565 570 575 Lys Lys Lys Lys Lys Lys Gln Gln Lys Ala Val Ser Gly Ser Thr Cys 580 585 590 His Ser Gly Val Thr Cys Gly 595 333345DNAHomo sapiens 33aggagttgta gttctgcggg tgaagctcgg cgttactatc aagcaaccaa actgcaagct 60ttgggagttg ttcgctgtcc ctgccctgct ctgctaggga gagaacgcca gagggaggcg 120gctggcccgg cggcaggctc tcagaaccgc taccggcgat gctactgctg tgggtgtcgg 180tggtcgcagc cttggcgctg gcggtactgg cccccggagc aggggagcag aggcggagag 240cagccaaagc gcccaatgtg gtgctggtcg tgagcgactc cttcgatgga aggttaacat 300ttcatccagg aagtcaggta gtgaaacttc cttttatcaa ctttatgaag acacgtggga 360cttcctttct gaatgcctac acaaactctc caatttgttg cccatcacgc gcagcaatgt 420ggagtggcct cttcactcac ttaacagaat cttggaataa ttttaagggt ctagatccaa 480attatacaac atggatggat gtcatggaga ggcatggcta ccgaacacag aaatttggga 540aactggacta tacttcagga catcactcca ttagtaatcg tgtggaagcg tggacaagag 600atgttgcttt cttactcaga caagaaggca ggcccatggt taatcttatc cgtaacagga 660ctaaagtcag agtgatggaa agggattggc agaatacaga caaagcagta aactggttaa 720gaaaggaagc aattaattac actgaaccat ttgttattta cttgggatta aatttaccac 780acccttaccc ttcaccatct tctggagaaa attttggatc ttcaacattt cacacatctc 840tttattggct tgaaaaagtg tctcatgatg ccatcaaaat cccaaagtgg tcacctttgt 900cagaaatgca ccctgtagat tattactctt cttatacaaa aaactgcact ggaagattta 960caaaaaaaga aattaagaat attagagcat tttattatgc tatgtgtgct gagacagatg 1020ccatgcttgg tgaaattatt ttggcccttc atcaattaga tcttcttcag aaaactattg 1080tcatatactc ctcagaccat ggagagctgg ccatggaaca tcgacagttt tataaaatga 1140gcatgtacga ggctagtgca catgttccgc ttttgatgat gggaccagga attaaagccg 1200gcctacaagt atcaaatgtg gtttctcttg tggatattta ccctaccatg cttgatattg 1260ctggaattcc tctgcctcag aacctgagtg gatactcttt gttgccgtta tcatcagaaa 1320catttaagaa tgaacataaa gtcaaaaacc tgcatccacc ctggattctg agtgaattcc 1380atggatgtaa tgtgaatgcc tccacctaca tgcttcgaac taaccactgg aaatatatag 1440cctattcgga tggtgcatca atattgcctc aactctttga tctttcctcg gatccagatg 1500aattaacaaa tgttgctgta aaatttccag aaattactta ttctttggat cagaagcttc 1560attccattat aaactaccct aaagtttctg cttctgtcca ccagtataat aaagagcagt 1620ttatcaagtg gaaacaaagt ataggacaga attattcaaa cgttatagca aatcttaggt 1680ggcaccaaga ctggcagaag gaaccaagga agtatgaaaa tgcaattgat cagtggctta 1740aaacccatat gaatccaaga gcagtttgaa caaaaagttt aaaaatagtg ttctagagat 1800acatataaat atattacaag atcataatta tgtattttaa atgaaacagt tttaataatt 1860accaagtttt ggccgggcac agtggctcac acctgtaatc ccaggacttt gggaggctga 1920ggaaagcaga tcacaaggtc aagagattga gaccatcctg gccaacatgg tgaaaccctg 1980tctctactaa aaatacaaaa attagctggg cgcggtggtg cacacctata gtctcagcta 2040ctcagaggct gaggcaggag gatcgcttga acccgggagg cagcagttgc agtgagctga 2100gattgcgcca ctgtactcca gcctggcaac agagtgagac tgtgtcgcaa aaaaataaaa 2160ataaaataat aataattacc aatttttcat tattttgtaa gaatgtagtg tattttaaga 2220taaaatgcca atgattataa aatcacatat tttcaaaaat ggttattatt taggcctttg 2280tacaatttct aacaatttag tggaagtatc aaaagaattg aagcaaatac tgtaacagtt 2340atgttccttt aaataataga gaatataaaa tattgtaata atatgtatca taaaatagtt 2400gtatgtgagc atttgatggt gctcgatgag ttacttgtat ttgatgggat tgtttggatg 2460tatttaatgg gagtatttgg agtatttaac gggatgtaaa ccctggatgt acctgatttt 2520gttactgttt tattttaata ggtaatatat atacagggta aaagcttcaa atggtacaaa 2580agggttaaca gtgatcgtga agtctctgtc ctttccctct tccctgccat ccagttcccc 2640ctccaagaag caagtaccga aaccacctgc ttacgcattt ttagagattg gccacaaatt 2700tataaacaaa tgtatatatt cctttccccc tacacaaacg gtaacatact gcacacattg 2760ttctgcatgt tgcttctttt tccttttttt tttcacttaa cagtagatat ctagaggtga 2820aattactgag tcaagactat atttagcaaa attacactag atactacaaa ttacctctaa 2880agaaggtata ctaactgata atctcaccat caatgcatgt cttcttatcc tttgccaacc 2940taacagataa aaatgttcta tttttatttt tctttttatg agtaacgtag agcatatttt 3000catgtattta acagccactg gaatctgctt taccatggcc tttcctattt ctattctttg 3060cctatttttc tgttggttgt tggtctttgt tttgtattac aggtgtgctt tagatattag 3120ctttttgtaa gagatcctgc aaatatcttc tttccagttt gtcattgtca tttgtctttt 3180gactttgttc tggtattttt tgatatgtag aaatttttat tttcatgtaa gcaaatttat 3240gaatctttgt acaccataag tatatacaat tatgatttgt caattaaaaa tattagtaca 3300aaatttacag atctttgctt ttgtggcttt tgggattttg tatca 334534536PRTHomo sapiens 34Met Leu Leu Leu Trp Val Ser Val Val Ala Ala Leu Ala Leu Ala Val 1 5 10 15 Leu Ala Pro Gly Ala Gly Glu Gln Arg Arg Arg Ala Ala Lys Ala Pro 20 25 30 Asn Val Val Leu Val Val Ser Asp Ser Phe Asp Gly Arg Leu Thr Phe 35 40 45 His Pro Gly Ser Gln Val Val Lys Leu Pro Phe Ile Asn Phe Met Lys 50 55 60 Thr Arg Gly Thr Ser Phe Leu Asn Ala Tyr Thr Asn Ser Pro Ile Cys 65 70 75 80 Cys Pro Ser Arg Ala Ala Met Trp Ser Gly Leu Phe Thr His Leu Thr 85 90 95 Glu Ser Trp Asn Asn Phe Lys Gly Leu Asp Pro Asn Tyr Thr Thr Trp 100 105 110 Met Asp Val Met Glu Arg His Gly Tyr Arg Thr Gln Lys Phe Gly Lys 115 120 125 Leu Asp Tyr Thr Ser Gly His His Ser Ile Ser Asn Arg Val Glu Ala 130 135 140 Trp Thr Arg Asp Val Ala Phe Leu Leu Arg Gln Glu Gly Arg Pro Met 145 150 155 160 Val Asn Leu Ile Arg Asn Arg Thr Lys Val Arg Val Met Glu Arg Asp 165 170 175 Trp Gln Asn Thr Asp Lys Ala Val Asn Trp Leu Arg Lys Glu Ala Ile 180 185 190 Asn Tyr Thr Glu Pro Phe Val Ile Tyr Leu Gly Leu Asn Leu Pro His 195 200 205 Pro Tyr Pro Ser Pro Ser Ser Gly Glu Asn Phe Gly Ser Ser Thr Phe 210 215 220 His Thr Ser Leu Tyr Trp Leu Glu Lys Val Ser His Asp Ala Ile Lys 225 230 235 240 Ile Pro Lys Trp Ser Pro Leu Ser Glu Met His Pro Val Asp Tyr Tyr 245 250 255 Ser Ser Tyr Thr Lys Asn Cys Thr Gly Arg Phe Thr Lys Lys Glu Ile 260 265 270 Lys Asn Ile Arg Ala Phe Tyr Tyr Ala Met Cys Ala Glu Thr Asp Ala 275 280 285 Met Leu Gly Glu Ile Ile Leu Ala Leu His Gln Leu Asp Leu Leu Gln 290 295 300 Lys Thr Ile Val Ile Tyr Ser Ser Asp His Gly Glu Leu Ala Met Glu 305 310 315 320 His Arg Gln Phe Tyr Lys Met Ser Met Tyr Glu Ala Ser Ala His Val 325 330 335 Pro Leu Leu Met Met Gly Pro Gly Ile Lys Ala Gly Leu Gln Val Ser 340 345 350 Asn Val Val Ser Leu Val Asp Ile Tyr Pro Thr Met Leu Asp Ile Ala 355 360 365 Gly Ile Pro Leu Pro Gln Asn Leu Ser Gly Tyr Ser Leu Leu Pro Leu 370 375 380 Ser Ser Glu Thr Phe Lys Asn Glu His Lys Val Lys Asn Leu His Pro 385 390 395 400 Pro Trp Ile Leu Ser Glu Phe His Gly Cys Asn Val Asn Ala Ser Thr 405 410 415 Tyr Met Leu Arg Thr Asn His Trp Lys Tyr Ile Ala Tyr Ser Asp Gly 420 425 430 Ala Ser Ile Leu Pro Gln Leu Phe Asp Leu Ser Ser Asp Pro Asp Glu 435 440 445 Leu Thr Asn Val Ala Val Lys Phe Pro Glu Ile Thr Tyr Ser Leu Asp 450 455 460 Gln Lys Leu His Ser Ile Ile Asn Tyr Pro Lys Val Ser Ala Ser Val 465 470 475 480 His Gln Tyr Asn Lys Glu Gln Phe Ile Lys Trp Lys Gln Ser Ile Gly 485 490 495 Gln Asn Tyr Ser Asn Val Ile Ala Asn Leu Arg Trp His Gln Asp Trp 500 505 510 Gln Lys Glu Pro Arg Lys Tyr Glu Asn Ala Ile Asp Gln Trp Leu Lys 515 520 525 Thr His Met Asn Pro Arg Ala Val 530 535 352179DNAHomo sapiens 35cacgtgacca accgggtcac atggcccgcg ggacaacatg gctgcgcccg cactagggct 60ggtgtgtgga cgttgccctg agctgggtct cgtcctcttg ctgctgctgc tctcgctgct 120gtgtggagcg gcagggagcc aggaggccgg gaccggtgcg ggcgcggggt cccttgcggg 180ttcttgcggc tgcggcacgc cccagcggcc tggcgcccat ggcagttcgg cagccgctca 240ccgatactcg cgggaggcta acgctccggg ccccgtaccc ggagagcggc aactcgcgca 300ctcaaagatg gtccccatcc ctgctggagt atttacaatg ggcacagatg atcctcagat 360aaagcaggat ggggaagcac ctgcgaggag agttactatt gatgcctttt acatggatgc 420ctatgaagtc agtaatactg aatttgagaa gtttgtgaac tcaactggct atttgacaga 480ggctgagaag tttggcgact cctttgtctt tgaaggcatg ttgagtgagc aagtgaagac 540caatattcaa caggcagttg cagctgctcc ctggtggtta cctgtgaaag gcgctaactg 600gagacaccca gaagggcctg actctactat tctgcacagg ccggatcatc cagttctcca 660tgtgtcctgg aatgatgcgg ttgcctactg cacttgggca gggaagcggc tgcccacgga 720agctgagtgg gaatacagct gtcgaggagg cctgcataat agacttttcc cctggggcaa 780caaactgcag cccaaaggcc agcattatgc caacatttgg cagggcgagt ttccggtgac 840caacactggt gaggatggct tccaaggaac tgcgcctgtt gatgccttcc ctcccaatgg

900ttatggctta tacaacatag tggggaacgc atgggaatgg acttcagact ggtggactgt 960tcatcattct gttgaagaaa cgcttaaccc aaaaggtccc ccttctggga aagaccgagt 1020gaagaaaggt ggatcctaca tgtgccatag gtcttattgt tacaggtatc gctgtgctgc 1080tcggagccag aacacacctg atagctctgc ttcgaatctg ggattccgct gtgcagccga 1140ccgcctgccc actatggact gacaaccaag gaaagtcttc cccagtccaa ggagcagtcg 1200tgtctgacct acattgggct tttctcagaa ctttgaacga tcccatgcaa agaattccca 1260ccctgaggtg ggttacatac ctgcccaatg gccaaaggaa ccgccttgtg agaccaaatt 1320gctgacctgg gtcagtgcat gtgctttatg gtgtggtgca tctttggaga tcatcaccat 1380attttacttt tgagagtctt taaagaggaa ggggagtgga gggaaccctg agctaggctt 1440caggaggccc gcgtcctacg caggctctgc cacaggggtt agaccccagg tccgacgctt 1500gaccttcctg ggcctcaagt gccctcccct atcaaatgaa gggatggaca gcatgacctc 1560tgggtgtctc tccaactcac cagttctaaa aagggtatca gattctattg tgacttcata 1620gtgagaattt attatagatt attttttagc tattttttcc atgtgtgaac cttgagtgat 1680actaatcatg taaagtaaga gttctcttat gtattatttt cggaagaggg gtgtggtgac 1740tcctttatat tcgtactgca ctttgttttt ccaaggaaat cagtgtcttt tacgttgtta 1800tgatgaatcc cacatggggc cggtgatggt atgctgaagt tcagccgttg aacacatagg 1860aatgtctgtg gggtgactct actgtgcttt atcttttaac attaagtgcc tttggttcag 1920aggggcagtc ataagctctg tttccccctc tccccaaagc cttcagcgaa cgtgaaatgt 1980gcgctaaacg gggaaacctg tttaattcta gatataggga aaaaggaacg aggaccttga 2040atgagctata ttcagggtat ccggtatttt gtaataggga ataggaaacc ttgttggctg 2100tggaatatcc gatgctttga atcatgcact gtgttgaata aacgtatctg ctaaatcagg 2160caaaaaaaaa aaaaaaaaa 217936374PRTHomo sapiens 36Met Ala Ala Pro Ala Leu Gly Leu Val Cys Gly Arg Cys Pro Glu Leu 1 5 10 15 Gly Leu Val Leu Leu Leu Leu Leu Leu Ser Leu Leu Cys Gly Ala Ala 20 25 30 Gly Ser Gln Glu Ala Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly 35 40 45 Ser Cys Gly Cys Gly Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser 50 55 60 Ala Ala Ala His Arg Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val 65 70 75 80 Pro Gly Glu Arg Gln Leu Ala His Ser Lys Met Val Pro Ile Pro Ala 85 90 95 Gly Val Phe Thr Met Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly 100 105 110 Glu Ala Pro Ala Arg Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala 115 120 125 Tyr Glu Val Ser Asn Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly 130 135 140 Tyr Leu Thr Glu Ala Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly 145 150 155 160 Met Leu Ser Glu Gln Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala 165 170 175 Ala Pro Trp Trp Leu Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu 180 185 190 Gly Pro Asp Ser Thr Ile Leu His Arg Pro Asp His Pro Val Leu His 195 200 205 Val Ser Trp Asn Asp Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg 210 215 220 Leu Pro Thr Glu Ala Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His 225 230 235 240 Asn Arg Leu Phe Pro Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His 245 250 255 Tyr Ala Asn Ile Trp Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu 260 265 270 Asp Gly Phe Gln Gly Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly 275 280 285 Tyr Gly Leu Tyr Asn Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp 290 295 300 Trp Trp Thr Val His His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly 305 310 315 320 Pro Pro Ser Gly Lys Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys 325 330 335 His Arg Ser Tyr Cys Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn 340 345 350 Thr Pro Asp Ser Ser Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp 355 360 365 Arg Leu Pro Thr Met Asp 370 3728PRTSolanum tuberosum 37Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp 20 25 381524DNAHomo sapiens 38atgagctgcc ccgtgcccgc ctgctgcgcg ctgctgctag tcctggggct ctgccgggcg 60cgtccccgga acgcactgct gctcctcgcg gatgacggag gctttgagag tggcgcgtac 120aacaacagcg ccatcgccac cccgcacctg gacgccttgg cccgccgcag cctcctcttt 180cgcaatgcct tcacctcggt cagcagctgc tctcccagcc gcgccagcct cctcactggc 240ctgccccagc atcagaatgg gatgtacggg ctgcaccagg acgtgcacca cttcaactcc 300ttcgacaagg tgcggagcct gccgctgctg ctcagccaag ctggtgtgcg cacaggcatc 360atcgggaaga agcacgtggg gccggagacc gtgtacccgt ttgactttgc gtacacggag 420gagaatggct ccgtcctcca ggtggggcgg aacatcacta gaattaagct gctcgtccgg 480aaattcctgc agactcagga tgaccggcct ttcttcctct acgtcgcctt ccacgacccc 540caccgctgtg ggcactccca gccccagtac ggaaccttct gtgagaagtt tggcaacgga 600gagagcggca tgggtcgtat cccagactgg accccccagg cctacgaccc actggacgtg 660ctggtgcctt acttcgtccc caacaccccg gcagcccgag ccgacctggc cgctcagtac 720accaccgtcg gccgcatgga ccaaggagtt ggactggtgc tccaggagct gcgtgacgcc 780ggtgtcctga acgacacact ggtgatcttc acgtccgaca acgggatccc cttccccagc 840ggcaggacca acctgtactg gccgggcact gctgaaccct tactggtgtc atccccggag 900cacccaaaac gctggggcca agtcagcgag gcctacgtga gcctcctaga cctcacgccc 960accatcttgg attggttctc gatcccgtac cccagctacg ccatctttgg ctcgaagacc 1020atccacctca ctggccggtc cctcctgccg gcgctggagg ccgagcccct ctgggccacc 1080gtctttggca gccagagcca ccacgaggtc accatgtcct accccatgcg ctccgtgcag 1140caccggcact tccgcctcgt gcacaacctc aacttcaaga tgccctttcc catcgaccag 1200gacttctacg tctcacccac cttccaggac ctcctgaacc gcaccacagc tggtcagccc 1260acgggctggt acaaggacct ccgtcattac tactaccggg cgcgctggga actctacgac 1320cggagccggg acccccacga gacccagaac ctggccaccg acccgcgctt tgctcagctt 1380ctggagatgc ttcgggacca gctggccaag tggcagtggg agacccacga cccctgggtg 1440tgcgcccccg acggcgtcct ggaggagaag ctctctcccc agtgccagcc cctccacaat 1500gagctgcatc atcatcatca tcat 152439508PRTHomo sapiens 39Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu His His His His His His 500 505 401524DNAHomo sapiens 40atgtcttgtc cagttccagc ttgttgcgct ctccttcttg ttcttggatt gtgtagggca 60aggcctagga acgctctttt gcttcttgct gatgatggcg gattcgagtc cggtgcttac 120aacaactctg ctatcgctac tccacacctc gatgctcttg ctaggcgttc tcttcttttc 180cgtaacgctt tcacttccgt gtcctcttgc tcaccttcta gggcttcact tcttactgga 240cttccacagc accagaacgg aatgtacgga cttcatcagg atgtgcacca cttcaactca 300ttcgataagg tgagatccct cccactcctc ttgtctcaag ctggtgttag gactggaatc 360atcggcaaaa agcacgtggg accagagact gtgtacccat tcgatttcgc ttacactgag 420gaaaacggct ccgttcttca agtgggcaga aatattacta ggatcaagct cctcgtgagg 480aagttcctcc agactcaaga tgataggcca ttcttcctct acgtggcatt ccatgatcca 540cataggtgcg gacattctca gccacagtac ggaactttct gcgagaagtt cggaaacggt 600gagtctggta tgggcaggat tccagattgg actccacagg cttacgatcc acttgatgtg 660ctcgttccat acttcgtgcc aaacactcca gctgctagag ctgatcttgc tgctcagtac 720actactgtgg gaaggatgga tcagggtgtg ggacttgtgc ttcaagagct tagagatgct 780ggcgtgctca acgatactct cgtgatcttc acttcagata acggcatccc attcccatcc 840ggaaggacta atctttactg gccaggtact gctgagcctc tccttgtttc ttcaccagag 900catccaaaga ggtggggaca agtttctgag gcttacgtgt cccttctcga tctcactcca 960actatcctcg attggttctc catcccttac ccatcctacg ctatcttcgg ctccaagact 1020atccacctta ctggcagatc tttgctccca gctttggaag ctgaaccact ttgggctact 1080gtgttcggat ctcagtctca ccacgaggtg acaatgtctt acccaatgag atctgtgcag 1140cacaggcact tcaggcttgt tcacaacctc aacttcaaga tgccattccc aatcgatcag 1200gatttctacg tgtcaccaac tttccaggat cttctcaaca ggactactgc aggacaacct 1260actggctggt acaaggatct taggcactac tactataggg ctaggtggga gctttacgat 1320aggtccagag atccacacga gactcagaac cttgctactg atccaaggtt cgctcagctc 1380cttgagatgc ttagggatca gcttgctaag tggcagtggg agactcatga tccatgggtt 1440tgcgctccag atggtgtgct tgaagagaag ttgtctccac agtgccagcc acttcataac 1500gagcttcatc atcaccatca ccac 152441508PRTHomo sapiens 41Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu His His His His His His 500 505 421552DNAHomo sapiens 42aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgaccg tccccggaac gcactgctgc tcctcgcgga 120tgacggaggc tttgagagtg gcgcgtacaa caacagcgcc atcgccaccc cgcacctgga 180cgccttggcc cgccgcagcc tcctctttcg caatgccttc acctcggtca gcagctgctc 240tcccagccgc gccagcctcc tcactggcct gccccagcat cagaatggga tgtacgggct 300gcaccaggac gtgcaccact tcaactcctt cgacaaggtg cggagcctgc cgctgctgct 360cagccaagct ggtgtgcgca caggcatcat cgggaagaag cacgtggggc cggagaccgt 420gtacccgttt gactttgcgt acacggagga gaatggctcc gtcctccagg tggggcggaa 480catcactaga attaagctgc tcgtccggaa attcctgcag actcaggatg accggccttt 540cttcctctac gtcgccttcc acgaccccca ccgctgtggg cactcccagc cccagtacgg 600aaccttctgt gagaagtttg gcaacggaga gagcggcatg ggtcgtatcc cagactggac 660cccccaggcc tacgacccac tggacgtgct ggtgccttac ttcgtcccca acaccccggc 720agcccgagcc gacctggccg ctcagtacac caccgtcggc cgcatggacc aaggagttgg 780actggtgctc caggagctgc gtgacgccgg tgtcctgaac gacacactgg tgatcttcac 840gtccgacaac gggatcccct tccccagcgg caggaccaac ctgtactggc cgggcactgc 900tgaaccctta ctggtgtcat ccccggagca cccaaaacgc tggggccaag tcagcgaggc 960ctacgtgagc ctcctagacc tcacgcccac catcttggat tggttctcga tcccgtaccc 1020cagctacgcc atctttggct cgaagaccat ccacctcact ggccggtccc tcctgccggc 1080gctggaggcc gagcccctct gggccaccgt ctttggcagc cagagccacc acgaggtcac 1140catgtcctac cccatgcgct ccgtgcagca ccggcacttc cgcctcgtgc acaacctcaa 1200cttcaagatg

ccctttccca tcgaccagga cttctacgtc tcacccacct tccaggacct 1260cctgaaccgc accacagctg gtcagcccac gggctggtac aaggacctcc gtcattacta 1320ctaccgggcg cgctgggaac tctacgaccg gagccgggac ccccacgaga cccagaacct 1380ggccaccgac ccgcgctttg ctcagcttct ggagatgctt cgggaccagc tggccaagtg 1440gcagtgggag acccacgacc cctgggtgtg cgcccccgac ggcgtcctgg aggagaagct 1500ctctccccag tgccagcccc tccacaatga gctgcatcat catcatcatc at 155243516PRTHomo sapiens 43Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu His His 500 505 510 His His His His 515 441552DNAHomo sapiens 44aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacag gcctaggaac gctcttttgc ttcttgctga 120tgatggcgga ttcgagtccg gtgcttacaa caactctgct atcgctactc cacacctcga 180tgctcttgct aggcgttctc ttcttttccg taacgctttc acttccgtgt cctcttgctc 240accttctagg gcttcacttc ttactggact tccacagcac cagaacggaa tgtacggact 300tcatcaggat gtgcaccact tcaactcatt cgataaggtg agatccctcc cactcctctt 360gtctcaagct ggtgttagga ctggaatcat cggcaaaaag cacgtgggac cagagactgt 420gtacccattc gatttcgctt acactgagga aaacggctcc gttcttcaag tgggcagaaa 480tattactagg atcaagctcc tcgtgaggaa gttcctccag actcaagatg ataggccatt 540cttcctctac gtggcattcc atgatccaca taggtgcgga cattctcagc cacagtacgg 600aactttctgc gagaagttcg gaaacggtga gtctggtatg ggcaggattc cagattggac 660tccacaggct tacgatccac ttgatgtgct cgttccatac ttcgtgccaa acactccagc 720tgctagagct gatcttgctg ctcagtacac tactgtggga aggatggatc agggtgtggg 780acttgtgctt caagagctta gagatgctgg cgtgctcaac gatactctcg tgatcttcac 840ttcagataac ggcatcccat tcccatccgg aaggactaat ctttactggc caggtactgc 900tgagcctctc cttgtttctt caccagagca tccaaagagg tggggacaag tttctgaggc 960ttacgtgtcc cttctcgatc tcactccaac tatcctcgat tggttctcca tcccttaccc 1020atcctacgct atcttcggct ccaagactat ccaccttact ggcagatctt tgctcccagc 1080tttggaagct gaaccacttt gggctactgt gttcggatct cagtctcacc acgaggtgac 1140aatgtcttac ccaatgagat ctgtgcagca caggcacttc aggcttgttc acaacctcaa 1200cttcaagatg ccattcccaa tcgatcagga tttctacgtg tcaccaactt tccaggatct 1260tctcaacagg actactgcag gacaacctac tggctggtac aaggatctta ggcactacta 1320ctatagggct aggtgggagc tttacgatag gtccagagat ccacacgaga ctcagaacct 1380tgctactgat ccaaggttcg ctcagctcct tgagatgctt agggatcagc ttgctaagtg 1440gcagtgggag actcatgatc catgggtttg cgctccagat ggtgtgcttg aagagaagtt 1500gtctccacag tgccagccac ttcataacga gcttcatcat caccatcacc ac 155245516PRTHomo sapiens 45Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu His His 500 505 510 His His His His 515 462326DNAHomo sapiens 46aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgaccc tgagcccata gtgcgtatcg taggtcgaaa 120tggtctatgt gttgatgtta gggatggaag attccacaac ggaaacgcaa tacagttgtg 180gccatgcaag tctaatacag atgcaaatca gctctggact ttgaaaagag acaatactat 240tcgatctaat ggaaagtgtt taactactta cgggtacagt ccgggagtct atgtgatgat 300ctatgattgc aatactgctg caactgatgc cacccgctgg caaatatggg ataatggaac 360catcataaat cccagatcta gtctagtttt agcagcgaca tcagggaaca gtggtactac 420acttacagtg caaaccaaca tttatgccgt tagtcaaggt tggcttccta ctaataatac 480acaacctttt gtgacaacca ttgttgggct atatggtctg tgcttgcaag caaatagtgg 540acaagtatgg atagaggact gtagcagtga aaaggctgaa caacagtggg ctctttatgc 600agatggttca atacgtcctc agcaaaaccg agataattgc cttacaagtg attctaatat 660acgggaaaca gttgtcaaga tcctctcttg tggccctgca tcctctggcc aacgatggat 720gttcaagaat gatggaacca ttttaaattt gtatagtggg ttggtgttag atgtgagggc 780atcggatccg agccttaaac aaatcattct ttaccctctc catggtgacc caaaccaaat 840atggttacca ttatttctcg agcgtccccg gaacgcactg ctgctcctcg cggatgacgg 900aggctttgag agtggcgcgt acaacaacag cgccatcgcc accccgcacc tggacgcctt 960ggcccgccgc agcctcctct ttcgcaatgc cttcacctcg gtcagcagct gctctcccag 1020ccgcgccagc ctcctcactg gcctgcccca gcatcagaat gggatgtacg ggctgcacca 1080ggacgtgcac cacttcaact ccttcgacaa ggtgcggagc ctgccgctgc tgctcagcca 1140agctggtgtg cgcacaggca tcatcgggaa gaagcacgtg gggccggaga ccgtgtaccc 1200gtttgacttt gcgtacacgg aggagaatgg ctccgtcctc caggtggggc ggaacatcac 1260tagaattaag ctgctcgtcc ggaaattcct gcagactcag gatgaccggc ctttcttcct 1320ctacgtcgcc ttccacgacc cccaccgctg tgggcactcc cagccccagt acggaacctt 1380ctgtgagaag tttggcaacg gagagagcgg catgggtcgt atcccagact ggacccccca 1440ggcctacgac ccactggacg tgctggtgcc ttacttcgtc cccaacaccc cggcagcccg 1500agccgacctg gccgctcagt acaccaccgt cggccgcatg gaccaaggag ttggactggt 1560gctccaggag ctgcgtgacg ccggtgtcct gaacgacaca ctggtgatct tcacgtccga 1620caacgggatc cccttcccca gcggcaggac caacctgtac tggccgggca ctgctgaacc 1680cttactggtg tcatccccgg agcacccaaa acgctggggc caagtcagcg aggcctacgt 1740gagcctccta gacctcacgc ccaccatctt ggattggttc tcgatcccgt accccagcta 1800cgccatcttt ggctcgaaga ccatccacct cactggccgg tccctcctgc cggcgctgga 1860ggccgagccc ctctgggcca ccgtctttgg cagccagagc caccacgagg tcaccatgtc 1920ctaccccatg cgctccgtgc agcaccggca cttccgcctc gtgcacaacc tcaacttcaa 1980gatgcccttt cccatcgacc aggacttcta cgtctcaccc accttccagg acctcctgaa 2040ccgcaccaca gctggtcagc ccacgggctg gtacaaggac ctccgtcatt actactaccg 2100ggcgcgctgg gaactctacg accggagccg ggacccccac gagacccaga acctggccac 2160cgacccgcgc tttgctcagc ttctggagat gcttcgggac cagctggcca agtggcagtg 2220ggagacccac gacccctggg tgtgcgcccc cgacggcgtc ctggaggaga agctctctcc 2280ccagtgccag cccctccaca atgagctgca tcatcatcat catcat 232647774PRTHomo sapiens 47Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Pro Glu Pro Ile 20 25 30 Val Arg Ile Val Gly Arg Asn Gly Leu Cys Val Asp Val Arg Asp Gly 35 40 45 Arg Phe His Asn Gly Asn Ala Ile Gln Leu Trp Pro Cys Lys Ser Asn 50 55 60 Thr Asp Ala Asn Gln Leu Trp Thr Leu Lys Arg Asp Asn Thr Ile Arg 65 70 75 80 Ser Asn Gly Lys Cys Leu Thr Thr Tyr Gly Tyr Ser Pro Gly Val Tyr 85 90 95 Val Met Ile Tyr Asp Cys Asn Thr Ala Ala Thr Asp Ala Thr Arg Trp 100 105 110 Gln Ile Trp Asp Asn Gly Thr Ile Ile Asn Pro Arg Ser Ser Leu Val 115 120 125 Leu Ala Ala Thr Ser Gly Asn Ser Gly Thr Thr Leu Thr Val Gln Thr 130 135 140 Asn Ile Tyr Ala Val Ser Gln Gly Trp Leu Pro Thr Asn Asn Thr Gln 145 150 155 160 Pro Phe Val Thr Thr Ile Val Gly Leu Tyr Gly Leu Cys Leu Gln Ala 165 170 175 Asn Ser Gly Gln Val Trp Ile Glu Asp Cys Ser Ser Glu Lys Ala Glu 180 185 190 Gln Gln Trp Ala Leu Tyr Ala Asp Gly Ser Ile Arg Pro Gln Gln Asn 195 200 205 Arg Asp Asn Cys Leu Thr Ser Asp Ser Asn Ile Arg Glu Thr Val Val 210 215 220 Lys Ile Leu Ser Cys Gly Pro Ala Ser Ser Gly Gln Arg Trp Met Phe 225 230 235 240 Lys Asn Asp Gly Thr Ile Leu Asn Leu Tyr Ser Gly Leu Val Leu Asp 245 250 255 Val Arg Ala Ser Asp Pro Ser Leu Lys Gln Ile Ile Leu Tyr Pro Leu 260 265 270 His Gly Asp Pro Asn Gln Ile Trp Leu Pro Leu Phe Leu Glu Arg Pro 275 280 285 Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly 290 295 300 Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala 305 310 315 320 Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys 325 330 335 Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn 340 345 350 Gly Met Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp 355 360 365 Lys Val Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr 370 375 380 Gly Ile Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe 385 390 395 400 Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg 405 410 415 Asn Ile Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln 420 425 430 Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg 435 440 445 Cys Gly His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly 450 455 460 Asn Gly Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala 465 470 475 480 Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro 485 490 495 Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met 500 505 510 Asp Gln Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val 515 520 525 Leu Asn Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe 530 535 540 Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu 545 550 555 560 Leu Val Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu 565 570 575 Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe 580 585 590 Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His 595 600 605 Leu Thr Gly Arg

Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp 610 615 620 Ala Thr Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr 625 630 635 640 Pro Met Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu 645 650 655 Asn Phe Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro 660 665 670 Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly 675 680 685 Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu 690 695 700 Tyr Asp Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp 705 710 715 720 Pro Arg Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys 725 730 735 Trp Gln Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val 740 745 750 Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu 755 760 765 His His His His His His 770 482326DNAHomo sapiens 48aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgaccc tgagcccata gtgcgtatcg taggtcgaaa 120tggtctatgt gttgatgtta gggatggaag attccacaac ggaaacgcaa tacagttgtg 180gccatgcaag tctaatacag atgcaaatca gctctggact ttgaaaagag acaatactat 240tcgatctaat ggaaagtgtt taactactta cgggtacagt ccgggagtct atgtgatgat 300ctatgattgc aatactgctg caactgatgc cacccgctgg caaatatggg ataatggaac 360catcataaat cccagatcta gtctagtttt agcagcgaca tcagggaaca gtggtactac 420acttacagtg caaaccaaca tttatgccgt tagtcaaggt tggcttccta ctaataatac 480acaacctttt gtgacaacca ttgttgggct atatggtctg tgcttgcaag caaatagtgg 540acaagtatgg atagaggact gtagcagtga aaaggctgaa caacagtggg ctctttatgc 600agatggttca atacgtcctc agcaaaaccg agataattgc cttacaagtg attctaatat 660acgggaaaca gttgtcaaga tcctctcttg tggccctgca tcctctggcc aacgatggat 720gttcaagaat gatggaacca ttttaaattt gtatagtggg ttggtgttag atgtgagggc 780atcggatccg agccttaaac aaatcattct ttaccctctc catggtgacc caaaccaaat 840atggttacca ttatttctcg agaggcctag gaacgctctt ttgcttcttg ctgatgatgg 900cggattcgag tccggtgctt acaacaactc tgctatcgct actccacacc tcgatgctct 960tgctaggcgt tctcttcttt tccgtaacgc tttcacttcc gtgtcctctt gctcaccttc 1020tagggcttca cttcttactg gacttccaca gcaccagaac ggaatgtacg gacttcatca 1080ggatgtgcac cacttcaact cattcgataa ggtgagatcc ctcccactcc tcttgtctca 1140agctggtgtt aggactggaa tcatcggcaa aaagcacgtg ggaccagaga ctgtgtaccc 1200attcgatttc gcttacactg aggaaaacgg ctccgttctt caagtgggca gaaatattac 1260taggatcaag ctcctcgtga ggaagttcct ccagactcaa gatgataggc cattcttcct 1320ctacgtggca ttccatgatc cacataggtg cggacattct cagccacagt acggaacttt 1380ctgcgagaag ttcggaaacg gtgagtctgg tatgggcagg attccagatt ggactccaca 1440ggcttacgat ccacttgatg tgctcgttcc atacttcgtg ccaaacactc cagctgctag 1500agctgatctt gctgctcagt acactactgt gggaaggatg gatcagggtg tgggacttgt 1560gcttcaagag cttagagatg ctggcgtgct caacgatact ctcgtgatct tcacttcaga 1620taacggcatc ccattcccat ccggaaggac taatctttac tggccaggta ctgctgagcc 1680tctccttgtt tcttcaccag agcatccaaa gaggtgggga caagtttctg aggcttacgt 1740gtcccttctc gatctcactc caactatcct cgattggttc tccatccctt acccatccta 1800cgctatcttc ggctccaaga ctatccacct tactggcaga tctttgctcc cagctttgga 1860agctgaacca ctttgggcta ctgtgttcgg atctcagtct caccacgagg tgacaatgtc 1920ttacccaatg agatctgtgc agcacaggca cttcaggctt gttcacaacc tcaacttcaa 1980gatgccattc ccaatcgatc aggatttcta cgtgtcacca actttccagg atcttctcaa 2040caggactact gcaggacaac ctactggctg gtacaaggat cttaggcact actactatag 2100ggctaggtgg gagctttacg ataggtccag agatccacac gagactcaga accttgctac 2160tgatccaagg ttcgctcagc tccttgagat gcttagggat cagcttgcta agtggcagtg 2220ggagactcat gatccatggg tttgcgctcc agatggtgtg cttgaagaga agttgtctcc 2280acagtgccag ccacttcata acgagcttca tcatcaccat caccac 232649774PRTHomo sapiens 49Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Pro Glu Pro Ile 20 25 30 Val Arg Ile Val Gly Arg Asn Gly Leu Cys Val Asp Val Arg Asp Gly 35 40 45 Arg Phe His Asn Gly Asn Ala Ile Gln Leu Trp Pro Cys Lys Ser Asn 50 55 60 Thr Asp Ala Asn Gln Leu Trp Thr Leu Lys Arg Asp Asn Thr Ile Arg 65 70 75 80 Ser Asn Gly Lys Cys Leu Thr Thr Tyr Gly Tyr Ser Pro Gly Val Tyr 85 90 95 Val Met Ile Tyr Asp Cys Asn Thr Ala Ala Thr Asp Ala Thr Arg Trp 100 105 110 Gln Ile Trp Asp Asn Gly Thr Ile Ile Asn Pro Arg Ser Ser Leu Val 115 120 125 Leu Ala Ala Thr Ser Gly Asn Ser Gly Thr Thr Leu Thr Val Gln Thr 130 135 140 Asn Ile Tyr Ala Val Ser Gln Gly Trp Leu Pro Thr Asn Asn Thr Gln 145 150 155 160 Pro Phe Val Thr Thr Ile Val Gly Leu Tyr Gly Leu Cys Leu Gln Ala 165 170 175 Asn Ser Gly Gln Val Trp Ile Glu Asp Cys Ser Ser Glu Lys Ala Glu 180 185 190 Gln Gln Trp Ala Leu Tyr Ala Asp Gly Ser Ile Arg Pro Gln Gln Asn 195 200 205 Arg Asp Asn Cys Leu Thr Ser Asp Ser Asn Ile Arg Glu Thr Val Val 210 215 220 Lys Ile Leu Ser Cys Gly Pro Ala Ser Ser Gly Gln Arg Trp Met Phe 225 230 235 240 Lys Asn Asp Gly Thr Ile Leu Asn Leu Tyr Ser Gly Leu Val Leu Asp 245 250 255 Val Arg Ala Ser Asp Pro Ser Leu Lys Gln Ile Ile Leu Tyr Pro Leu 260 265 270 His Gly Asp Pro Asn Gln Ile Trp Leu Pro Leu Phe Leu Glu Arg Pro 275 280 285 Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly 290 295 300 Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala 305 310 315 320 Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys 325 330 335 Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn 340 345 350 Gly Met Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp 355 360 365 Lys Val Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr 370 375 380 Gly Ile Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe 385 390 395 400 Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg 405 410 415 Asn Ile Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln 420 425 430 Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg 435 440 445 Cys Gly His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly 450 455 460 Asn Gly Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala 465 470 475 480 Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro 485 490 495 Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met 500 505 510 Asp Gln Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val 515 520 525 Leu Asn Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe 530 535 540 Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu 545 550 555 560 Leu Val Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu 565 570 575 Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe 580 585 590 Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His 595 600 605 Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp 610 615 620 Ala Thr Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr 625 630 635 640 Pro Met Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu 645 650 655 Asn Phe Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro 660 665 670 Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly 675 680 685 Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu 690 695 700 Tyr Asp Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp 705 710 715 720 Pro Arg Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys 725 730 735 Trp Gln Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val 740 745 750 Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu 755 760 765 His His His His His His 770 502353DNAHomo sapiens 50aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacgg agaaacttct actcttagga cttcattcac 120aagaaacatc gttggtcgtg atggattgtg cgtggatgtg aggaatggat acgacactga 180tggaactcca cttcagttgt ggccatgtgg aacccagaga aaccaacgat ggacttttga 240ctcagacgat acaatcaggt caatgggtaa atgcatgact gcaaacgggt taaacaatgg 300aagcaatatc gtgatattca actgttctac agctgctgag aacgccatta agtgggaagt 360acctattgat ggcagcatca tcaatccttc ctccggattg gttatgaccg ctcctcgtgc 420tgcatcccgt accatcctgt tgcttgagga caatatctac gccgctagcc agggttggac 480tgtgacaaac aatgtaaagc ccatcgttgc ttccattgtg ggttataaag aaatgtgctt 540gcagtctaac ggtgaaaaca atggtgtttg gatggaggat tgtgaggcca ccagtttgca 600gcaacagtgg gcactctatg gtgaccgtac catccgagta aatagtactc gtggcttatg 660cgtcaccacc aatgggtaca actccaagga tctcatcatc atccttaaat gccaaggatt 720gcccagccag aggtggtttt tcaactccga cggcgccatc gtaaacccaa agtcaagaca 780tgttatggat gtgagagcaa gcaatgtctc tcttcgagaa atcattatct ttccagccac 840tgggaaccct aatcagcaat gggtgacaca agtccttcca agtctcgagc gtccccggaa 900cgcactgctg ctcctcgcgg atgacggagg ctttgagagt ggcgcgtaca acaacagcgc 960catcgccacc ccgcacctgg acgccttggc ccgccgcagc ctcctctttc gcaatgcctt 1020cacctcggtc agcagctgct ctcccagccg cgccagcctc ctcactggcc tgccccagca 1080tcagaatggg atgtacgggc tgcaccagga cgtgcaccac ttcaactcct tcgacaaggt 1140gcggagcctg ccgctgctgc tcagccaagc tggtgtgcgc acaggcatca tcgggaagaa 1200gcacgtgggg ccggagaccg tgtacccgtt tgactttgcg tacacggagg agaatggctc 1260cgtcctccag gtggggcgga acatcactag aattaagctg ctcgtccgga aattcctgca 1320gactcaggat gaccggcctt tcttcctcta cgtcgccttc cacgaccccc accgctgtgg 1380gcactcccag ccccagtacg gaaccttctg tgagaagttt ggcaacggag agagcggcat 1440gggtcgtatc ccagactgga ccccccaggc ctacgaccca ctggacgtgc tggtgcctta 1500cttcgtcccc aacaccccgg cagcccgagc cgacctggcc gctcagtaca ccaccgtcgg 1560ccgcatggac caaggagttg gactggtgct ccaggagctg cgtgacgccg gtgtcctgaa 1620cgacacactg gtgatcttca cgtccgacaa cgggatcccc ttccccagcg gcaggaccaa 1680cctgtactgg ccgggcactg ctgaaccctt actggtgtca tccccggagc acccaaaacg 1740ctggggccaa gtcagcgagg cctacgtgag cctcctagac ctcacgccca ccatcttgga 1800ttggttctcg atcccgtacc ccagctacgc catctttggc tcgaagacca tccacctcac 1860tggccggtcc ctcctgccgg cgctggaggc cgagcccctc tgggccaccg tctttggcag 1920ccagagccac cacgaggtca ccatgtccta ccccatgcgc tccgtgcagc accggcactt 1980ccgcctcgtg cacaacctca acttcaagat gccctttccc atcgaccagg acttctacgt 2040ctcacccacc ttccaggacc tcctgaaccg caccacagct ggtcagccca cgggctggta 2100caaggacctc cgtcattact actaccgggc gcgctgggaa ctctacgacc ggagccggga 2160cccccacgag acccagaacc tggccaccga cccgcgcttt gctcagcttc tggagatgct 2220tcgggaccag ctggccaagt ggcagtggga gacccacgac ccctgggtgt gcgcccccga 2280cggcgtcctg gaggagaagc tctctcccca gtgccagccc ctccacaatg agctgcatca 2340tcatcatcat cat 235351783PRTHomo sapiens 51Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Gly Glu Thr Ser 20 25 30 Thr Leu Arg Thr Ser Phe Thr Arg Asn Ile Val Gly Arg Asp Gly Leu 35 40 45 Cys Val Asp Val Arg Asn Gly Tyr Asp Thr Asp Gly Thr Pro Leu Gln 50 55 60 Leu Trp Pro Cys Gly Thr Gln Arg Asn Gln Arg Trp Thr Phe Asp Ser 65 70 75 80 Asp Asp Thr Ile Arg Ser Met Gly Lys Cys Met Thr Ala Asn Gly Leu 85 90 95 Asn Asn Gly Ser Asn Ile Val Ile Phe Asn Cys Ser Thr Ala Ala Glu 100 105 110 Asn Ala Ile Lys Trp Glu Val Pro Ile Asp Gly Ser Ile Ile Asn Pro 115 120 125 Ser Ser Gly Leu Val Met Thr Ala Pro Arg Ala Ala Ser Arg Thr Ile 130 135 140 Leu Leu Leu Glu Asp Asn Ile Tyr Ala Ala Ser Gln Gly Trp Thr Val 145 150 155 160 Thr Asn Asn Val Lys Pro Ile Val Ala Ser Ile Val Gly Tyr Lys Glu 165 170 175 Met Cys Leu Gln Ser Asn Gly Glu Asn Asn Gly Val Trp Met Glu Asp 180 185 190 Cys Glu Ala Thr Ser Leu Gln Gln Gln Trp Ala Leu Tyr Gly Asp Arg 195 200 205 Thr Ile Arg Val Asn Ser Thr Arg Gly Leu Cys Val Thr Thr Asn Gly 210 215 220 Tyr Asn Ser Lys Asp Leu Ile Ile Ile Leu Lys Cys Gln Gly Leu Pro 225 230 235 240 Ser Gln Arg Trp Phe Phe Asn Ser Asp Gly Ala Ile Val Asn Pro Lys 245 250 255 Ser Arg His Val Met Asp Val Arg Ala Ser Asn Val Ser Leu Arg Glu 260 265 270 Ile Ile Ile Phe Pro Ala Thr Gly Asn Pro Asn Gln Gln Trp Val Thr 275 280 285 Gln Val Leu Pro Ser Leu Glu Arg Pro Arg Asn Ala Leu Leu Leu Leu 290 295 300 Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile 305 310 315 320 Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg 325 330 335 Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu 340 345 350 Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln 355 360 365 Asp Val His His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu 370 375 380 Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His 385 390 395 400 Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu 405 410 415 Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu 420 425 430 Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu 435 440 445 Tyr Val Ala Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln 450 455 460 Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly 465 470 475 480 Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu 485 490 495 Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala 500 505 510 Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val 515 520 525 Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile 530 535 540 Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu 545 550 555 560 Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His 565 570 575 Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp 580 585 590 Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr 595 600 605 Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu 610 615 620 Pro Ala Leu Glu Ala Glu Pro Leu

Trp Ala Thr Val Phe Gly Ser Gln 625 630 635 640 Ser His His Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His 645 650 655 Arg His Phe Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro 660 665 670 Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn 675 680 685 Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His 690 695 700 Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro 705 710 715 720 His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu 725 730 735 Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp 740 745 750 Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro 755 760 765 Gln Cys Gln Pro Leu His Asn Glu Leu His His His His His His 770 775 780 522353DNAHomo sapiens 52aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacgg agaaacttct actcttagga cttcattcac 120aagaaacatc gttggtcgtg atggattgtg cgtggatgtg aggaatggat acgacactga 180tggaactcca cttcagttgt ggccatgtgg aacccagaga aaccaacgat ggacttttga 240ctcagacgat acaatcaggt caatgggtaa atgcatgact gcaaacgggt taaacaatgg 300aagcaatatc gtgatattca actgttctac agctgctgag aacgccatta agtgggaagt 360acctattgat ggcagcatca tcaatccttc ctccggattg gttatgaccg ctcctcgtgc 420tgcatcccgt accatcctgt tgcttgagga caatatctac gccgctagcc agggttggac 480tgtgacaaac aatgtaaagc ccatcgttgc ttccattgtg ggttataaag aaatgtgctt 540gcagtctaac ggtgaaaaca atggtgtttg gatggaggat tgtgaggcca ccagtttgca 600gcaacagtgg gcactctatg gtgaccgtac catccgagta aatagtactc gtggcttatg 660cgtcaccacc aatgggtaca actccaagga tctcatcatc atccttaaat gccaaggatt 720gcccagccag aggtggtttt tcaactccga cggcgccatc gtaaacccaa agtcaagaca 780tgttatggat gtgagagcaa gcaatgtctc tcttcgagaa atcattatct ttccagccac 840tgggaaccct aatcagcaat gggtgacaca agtccttcca agtctcgaga ggcctaggaa 900cgctcttttg cttcttgctg atgatggcgg attcgagtcc ggtgcttaca acaactctgc 960tatcgctact ccacacctcg atgctcttgc taggcgttct cttcttttcc gtaacgcttt 1020cacttccgtg tcctcttgct caccttctag ggcttcactt cttactggac ttccacagca 1080ccagaacgga atgtacggac ttcatcagga tgtgcaccac ttcaactcat tcgataaggt 1140gagatccctc ccactcctct tgtctcaagc tggtgttagg actggaatca tcggcaaaaa 1200gcacgtggga ccagagactg tgtacccatt cgatttcgct tacactgagg aaaacggctc 1260cgttcttcaa gtgggcagaa atattactag gatcaagctc ctcgtgagga agttcctcca 1320gactcaagat gataggccat tcttcctcta cgtggcattc catgatccac ataggtgcgg 1380acattctcag ccacagtacg gaactttctg cgagaagttc ggaaacggtg agtctggtat 1440gggcaggatt ccagattgga ctccacaggc ttacgatcca cttgatgtgc tcgttccata 1500cttcgtgcca aacactccag ctgctagagc tgatcttgct gctcagtaca ctactgtggg 1560aaggatggat cagggtgtgg gacttgtgct tcaagagctt agagatgctg gcgtgctcaa 1620cgatactctc gtgatcttca cttcagataa cggcatccca ttcccatccg gaaggactaa 1680tctttactgg ccaggtactg ctgagcctct ccttgtttct tcaccagagc atccaaagag 1740gtggggacaa gtttctgagg cttacgtgtc ccttctcgat ctcactccaa ctatcctcga 1800ttggttctcc atcccttacc catcctacgc tatcttcggc tccaagacta tccaccttac 1860tggcagatct ttgctcccag ctttggaagc tgaaccactt tgggctactg tgttcggatc 1920tcagtctcac cacgaggtga caatgtctta cccaatgaga tctgtgcagc acaggcactt 1980caggcttgtt cacaacctca acttcaagat gccattccca atcgatcagg atttctacgt 2040gtcaccaact ttccaggatc ttctcaacag gactactgca ggacaaccta ctggctggta 2100caaggatctt aggcactact actatagggc taggtgggag ctttacgata ggtccagaga 2160tccacacgag actcagaacc ttgctactga tccaaggttc gctcagctcc ttgagatgct 2220tagggatcag cttgctaagt ggcagtggga gactcatgat ccatgggttt gcgctccaga 2280tggtgtgctt gaagagaagt tgtctccaca gtgccagcca cttcataacg agcttcatca 2340tcaccatcac cac 235353783PRTHomo sapiens 53Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Gly Glu Thr Ser 20 25 30 Thr Leu Arg Thr Ser Phe Thr Arg Asn Ile Val Gly Arg Asp Gly Leu 35 40 45 Cys Val Asp Val Arg Asn Gly Tyr Asp Thr Asp Gly Thr Pro Leu Gln 50 55 60 Leu Trp Pro Cys Gly Thr Gln Arg Asn Gln Arg Trp Thr Phe Asp Ser 65 70 75 80 Asp Asp Thr Ile Arg Ser Met Gly Lys Cys Met Thr Ala Asn Gly Leu 85 90 95 Asn Asn Gly Ser Asn Ile Val Ile Phe Asn Cys Ser Thr Ala Ala Glu 100 105 110 Asn Ala Ile Lys Trp Glu Val Pro Ile Asp Gly Ser Ile Ile Asn Pro 115 120 125 Ser Ser Gly Leu Val Met Thr Ala Pro Arg Ala Ala Ser Arg Thr Ile 130 135 140 Leu Leu Leu Glu Asp Asn Ile Tyr Ala Ala Ser Gln Gly Trp Thr Val 145 150 155 160 Thr Asn Asn Val Lys Pro Ile Val Ala Ser Ile Val Gly Tyr Lys Glu 165 170 175 Met Cys Leu Gln Ser Asn Gly Glu Asn Asn Gly Val Trp Met Glu Asp 180 185 190 Cys Glu Ala Thr Ser Leu Gln Gln Gln Trp Ala Leu Tyr Gly Asp Arg 195 200 205 Thr Ile Arg Val Asn Ser Thr Arg Gly Leu Cys Val Thr Thr Asn Gly 210 215 220 Tyr Asn Ser Lys Asp Leu Ile Ile Ile Leu Lys Cys Gln Gly Leu Pro 225 230 235 240 Ser Gln Arg Trp Phe Phe Asn Ser Asp Gly Ala Ile Val Asn Pro Lys 245 250 255 Ser Arg His Val Met Asp Val Arg Ala Ser Asn Val Ser Leu Arg Glu 260 265 270 Ile Ile Ile Phe Pro Ala Thr Gly Asn Pro Asn Gln Gln Trp Val Thr 275 280 285 Gln Val Leu Pro Ser Leu Glu Arg Pro Arg Asn Ala Leu Leu Leu Leu 290 295 300 Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile 305 310 315 320 Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg 325 330 335 Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu 340 345 350 Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln 355 360 365 Asp Val His His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu 370 375 380 Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His 385 390 395 400 Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu 405 410 415 Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu 420 425 430 Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu 435 440 445 Tyr Val Ala Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln 450 455 460 Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly 465 470 475 480 Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu 485 490 495 Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala 500 505 510 Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val 515 520 525 Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile 530 535 540 Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu 545 550 555 560 Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His 565 570 575 Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp 580 585 590 Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr 595 600 605 Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu 610 615 620 Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln 625 630 635 640 Ser His His Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His 645 650 655 Arg His Phe Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro 660 665 670 Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn 675 680 685 Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His 690 695 700 Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro 705 710 715 720 His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu 725 730 735 Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp 740 745 750 Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro 755 760 765 Gln Cys Gln Pro Leu His Asn Glu Leu His His His His His His 770 775 780 542298DNAHomo sapiens 54atgagctgcc ccgtgcccgc ctgctgcgcg ctgctgctag tcctggggct ctgccgggcg 60cgtccccgga acgcactgct gctcctcgcg gatgacggag gctttgagag tggcgcgtac 120aacaacagcg ccatcgccac cccgcacctg gacgccttgg cccgccgcag cctcctcttt 180cgcaatgcct tcacctcggt cagcagctgc tctcccagcc gcgccagcct cctcactggc 240ctgccccagc atcagaatgg gatgtacggg ctgcaccagg acgtgcacca cttcaactcc 300ttcgacaagg tgcggagcct gccgctgctg ctcagccaag ctggtgtgcg cacaggcatc 360atcgggaaga agcacgtggg gccggagacc gtgtacccgt ttgactttgc gtacacggag 420gagaatggct ccgtcctcca ggtggggcgg aacatcacta gaattaagct gctcgtccgg 480aaattcctgc agactcagga tgaccggcct ttcttcctct acgtcgcctt ccacgacccc 540caccgctgtg ggcactccca gccccagtac ggaaccttct gtgagaagtt tggcaacgga 600gagagcggca tgggtcgtat cccagactgg accccccagg cctacgaccc actggacgtg 660ctggtgcctt acttcgtccc caacaccccg gcagcccgag ccgacctggc cgctcagtac 720accaccgtcg gccgcatgga ccaaggagtt ggactggtgc tccaggagct gcgtgacgcc 780ggtgtcctga acgacacact ggtgatcttc acgtccgaca acgggatccc cttccccagc 840ggcaggacca acctgtactg gccgggcact gctgaaccct tactggtgtc atccccggag 900cacccaaaac gctggggcca agtcagcgag gcctacgtga gcctcctaga cctcacgccc 960accatcttgg attggttctc gatcccgtac cccagctacg ccatctttgg ctcgaagacc 1020atccacctca ctggccggtc cctcctgccg gcgctggagg ccgagcccct ctgggccacc 1080gtctttggca gccagagcca ccacgaggtc accatgtcct accccatgcg ctccgtgcag 1140caccggcact tccgcctcgt gcacaacctc aacttcaaga tgccctttcc catcgaccag 1200gacttctacg tctcacccac cttccaggac ctcctgaacc gcaccacagc tggtcagccc 1260acgggctggt acaaggacct ccgtcattac tactaccggg cgcgctggga actctacgac 1320cggagccggg acccccacga gacccagaac ctggccaccg acccgcgctt tgctcagctt 1380ctggagatgc ttcgggacca gctggccaag tggcagtggg agacccacga cccctgggtg 1440tgcgcccccg acggcgtcct ggaggagaag ctctctcccc agtgccagcc cctccacaat 1500gagctgctcg agcctgagcc catagtgcgt atcgtaggtc gaaatggtct atgtgttgat 1560gttagggatg gaagattcca caacggaaac gcaatacagt tgtggccatg caagtctaat 1620acagatgcaa atcagctctg gactttgaaa agagacaata ctattcgatc taatggaaag 1680tgtttaacta cttacgggta cagtccggga gtctatgtga tgatctatga ttgcaatact 1740gctgcaactg atgccacccg ctggcaaata tgggataatg gaaccatcat aaatcccaga 1800tctagtctag ttttagcagc gacatcaggg aacagtggta ctacacttac agtgcaaacc 1860aacatttatg ccgttagtca aggttggctt cctactaata atacacaacc ttttgtgaca 1920accattgttg ggctatatgg tctgtgcttg caagcaaata gtggacaagt atggatagag 1980gactgtagca gtgaaaaggc tgaacaacag tgggctcttt atgcagatgg ttcaatacgt 2040cctcagcaaa accgagataa ttgccttaca agtgattcta atatacggga aacagttgtc 2100aagatcctct cttgtggccc tgcatcctct ggccaacgat ggatgttcaa gaatgatgga 2160accattttaa atttgtatag tgggttggtg ttagatgtga gggcatcgga tccgagcctt 2220aaacaaatca ttctttaccc tctccatggt gacccaaacc aaatatggtt accattattt 2280catcatcatc accaccac 229855766PRTHomo sapiens 55Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu Leu Glu Pro Glu Pro Ile Val Arg Ile Val 500 505 510 Gly Arg Asn Gly Leu Cys Val Asp Val Arg Asp Gly Arg Phe His Asn 515 520 525 Gly Asn Ala Ile Gln Leu Trp Pro Cys Lys Ser Asn Thr Asp Ala Asn 530 535 540 Gln Leu Trp Thr Leu Lys Arg Asp Asn Thr Ile Arg Ser Asn Gly Lys 545 550 555 560 Cys Leu Thr Thr Tyr Gly Tyr Ser Pro Gly Val Tyr Val Met Ile Tyr 565 570 575 Asp Cys Asn Thr Ala Ala Thr Asp Ala Thr Arg Trp Gln Ile Trp Asp 580 585 590 Asn Gly Thr Ile Ile Asn Pro Arg Ser Ser Leu Val Leu Ala Ala Thr 595 600 605 Ser Gly Asn Ser Gly Thr Thr Leu Thr Val Gln Thr Asn Ile Tyr Ala 610 615 620 Val Ser Gln Gly Trp Leu Pro Thr

Asn Asn Thr Gln Pro Phe Val Thr 625 630 635 640 Thr Ile Val Gly Leu Tyr Gly Leu Cys Leu Gln Ala Asn Ser Gly Gln 645 650 655 Val Trp Ile Glu Asp Cys Ser Ser Glu Lys Ala Glu Gln Gln Trp Ala 660 665 670 Leu Tyr Ala Asp Gly Ser Ile Arg Pro Gln Gln Asn Arg Asp Asn Cys 675 680 685 Leu Thr Ser Asp Ser Asn Ile Arg Glu Thr Val Val Lys Ile Leu Ser 690 695 700 Cys Gly Pro Ala Ser Ser Gly Gln Arg Trp Met Phe Lys Asn Asp Gly 705 710 715 720 Thr Ile Leu Asn Leu Tyr Ser Gly Leu Val Leu Asp Val Arg Ala Ser 725 730 735 Asp Pro Ser Leu Lys Gln Ile Ile Leu Tyr Pro Leu His Gly Asp Pro 740 745 750 Asn Gln Ile Trp Leu Pro Leu Phe His His His His His His 755 760 765 562298DNAHomo sapiens 56atgtcttgtc cagttccagc ttgttgcgct ctccttcttg ttcttggatt gtgtagggca 60aggcctagga acgctctttt gcttcttgct gatgatggcg gattcgagtc cggtgcttac 120aacaactctg ctatcgctac tccacacctc gatgctcttg ctaggcgttc tcttcttttc 180cgtaacgctt tcacttccgt gtcctcttgc tcaccttcta gggcttcact tcttactgga 240cttccacagc accagaacgg aatgtacgga cttcatcagg atgtgcacca cttcaactca 300ttcgataagg tgagatccct cccactcctc ttgtctcaag ctggtgttag gactggaatc 360atcggcaaaa agcacgtggg accagagact gtgtacccat tcgatttcgc ttacactgag 420gaaaacggct ccgttcttca agtgggcaga aatattacta ggatcaagct cctcgtgagg 480aagttcctcc agactcaaga tgataggcca ttcttcctct acgtggcatt ccatgatcca 540cataggtgcg gacattctca gccacagtac ggaactttct gcgagaagtt cggaaacggt 600gagtctggta tgggcaggat tccagattgg actccacagg cttacgatcc acttgatgtg 660ctcgttccat acttcgtgcc aaacactcca gctgctagag ctgatcttgc tgctcagtac 720actactgtgg gaaggatgga tcagggtgtg ggacttgtgc ttcaagagct tagagatgct 780ggcgtgctca acgatactct cgtgatcttc acttcagata acggcatccc attcccatcc 840ggaaggacta atctttactg gccaggtact gctgagcctc tccttgtttc ttcaccagag 900catccaaaga ggtggggaca agtttctgag gcttacgtgt cccttctcga tctcactcca 960actatcctcg attggttctc catcccttac ccatcctacg ctatcttcgg ctccaagact 1020atccacctta ctggcagatc tttgctccca gctttggaag ctgaaccact ttgggctact 1080gtgttcggat ctcagtctca ccacgaggtg acaatgtctt acccaatgag atctgtgcag 1140cacaggcact tcaggcttgt tcacaacctc aacttcaaga tgccattccc aatcgatcag 1200gatttctacg tgtcaccaac tttccaggat cttctcaaca ggactactgc aggacaacct 1260actggctggt acaaggatct taggcactac tactataggg ctaggtggga gctttacgat 1320aggtccagag atccacacga gactcagaac cttgctactg atccaaggtt cgctcagctc 1380cttgagatgc ttagggatca gcttgctaag tggcagtggg agactcatga tccatgggtt 1440tgcgctccag atggtgtgct tgaagagaag ttgtctccac agtgccagcc acttcataac 1500gagcttctcg agcctgagcc catagtgcgt atcgtaggtc gaaatggtct atgtgttgat 1560gttagggatg gaagattcca caacggaaac gcaatacagt tgtggccatg caagtctaat 1620acagatgcaa atcagctctg gactttgaaa agagacaata ctattcgatc taatggaaag 1680tgtttaacta cttacgggta cagtccggga gtctatgtga tgatctatga ttgcaatact 1740gctgcaactg atgccacccg ctggcaaata tgggataatg gaaccatcat aaatcccaga 1800tctagtctag ttttagcagc gacatcaggg aacagtggta ctacacttac agtgcaaacc 1860aacatttatg ccgttagtca aggttggctt cctactaata atacacaacc ttttgtgaca 1920accattgttg ggctatatgg tctgtgcttg caagcaaata gtggacaagt atggatagag 1980gactgtagca gtgaaaaggc tgaacaacag tgggctcttt atgcagatgg ttcaatacgt 2040cctcagcaaa accgagataa ttgccttaca agtgattcta atatacggga aacagttgtc 2100aagatcctct cttgtggccc tgcatcctct ggccaacgat ggatgttcaa gaatgatgga 2160accattttaa atttgtatag tgggttggtg ttagatgtga gggcatcgga tccgagcctt 2220aaacaaatca ttctttaccc tctccatggt gacccaaacc aaatatggtt accattattt 2280catcatcatc accaccac 229857766PRTHomo sapiens 57Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu Leu Glu Pro Glu Pro Ile Val Arg Ile Val 500 505 510 Gly Arg Asn Gly Leu Cys Val Asp Val Arg Asp Gly Arg Phe His Asn 515 520 525 Gly Asn Ala Ile Gln Leu Trp Pro Cys Lys Ser Asn Thr Asp Ala Asn 530 535 540 Gln Leu Trp Thr Leu Lys Arg Asp Asn Thr Ile Arg Ser Asn Gly Lys 545 550 555 560 Cys Leu Thr Thr Tyr Gly Tyr Ser Pro Gly Val Tyr Val Met Ile Tyr 565 570 575 Asp Cys Asn Thr Ala Ala Thr Asp Ala Thr Arg Trp Gln Ile Trp Asp 580 585 590 Asn Gly Thr Ile Ile Asn Pro Arg Ser Ser Leu Val Leu Ala Ala Thr 595 600 605 Ser Gly Asn Ser Gly Thr Thr Leu Thr Val Gln Thr Asn Ile Tyr Ala 610 615 620 Val Ser Gln Gly Trp Leu Pro Thr Asn Asn Thr Gln Pro Phe Val Thr 625 630 635 640 Thr Ile Val Gly Leu Tyr Gly Leu Cys Leu Gln Ala Asn Ser Gly Gln 645 650 655 Val Trp Ile Glu Asp Cys Ser Ser Glu Lys Ala Glu Gln Gln Trp Ala 660 665 670 Leu Tyr Ala Asp Gly Ser Ile Arg Pro Gln Gln Asn Arg Asp Asn Cys 675 680 685 Leu Thr Ser Asp Ser Asn Ile Arg Glu Thr Val Val Lys Ile Leu Ser 690 695 700 Cys Gly Pro Ala Ser Ser Gly Gln Arg Trp Met Phe Lys Asn Asp Gly 705 710 715 720 Thr Ile Leu Asn Leu Tyr Ser Gly Leu Val Leu Asp Val Arg Ala Ser 725 730 735 Asp Pro Ser Leu Lys Gln Ile Ile Leu Tyr Pro Leu His Gly Asp Pro 740 745 750 Asn Gln Ile Trp Leu Pro Leu Phe His His His His His His 755 760 765 582326DNAHomo sapiens 58aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgaccg tccccggaac gcactgctgc tcctcgcgga 120tgacggaggc tttgagagtg gcgcgtacaa caacagcgcc atcgccaccc cgcacctgga 180cgccttggcc cgccgcagcc tcctctttcg caatgccttc acctcggtca gcagctgctc 240tcccagccgc gccagcctcc tcactggcct gccccagcat cagaatggga tgtacgggct 300gcaccaggac gtgcaccact tcaactcctt cgacaaggtg cggagcctgc cgctgctgct 360cagccaagct ggtgtgcgca caggcatcat cgggaagaag cacgtggggc cggagaccgt 420gtacccgttt gactttgcgt acacggagga gaatggctcc gtcctccagg tggggcggaa 480catcactaga attaagctgc tcgtccggaa attcctgcag actcaggatg accggccttt 540cttcctctac gtcgccttcc acgaccccca ccgctgtggg cactcccagc cccagtacgg 600aaccttctgt gagaagtttg gcaacggaga gagcggcatg ggtcgtatcc cagactggac 660cccccaggcc tacgacccac tggacgtgct ggtgccttac ttcgtcccca acaccccggc 720agcccgagcc gacctggccg ctcagtacac caccgtcggc cgcatggacc aaggagttgg 780actggtgctc caggagctgc gtgacgccgg tgtcctgaac gacacactgg tgatcttcac 840gtccgacaac gggatcccct tccccagcgg caggaccaac ctgtactggc cgggcactgc 900tgaaccctta ctggtgtcat ccccggagca cccaaaacgc tggggccaag tcagcgaggc 960ctacgtgagc ctcctagacc tcacgcccac catcttggat tggttctcga tcccgtaccc 1020cagctacgcc atctttggct cgaagaccat ccacctcact ggccggtccc tcctgccggc 1080gctggaggcc gagcccctct gggccaccgt ctttggcagc cagagccacc acgaggtcac 1140catgtcctac cccatgcgct ccgtgcagca ccggcacttc cgcctcgtgc acaacctcaa 1200cttcaagatg ccctttccca tcgaccagga cttctacgtc tcacccacct tccaggacct 1260cctgaaccgc accacagctg gtcagcccac gggctggtac aaggacctcc gtcattacta 1320ctaccgggcg cgctgggaac tctacgaccg gagccgggac ccccacgaga cccagaacct 1380ggccaccgac ccgcgctttg ctcagcttct ggagatgctt cgggaccagc tggccaagtg 1440gcagtgggag acccacgacc cctgggtgtg cgcccccgac ggcgtcctgg aggagaagct 1500ctctccccag tgccagcccc tccacaatga gctgctcgag cctgagccca tagtgcgtat 1560cgtaggtcga aatggtctat gtgttgatgt tagggatgga agattccaca acggaaacgc 1620aatacagttg tggccatgca agtctaatac agatgcaaat cagctctgga ctttgaaaag 1680agacaatact attcgatcta atggaaagtg tttaactact tacgggtaca gtccgggagt 1740ctatgtgatg atctatgatt gcaatactgc tgcaactgat gccacccgct ggcaaatatg 1800ggataatgga accatcataa atcccagatc tagtctagtt ttagcagcga catcagggaa 1860cagtggtact acacttacag tgcaaaccaa catttatgcc gttagtcaag gttggcttcc 1920tactaataat acacaacctt ttgtgacaac cattgttggg ctatatggtc tgtgcttgca 1980agcaaatagt ggacaagtat ggatagagga ctgtagcagt gaaaaggctg aacaacagtg 2040ggctctttat gcagatggtt caatacgtcc tcagcaaaac cgagataatt gccttacaag 2100tgattctaat atacgggaaa cagttgtcaa gatcctctct tgtggccctg catcctctgg 2160ccaacgatgg atgttcaaga atgatggaac cattttaaat ttgtatagtg ggttggtgtt 2220agatgtgagg gcatcggatc cgagccttaa acaaatcatt ctttaccctc tccatggtga 2280cccaaaccaa atatggttac cattatttca tcatcatcac caccac 232659774PRTHomo sapiens 59Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu Leu Glu 500 505 510 Pro Glu Pro Ile Val Arg Ile Val Gly Arg Asn Gly Leu Cys Val Asp 515 520 525 Val Arg Asp Gly Arg Phe His Asn Gly Asn Ala Ile Gln Leu Trp Pro 530 535 540 Cys Lys Ser Asn Thr Asp Ala Asn Gln Leu Trp Thr Leu Lys Arg Asp 545 550 555 560 Asn Thr Ile Arg Ser Asn Gly Lys Cys Leu Thr Thr Tyr Gly Tyr Ser 565 570 575 Pro Gly Val Tyr Val Met Ile Tyr Asp Cys Asn Thr Ala Ala Thr Asp 580 585 590 Ala Thr Arg Trp Gln Ile Trp Asp Asn Gly Thr Ile Ile Asn Pro Arg 595 600 605 Ser Ser Leu Val Leu Ala Ala Thr Ser Gly Asn Ser Gly Thr Thr Leu 610 615 620 Thr Val Gln Thr Asn Ile Tyr Ala Val Ser Gln Gly Trp Leu Pro Thr 625 630 635 640 Asn Asn Thr Gln Pro Phe Val Thr Thr Ile Val Gly Leu Tyr Gly Leu 645 650 655 Cys Leu Gln Ala Asn Ser Gly Gln Val Trp Ile Glu Asp Cys Ser Ser 660 665 670 Glu Lys Ala

Glu Gln Gln Trp Ala Leu Tyr Ala Asp Gly Ser Ile Arg 675 680 685 Pro Gln Gln Asn Arg Asp Asn Cys Leu Thr Ser Asp Ser Asn Ile Arg 690 695 700 Glu Thr Val Val Lys Ile Leu Ser Cys Gly Pro Ala Ser Ser Gly Gln 705 710 715 720 Arg Trp Met Phe Lys Asn Asp Gly Thr Ile Leu Asn Leu Tyr Ser Gly 725 730 735 Leu Val Leu Asp Val Arg Ala Ser Asp Pro Ser Leu Lys Gln Ile Ile 740 745 750 Leu Tyr Pro Leu His Gly Asp Pro Asn Gln Ile Trp Leu Pro Leu Phe 755 760 765 His His His His His His 770 602326DNAHomo sapiens 60aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacag gcctaggaac gctcttttgc ttcttgctga 120tgatggcgga ttcgagtccg gtgcttacaa caactctgct atcgctactc cacacctcga 180tgctcttgct aggcgttctc ttcttttccg taacgctttc acttccgtgt cctcttgctc 240accttctagg gcttcacttc ttactggact tccacagcac cagaacggaa tgtacggact 300tcatcaggat gtgcaccact tcaactcatt cgataaggtg agatccctcc cactcctctt 360gtctcaagct ggtgttagga ctggaatcat cggcaaaaag cacgtgggac cagagactgt 420gtacccattc gatttcgctt acactgagga aaacggctcc gttcttcaag tgggcagaaa 480tattactagg atcaagctcc tcgtgaggaa gttcctccag actcaagatg ataggccatt 540cttcctctac gtggcattcc atgatccaca taggtgcgga cattctcagc cacagtacgg 600aactttctgc gagaagttcg gaaacggtga gtctggtatg ggcaggattc cagattggac 660tccacaggct tacgatccac ttgatgtgct cgttccatac ttcgtgccaa acactccagc 720tgctagagct gatcttgctg ctcagtacac tactgtggga aggatggatc agggtgtggg 780acttgtgctt caagagctta gagatgctgg cgtgctcaac gatactctcg tgatcttcac 840ttcagataac ggcatcccat tcccatccgg aaggactaat ctttactggc caggtactgc 900tgagcctctc cttgtttctt caccagagca tccaaagagg tggggacaag tttctgaggc 960ttacgtgtcc cttctcgatc tcactccaac tatcctcgat tggttctcca tcccttaccc 1020atcctacgct atcttcggct ccaagactat ccaccttact ggcagatctt tgctcccagc 1080tttggaagct gaaccacttt gggctactgt gttcggatct cagtctcacc acgaggtgac 1140aatgtcttac ccaatgagat ctgtgcagca caggcacttc aggcttgttc acaacctcaa 1200cttcaagatg ccattcccaa tcgatcagga tttctacgtg tcaccaactt tccaggatct 1260tctcaacagg actactgcag gacaacctac tggctggtac aaggatctta ggcactacta 1320ctatagggct aggtgggagc tttacgatag gtccagagat ccacacgaga ctcagaacct 1380tgctactgat ccaaggttcg ctcagctcct tgagatgctt agggatcagc ttgctaagtg 1440gcagtgggag actcatgatc catgggtttg cgctccagat ggtgtgcttg aagagaagtt 1500gtctccacag tgccagccac ttcataacga gcttctcgag cctgagccca tagtgcgtat 1560cgtaggtcga aatggtctat gtgttgatgt tagggatgga agattccaca acggaaacgc 1620aatacagttg tggccatgca agtctaatac agatgcaaat cagctctgga ctttgaaaag 1680agacaatact attcgatcta atggaaagtg tttaactact tacgggtaca gtccgggagt 1740ctatgtgatg atctatgatt gcaatactgc tgcaactgat gccacccgct ggcaaatatg 1800ggataatgga accatcataa atcccagatc tagtctagtt ttagcagcga catcagggaa 1860cagtggtact acacttacag tgcaaaccaa catttatgcc gttagtcaag gttggcttcc 1920tactaataat acacaacctt ttgtgacaac cattgttggg ctatatggtc tgtgcttgca 1980agcaaatagt ggacaagtat ggatagagga ctgtagcagt gaaaaggctg aacaacagtg 2040ggctctttat gcagatggtt caatacgtcc tcagcaaaac cgagataatt gccttacaag 2100tgattctaat atacgggaaa cagttgtcaa gatcctctct tgtggccctg catcctctgg 2160ccaacgatgg atgttcaaga atgatggaac cattttaaat ttgtatagtg ggttggtgtt 2220agatgtgagg gcatcggatc cgagccttaa acaaatcatt ctttaccctc tccatggtga 2280cccaaaccaa atatggttac cattatttca tcatcatcac caccac 232661774PRTHomo sapiens 61Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu Leu Glu 500 505 510 Pro Glu Pro Ile Val Arg Ile Val Gly Arg Asn Gly Leu Cys Val Asp 515 520 525 Val Arg Asp Gly Arg Phe His Asn Gly Asn Ala Ile Gln Leu Trp Pro 530 535 540 Cys Lys Ser Asn Thr Asp Ala Asn Gln Leu Trp Thr Leu Lys Arg Asp 545 550 555 560 Asn Thr Ile Arg Ser Asn Gly Lys Cys Leu Thr Thr Tyr Gly Tyr Ser 565 570 575 Pro Gly Val Tyr Val Met Ile Tyr Asp Cys Asn Thr Ala Ala Thr Asp 580 585 590 Ala Thr Arg Trp Gln Ile Trp Asp Asn Gly Thr Ile Ile Asn Pro Arg 595 600 605 Ser Ser Leu Val Leu Ala Ala Thr Ser Gly Asn Ser Gly Thr Thr Leu 610 615 620 Thr Val Gln Thr Asn Ile Tyr Ala Val Ser Gln Gly Trp Leu Pro Thr 625 630 635 640 Asn Asn Thr Gln Pro Phe Val Thr Thr Ile Val Gly Leu Tyr Gly Leu 645 650 655 Cys Leu Gln Ala Asn Ser Gly Gln Val Trp Ile Glu Asp Cys Ser Ser 660 665 670 Glu Lys Ala Glu Gln Gln Trp Ala Leu Tyr Ala Asp Gly Ser Ile Arg 675 680 685 Pro Gln Gln Asn Arg Asp Asn Cys Leu Thr Ser Asp Ser Asn Ile Arg 690 695 700 Glu Thr Val Val Lys Ile Leu Ser Cys Gly Pro Ala Ser Ser Gly Gln 705 710 715 720 Arg Trp Met Phe Lys Asn Asp Gly Thr Ile Leu Asn Leu Tyr Ser Gly 725 730 735 Leu Val Leu Asp Val Arg Ala Ser Asp Pro Ser Leu Lys Gln Ile Ile 740 745 750 Leu Tyr Pro Leu His Gly Asp Pro Asn Gln Ile Trp Leu Pro Leu Phe 755 760 765 His His His His His His 770 622331DNAHomo sapiens 62atgagctgcc ccgtgcccgc ctgctgcgcg ctgctgctag tcctggggct ctgccgggcg 60cgtccccgga acgcactgct gctcctcgcg gatgacggag gctttgagag tggcgcgtac 120aacaacagcg ccatcgccac cccgcacctg gacgccttgg cccgccgcag cctcctcttt 180cgcaatgcct tcacctcggt cagcagctgc tctcccagcc gcgccagcct cctcactggc 240ctgccccagc atcagaatgg gatgtacggg ctgcaccagg acgtgcacca cttcaactcc 300ttcgacaagg tgcggagcct gccgctgctg ctcagccaag ctggtgtgcg cacaggcatc 360atcgggaaga agcacgtggg gccggagacc gtgtacccgt ttgactttgc gtacacggag 420gagaatggct ccgtcctcca ggtggggcgg aacatcacta gaattaagct gctcgtccgg 480aaattcctgc agactcagga tgaccggcct ttcttcctct acgtcgcctt ccacgacccc 540caccgctgtg ggcactccca gccccagtac ggaaccttct gtgagaagtt tggcaacgga 600gagagcggca tgggtcgtat cccagactgg accccccagg cctacgaccc actggacgtg 660ctggtgcctt acttcgtccc caacaccccg gcagcccgag ccgacctggc cgctcagtac 720accaccgtcg gccgcatgga ccaaggagtt ggactggtgc tccaggagct gcgtgacgcc 780ggtgtcctga acgacacact ggtgatcttc acgtccgaca acgggatccc cttccccagc 840ggcaggacca acctgtactg gccgggcact gctgaaccct tactggtgtc atccccggag 900cacccaaaac gctggggcca agtcagcgag gcctacgtga gcctcctaga cctcacgccc 960accatcttgg attggttctc gatcccgtac cccagctacg ccatctttgg ctcgaagacc 1020atccacctca ctggccggtc cctcctgccg gcgctggagg ccgagcccct ctgggccacc 1080gtctttggca gccagagcca ccacgaggtc accatgtcct accccatgcg ctccgtgcag 1140caccggcact tccgcctcgt gcacaacctc aacttcaaga tgccctttcc catcgaccag 1200gacttctacg tctcacccac cttccaggac ctcctgaacc gcaccacagc tggtcagccc 1260acgggctggt acaaggacct ccgtcattac tactaccggg cgcgctggga actctacgac 1320cggagccggg acccccacga gacccagaac ctggccaccg acccgcgctt tgctcagctt 1380ctggagatgc ttcgggacca gctggccaag tggcagtggg agacccacga cccctgggtg 1440tgcgcccccg acggcgtcct ggaggagaag ctctctcccc agtgccagcc cctccacaat 1500gagctgctcg agggagaaac ttctactctt aggacttcat tcacaagaaa catcgttggt 1560cgtgatggat tgtgcgtgga tgtgaggaat ggatacgaca ctgatggaac tccacttcag 1620ttgtggccat gtggaaccca gagaaaccaa cgatggactt ttgactcaga cgatacaatc 1680aggtcaatgg gtaaatgcat gactgcaaac gggttaaaca atggaagcaa tatcgtgata 1740ttcaactgtt ctacagctgc tgagaacgcc attaagtggg aagtacctat tgatggcagc 1800atcatcaatc cttcctccgg attggttatg accgctcctc gtgctgcatc ccgtaccatc 1860ctgttgcttg aggacaatat ctacgccgct agccagggtt ggactgtgac aaacaatgta 1920aagcccatcg ttgcttccat tgtgggttat aaagaaatgt gcttgcagtc taacggtgaa 1980aacaatggtg tttggatgga ggattgtgag gccaccagtt tgcagcaaca gtgggcactc 2040tatggtgacc gtaccatccg agtaaatagt actcgtggct tatgcgtcac caccaatggg 2100tacaactcca aggatctcat catcatcctt aaatgccaag gattgcccag ccagaggtgg 2160tttttcaact ccgacggcgc catcgtaaac ccaaagtcaa gacatgttat ggatgtgaga 2220gcaagcaatg tctctcttcg agaaatcatt atctttccag ccactgggaa ccctaatcag 2280caatgggtga cacaagtcct tccaagtccc gggcatcatc atcatcatca t 233163777PRTHomo sapiens 63Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu Leu Glu Gly Glu Thr Ser Thr Leu Arg Thr 500 505 510 Ser Phe Thr Arg Asn Ile Val Gly Arg Asp Gly Leu Cys Val Asp Val 515 520 525 Arg Asn Gly Tyr Asp Thr Asp Gly Thr Pro Leu Gln Leu Trp Pro Cys 530 535 540 Gly Thr Gln Arg Asn Gln Arg Trp Thr Phe Asp Ser Asp Asp Thr Ile 545 550 555 560 Arg Ser Met Gly Lys Cys Met Thr Ala Asn Gly Leu Asn Asn Gly Ser 565 570 575 Asn Ile Val Ile Phe Asn Cys Ser Thr Ala Ala Glu Asn Ala Ile Lys 580 585 590 Trp Glu Val Pro Ile Asp Gly Ser Ile Ile Asn Pro Ser Ser Gly Leu 595 600 605 Val Met Thr Ala Pro Arg Ala Ala Ser Arg Thr Ile Leu Leu Leu Glu 610 615 620 Asp Asn Ile Tyr Ala Ala Ser Gln Gly Trp Thr Val Thr Asn Asn Val 625 630 635 640 Lys Pro Ile Val Ala Ser Ile Val Gly Tyr Lys Glu Met Cys Leu Gln 645 650 655 Ser Asn Gly Glu Asn Asn Gly Val Trp Met Glu Asp Cys Glu Ala Thr 660 665 670 Ser Leu Gln Gln Gln Trp Ala Leu Tyr Gly Asp Arg Thr Ile Arg Val 675 680 685 Asn Ser Thr Arg Gly Leu Cys Val Thr Thr Asn Gly Tyr Asn Ser Lys 690 695

700 Asp Leu Ile Ile Ile Leu Lys Cys Gln Gly Leu Pro Ser Gln Arg Trp 705 710 715 720 Phe Phe Asn Ser Asp Gly Ala Ile Val Asn Pro Lys Ser Arg His Val 725 730 735 Met Asp Val Arg Ala Ser Asn Val Ser Leu Arg Glu Ile Ile Ile Phe 740 745 750 Pro Ala Thr Gly Asn Pro Asn Gln Gln Trp Val Thr Gln Val Leu Pro 755 760 765 Ser Pro Gly His His His His His His 770 775 642331DNAHomo sapiens 64atgtcttgtc cagttccagc ttgttgcgct ctccttcttg ttcttggatt gtgtagggca 60aggcctagga acgctctttt gcttcttgct gatgatggcg gattcgagtc cggtgcttac 120aacaactctg ctatcgctac tccacacctc gatgctcttg ctaggcgttc tcttcttttc 180cgtaacgctt tcacttccgt gtcctcttgc tcaccttcta gggcttcact tcttactgga 240cttccacagc accagaacgg aatgtacgga cttcatcagg atgtgcacca cttcaactca 300ttcgataagg tgagatccct cccactcctc ttgtctcaag ctggtgttag gactggaatc 360atcggcaaaa agcacgtggg accagagact gtgtacccat tcgatttcgc ttacactgag 420gaaaacggct ccgttcttca agtgggcaga aatattacta ggatcaagct cctcgtgagg 480aagttcctcc agactcaaga tgataggcca ttcttcctct acgtggcatt ccatgatcca 540cataggtgcg gacattctca gccacagtac ggaactttct gcgagaagtt cggaaacggt 600gagtctggta tgggcaggat tccagattgg actccacagg cttacgatcc acttgatgtg 660ctcgttccat acttcgtgcc aaacactcca gctgctagag ctgatcttgc tgctcagtac 720actactgtgg gaaggatgga tcagggtgtg ggacttgtgc ttcaagagct tagagatgct 780ggcgtgctca acgatactct cgtgatcttc acttcagata acggcatccc attcccatcc 840ggaaggacta atctttactg gccaggtact gctgagcctc tccttgtttc ttcaccagag 900catccaaaga ggtggggaca agtttctgag gcttacgtgt cccttctcga tctcactcca 960actatcctcg attggttctc catcccttac ccatcctacg ctatcttcgg ctccaagact 1020atccacctta ctggcagatc tttgctccca gctttggaag ctgaaccact ttgggctact 1080gtgttcggat ctcagtctca ccacgaggtg acaatgtctt acccaatgag atctgtgcag 1140cacaggcact tcaggcttgt tcacaacctc aacttcaaga tgccattccc aatcgatcag 1200gatttctacg tgtcaccaac tttccaggat cttctcaaca ggactactgc aggacaacct 1260actggctggt acaaggatct taggcactac tactataggg ctaggtggga gctttacgat 1320aggtccagag atccacacga gactcagaac cttgctactg atccaaggtt cgctcagctc 1380cttgagatgc ttagggatca gcttgctaag tggcagtggg agactcatga tccatgggtt 1440tgcgctccag atggtgtgct tgaagagaag ttgtctccac agtgccagcc acttcataac 1500gagcttctcg agggagaaac ttctactctt aggacttcat tcacaagaaa catcgttggt 1560cgtgatggat tgtgcgtgga tgtgaggaat ggatacgaca ctgatggaac tccacttcag 1620ttgtggccat gtggaaccca gagaaaccaa cgatggactt ttgactcaga cgatacaatc 1680aggtcaatgg gtaaatgcat gactgcaaac gggttaaaca atggaagcaa tatcgtgata 1740ttcaactgtt ctacagctgc tgagaacgcc attaagtggg aagtacctat tgatggcagc 1800atcatcaatc cttcctccgg attggttatg accgctcctc gtgctgcatc ccgtaccatc 1860ctgttgcttg aggacaatat ctacgccgct agccagggtt ggactgtgac aaacaatgta 1920aagcccatcg ttgcttccat tgtgggttat aaagaaatgt gcttgcagtc taacggtgaa 1980aacaatggtg tttggatgga ggattgtgag gccaccagtt tgcagcaaca gtgggcactc 2040tatggtgacc gtaccatccg agtaaatagt actcgtggct tatgcgtcac caccaatggg 2100tacaactcca aggatctcat catcatcctt aaatgccaag gattgcccag ccagaggtgg 2160tttttcaact ccgacggcgc catcgtaaac ccaaagtcaa gacatgttat ggatgtgaga 2220gcaagcaatg tctctcttcg agaaatcatt atctttccag ccactgggaa ccctaatcag 2280caatgggtga cacaagtcct tccaagtccc gggcatcatc atcatcatca t 233165777PRTHomo sapiens 65Met Ser Cys Pro Val Pro Ala Cys Cys Ala Leu Leu Leu Val Leu Gly 1 5 10 15 Leu Cys Arg Ala Arg Pro Arg Asn Ala Leu Leu Leu Leu Ala Asp Asp 20 25 30 Gly Gly Phe Glu Ser Gly Ala Tyr Asn Asn Ser Ala Ile Ala Thr Pro 35 40 45 His Leu Asp Ala Leu Ala Arg Arg Ser Leu Leu Phe Arg Asn Ala Phe 50 55 60 Thr Ser Val Ser Ser Cys Ser Pro Ser Arg Ala Ser Leu Leu Thr Gly 65 70 75 80 Leu Pro Gln His Gln Asn Gly Met Tyr Gly Leu His Gln Asp Val His 85 90 95 His Phe Asn Ser Phe Asp Lys Val Arg Ser Leu Pro Leu Leu Leu Ser 100 105 110 Gln Ala Gly Val Arg Thr Gly Ile Ile Gly Lys Lys His Val Gly Pro 115 120 125 Glu Thr Val Tyr Pro Phe Asp Phe Ala Tyr Thr Glu Glu Asn Gly Ser 130 135 140 Val Leu Gln Val Gly Arg Asn Ile Thr Arg Ile Lys Leu Leu Val Arg 145 150 155 160 Lys Phe Leu Gln Thr Gln Asp Asp Arg Pro Phe Phe Leu Tyr Val Ala 165 170 175 Phe His Asp Pro His Arg Cys Gly His Ser Gln Pro Gln Tyr Gly Thr 180 185 190 Phe Cys Glu Lys Phe Gly Asn Gly Glu Ser Gly Met Gly Arg Ile Pro 195 200 205 Asp Trp Thr Pro Gln Ala Tyr Asp Pro Leu Asp Val Leu Val Pro Tyr 210 215 220 Phe Val Pro Asn Thr Pro Ala Ala Arg Ala Asp Leu Ala Ala Gln Tyr 225 230 235 240 Thr Thr Val Gly Arg Met Asp Gln Gly Val Gly Leu Val Leu Gln Glu 245 250 255 Leu Arg Asp Ala Gly Val Leu Asn Asp Thr Leu Val Ile Phe Thr Ser 260 265 270 Asp Asn Gly Ile Pro Phe Pro Ser Gly Arg Thr Asn Leu Tyr Trp Pro 275 280 285 Gly Thr Ala Glu Pro Leu Leu Val Ser Ser Pro Glu His Pro Lys Arg 290 295 300 Trp Gly Gln Val Ser Glu Ala Tyr Val Ser Leu Leu Asp Leu Thr Pro 305 310 315 320 Thr Ile Leu Asp Trp Phe Ser Ile Pro Tyr Pro Ser Tyr Ala Ile Phe 325 330 335 Gly Ser Lys Thr Ile His Leu Thr Gly Arg Ser Leu Leu Pro Ala Leu 340 345 350 Glu Ala Glu Pro Leu Trp Ala Thr Val Phe Gly Ser Gln Ser His His 355 360 365 Glu Val Thr Met Ser Tyr Pro Met Arg Ser Val Gln His Arg His Phe 370 375 380 Arg Leu Val His Asn Leu Asn Phe Lys Met Pro Phe Pro Ile Asp Gln 385 390 395 400 Asp Phe Tyr Val Ser Pro Thr Phe Gln Asp Leu Leu Asn Arg Thr Thr 405 410 415 Ala Gly Gln Pro Thr Gly Trp Tyr Lys Asp Leu Arg His Tyr Tyr Tyr 420 425 430 Arg Ala Arg Trp Glu Leu Tyr Asp Arg Ser Arg Asp Pro His Glu Thr 435 440 445 Gln Asn Leu Ala Thr Asp Pro Arg Phe Ala Gln Leu Leu Glu Met Leu 450 455 460 Arg Asp Gln Leu Ala Lys Trp Gln Trp Glu Thr His Asp Pro Trp Val 465 470 475 480 Cys Ala Pro Asp Gly Val Leu Glu Glu Lys Leu Ser Pro Gln Cys Gln 485 490 495 Pro Leu His Asn Glu Leu Leu Glu Gly Glu Thr Ser Thr Leu Arg Thr 500 505 510 Ser Phe Thr Arg Asn Ile Val Gly Arg Asp Gly Leu Cys Val Asp Val 515 520 525 Arg Asn Gly Tyr Asp Thr Asp Gly Thr Pro Leu Gln Leu Trp Pro Cys 530 535 540 Gly Thr Gln Arg Asn Gln Arg Trp Thr Phe Asp Ser Asp Asp Thr Ile 545 550 555 560 Arg Ser Met Gly Lys Cys Met Thr Ala Asn Gly Leu Asn Asn Gly Ser 565 570 575 Asn Ile Val Ile Phe Asn Cys Ser Thr Ala Ala Glu Asn Ala Ile Lys 580 585 590 Trp Glu Val Pro Ile Asp Gly Ser Ile Ile Asn Pro Ser Ser Gly Leu 595 600 605 Val Met Thr Ala Pro Arg Ala Ala Ser Arg Thr Ile Leu Leu Leu Glu 610 615 620 Asp Asn Ile Tyr Ala Ala Ser Gln Gly Trp Thr Val Thr Asn Asn Val 625 630 635 640 Lys Pro Ile Val Ala Ser Ile Val Gly Tyr Lys Glu Met Cys Leu Gln 645 650 655 Ser Asn Gly Glu Asn Asn Gly Val Trp Met Glu Asp Cys Glu Ala Thr 660 665 670 Ser Leu Gln Gln Gln Trp Ala Leu Tyr Gly Asp Arg Thr Ile Arg Val 675 680 685 Asn Ser Thr Arg Gly Leu Cys Val Thr Thr Asn Gly Tyr Asn Ser Lys 690 695 700 Asp Leu Ile Ile Ile Leu Lys Cys Gln Gly Leu Pro Ser Gln Arg Trp 705 710 715 720 Phe Phe Asn Ser Asp Gly Ala Ile Val Asn Pro Lys Ser Arg His Val 725 730 735 Met Asp Val Arg Ala Ser Asn Val Ser Leu Arg Glu Ile Ile Ile Phe 740 745 750 Pro Ala Thr Gly Asn Pro Asn Gln Gln Trp Val Thr Gln Val Leu Pro 755 760 765 Ser Pro Gly His His His His His His 770 775 662359DNAHomo sapiens 66aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgaccg tccccggaac gcactgctgc tcctcgcgga 120tgacggaggc tttgagagtg gcgcgtacaa caacagcgcc atcgccaccc cgcacctgga 180cgccttggcc cgccgcagcc tcctctttcg caatgccttc acctcggtca gcagctgctc 240tcccagccgc gccagcctcc tcactggcct gccccagcat cagaatggga tgtacgggct 300gcaccaggac gtgcaccact tcaactcctt cgacaaggtg cggagcctgc cgctgctgct 360cagccaagct ggtgtgcgca caggcatcat cgggaagaag cacgtggggc cggagaccgt 420gtacccgttt gactttgcgt acacggagga gaatggctcc gtcctccagg tggggcggaa 480catcactaga attaagctgc tcgtccggaa attcctgcag actcaggatg accggccttt 540cttcctctac gtcgccttcc acgaccccca ccgctgtggg cactcccagc cccagtacgg 600aaccttctgt gagaagtttg gcaacggaga gagcggcatg ggtcgtatcc cagactggac 660cccccaggcc tacgacccac tggacgtgct ggtgccttac ttcgtcccca acaccccggc 720agcccgagcc gacctggccg ctcagtacac caccgtcggc cgcatggacc aaggagttgg 780actggtgctc caggagctgc gtgacgccgg tgtcctgaac gacacactgg tgatcttcac 840gtccgacaac gggatcccct tccccagcgg caggaccaac ctgtactggc cgggcactgc 900tgaaccctta ctggtgtcat ccccggagca cccaaaacgc tggggccaag tcagcgaggc 960ctacgtgagc ctcctagacc tcacgcccac catcttggat tggttctcga tcccgtaccc 1020cagctacgcc atctttggct cgaagaccat ccacctcact ggccggtccc tcctgccggc 1080gctggaggcc gagcccctct gggccaccgt ctttggcagc cagagccacc acgaggtcac 1140catgtcctac cccatgcgct ccgtgcagca ccggcacttc cgcctcgtgc acaacctcaa 1200cttcaagatg ccctttccca tcgaccagga cttctacgtc tcacccacct tccaggacct 1260cctgaaccgc accacagctg gtcagcccac gggctggtac aaggacctcc gtcattacta 1320ctaccgggcg cgctgggaac tctacgaccg gagccgggac ccccacgaga cccagaacct 1380ggccaccgac ccgcgctttg ctcagcttct ggagatgctt cgggaccagc tggccaagtg 1440gcagtgggag acccacgacc cctgggtgtg cgcccccgac ggcgtcctgg aggagaagct 1500ctctccccag tgccagcccc tccacaatga gctgctcgag ggagaaactt ctactcttag 1560gacttcattc acaagaaaca tcgttggtcg tgatggattg tgcgtggatg tgaggaatgg 1620atacgacact gatggaactc cacttcagtt gtggccatgt ggaacccaga gaaaccaacg 1680atggactttt gactcagacg atacaatcag gtcaatgggt aaatgcatga ctgcaaacgg 1740gttaaacaat ggaagcaata tcgtgatatt caactgttct acagctgctg agaacgccat 1800taagtgggaa gtacctattg atggcagcat catcaatcct tcctccggat tggttatgac 1860cgctcctcgt gctgcatccc gtaccatcct gttgcttgag gacaatatct acgccgctag 1920ccagggttgg actgtgacaa acaatgtaaa gcccatcgtt gcttccattg tgggttataa 1980agaaatgtgc ttgcagtcta acggtgaaaa caatggtgtt tggatggagg attgtgaggc 2040caccagtttg cagcaacagt gggcactcta tggtgaccgt accatccgag taaatagtac 2100tcgtggctta tgcgtcacca ccaatgggta caactccaag gatctcatca tcatccttaa 2160atgccaagga ttgcccagcc agaggtggtt tttcaactcc gacggcgcca tcgtaaaccc 2220aaagtcaaga catgttatgg atgtgagagc aagcaatgtc tctcttcgag aaatcattat 2280ctttccagcc actgggaacc ctaatcagca atgggtgaca caagtccttc caagtcccgg 2340gcatcatcat catcatcat 235967785PRTHomo sapiens 67Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu Leu Glu 500 505 510 Gly Glu Thr Ser Thr Leu Arg Thr Ser Phe Thr Arg Asn Ile Val Gly 515 520 525 Arg Asp Gly Leu Cys Val Asp Val Arg Asn Gly Tyr Asp Thr Asp Gly 530 535 540 Thr Pro Leu Gln Leu Trp Pro Cys Gly Thr Gln Arg Asn Gln Arg Trp 545 550 555 560 Thr Phe Asp Ser Asp Asp Thr Ile Arg Ser Met Gly Lys Cys Met Thr 565 570 575 Ala Asn Gly Leu Asn Asn Gly Ser Asn Ile Val Ile Phe Asn Cys Ser 580 585 590 Thr Ala Ala Glu Asn Ala Ile Lys Trp Glu Val Pro Ile Asp Gly Ser 595 600 605 Ile Ile Asn Pro Ser Ser Gly Leu Val Met Thr Ala Pro Arg Ala Ala 610 615 620 Ser Arg Thr Ile Leu Leu Leu Glu Asp Asn Ile Tyr Ala Ala Ser Gln 625 630 635 640 Gly Trp Thr Val Thr Asn Asn Val Lys Pro Ile Val Ala Ser Ile Val 645 650 655 Gly Tyr Lys Glu Met Cys Leu Gln Ser Asn Gly Glu Asn Asn Gly Val 660 665 670 Trp Met Glu Asp Cys Glu Ala Thr Ser Leu Gln Gln Gln Trp Ala Leu 675 680 685 Tyr Gly Asp Arg Thr Ile Arg Val Asn Ser Thr Arg Gly Leu Cys Val 690 695 700 Thr Thr Asn Gly Tyr Asn Ser Lys Asp Leu Ile Ile Ile Leu Lys Cys 705 710

715 720 Gln Gly Leu Pro Ser Gln Arg Trp Phe Phe Asn Ser Asp Gly Ala Ile 725 730 735 Val Asn Pro Lys Ser Arg His Val Met Asp Val Arg Ala Ser Asn Val 740 745 750 Ser Leu Arg Glu Ile Ile Ile Phe Pro Ala Thr Gly Asn Pro Asn Gln 755 760 765 Gln Trp Val Thr Gln Val Leu Pro Ser Pro Gly His His His His His 770 775 780 His 785 682359DNAHomo sapiens 68aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacag gcctaggaac gctcttttgc ttcttgctga 120tgatggcgga ttcgagtccg gtgcttacaa caactctgct atcgctactc cacacctcga 180tgctcttgct aggcgttctc ttcttttccg taacgctttc acttccgtgt cctcttgctc 240accttctagg gcttcacttc ttactggact tccacagcac cagaacggaa tgtacggact 300tcatcaggat gtgcaccact tcaactcatt cgataaggtg agatccctcc cactcctctt 360gtctcaagct ggtgttagga ctggaatcat cggcaaaaag cacgtgggac cagagactgt 420gtacccattc gatttcgctt acactgagga aaacggctcc gttcttcaag tgggcagaaa 480tattactagg atcaagctcc tcgtgaggaa gttcctccag actcaagatg ataggccatt 540cttcctctac gtggcattcc atgatccaca taggtgcgga cattctcagc cacagtacgg 600aactttctgc gagaagttcg gaaacggtga gtctggtatg ggcaggattc cagattggac 660tccacaggct tacgatccac ttgatgtgct cgttccatac ttcgtgccaa acactccagc 720tgctagagct gatcttgctg ctcagtacac tactgtggga aggatggatc agggtgtggg 780acttgtgctt caagagctta gagatgctgg cgtgctcaac gatactctcg tgatcttcac 840ttcagataac ggcatcccat tcccatccgg aaggactaat ctttactggc caggtactgc 900tgagcctctc cttgtttctt caccagagca tccaaagagg tggggacaag tttctgaggc 960ttacgtgtcc cttctcgatc tcactccaac tatcctcgat tggttctcca tcccttaccc 1020atcctacgct atcttcggct ccaagactat ccaccttact ggcagatctt tgctcccagc 1080tttggaagct gaaccacttt gggctactgt gttcggatct cagtctcacc acgaggtgac 1140aatgtcttac ccaatgagat ctgtgcagca caggcacttc aggcttgttc acaacctcaa 1200cttcaagatg ccattcccaa tcgatcagga tttctacgtg tcaccaactt tccaggatct 1260tctcaacagg actactgcag gacaacctac tggctggtac aaggatctta ggcactacta 1320ctatagggct aggtgggagc tttacgatag gtccagagat ccacacgaga ctcagaacct 1380tgctactgat ccaaggttcg ctcagctcct tgagatgctt agggatcagc ttgctaagtg 1440gcagtgggag actcatgatc catgggtttg cgctccagat ggtgtgcttg aagagaagtt 1500gtctccacag tgccagccac ttcataacga gcttctcgag ggagaaactt ctactcttag 1560gacttcattc acaagaaaca tcgttggtcg tgatggattg tgcgtggatg tgaggaatgg 1620atacgacact gatggaactc cacttcagtt gtggccatgt ggaacccaga gaaaccaacg 1680atggactttt gactcagacg atacaatcag gtcaatgggt aaatgcatga ctgcaaacgg 1740gttaaacaat ggaagcaata tcgtgatatt caactgttct acagctgctg agaacgccat 1800taagtgggaa gtacctattg atggcagcat catcaatcct tcctccggat tggttatgac 1860cgctcctcgt gctgcatccc gtaccatcct gttgcttgag gacaatatct acgccgctag 1920ccagggttgg actgtgacaa acaatgtaaa gcccatcgtt gcttccattg tgggttataa 1980agaaatgtgc ttgcagtcta acggtgaaaa caatggtgtt tggatggagg attgtgaggc 2040caccagtttg cagcaacagt gggcactcta tggtgaccgt accatccgag taaatagtac 2100tcgtggctta tgcgtcacca ccaatgggta caactccaag gatctcatca tcatccttaa 2160atgccaagga ttgcccagcc agaggtggtt tttcaactcc gacggcgcca tcgtaaaccc 2220aaagtcaaga catgttatgg atgtgagagc aagcaatgtc tctcttcgag aaatcattat 2280ctttccagcc actgggaacc ctaatcagca atgggtgaca caagtccttc caagtcccgg 2340gcatcatcat catcatcat 235969785PRTHomo sapiens 69Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Arg Pro Arg Asn 20 25 30 Ala Leu Leu Leu Leu Ala Asp Asp Gly Gly Phe Glu Ser Gly Ala Tyr 35 40 45 Asn Asn Ser Ala Ile Ala Thr Pro His Leu Asp Ala Leu Ala Arg Arg 50 55 60 Ser Leu Leu Phe Arg Asn Ala Phe Thr Ser Val Ser Ser Cys Ser Pro 65 70 75 80 Ser Arg Ala Ser Leu Leu Thr Gly Leu Pro Gln His Gln Asn Gly Met 85 90 95 Tyr Gly Leu His Gln Asp Val His His Phe Asn Ser Phe Asp Lys Val 100 105 110 Arg Ser Leu Pro Leu Leu Leu Ser Gln Ala Gly Val Arg Thr Gly Ile 115 120 125 Ile Gly Lys Lys His Val Gly Pro Glu Thr Val Tyr Pro Phe Asp Phe 130 135 140 Ala Tyr Thr Glu Glu Asn Gly Ser Val Leu Gln Val Gly Arg Asn Ile 145 150 155 160 Thr Arg Ile Lys Leu Leu Val Arg Lys Phe Leu Gln Thr Gln Asp Asp 165 170 175 Arg Pro Phe Phe Leu Tyr Val Ala Phe His Asp Pro His Arg Cys Gly 180 185 190 His Ser Gln Pro Gln Tyr Gly Thr Phe Cys Glu Lys Phe Gly Asn Gly 195 200 205 Glu Ser Gly Met Gly Arg Ile Pro Asp Trp Thr Pro Gln Ala Tyr Asp 210 215 220 Pro Leu Asp Val Leu Val Pro Tyr Phe Val Pro Asn Thr Pro Ala Ala 225 230 235 240 Arg Ala Asp Leu Ala Ala Gln Tyr Thr Thr Val Gly Arg Met Asp Gln 245 250 255 Gly Val Gly Leu Val Leu Gln Glu Leu Arg Asp Ala Gly Val Leu Asn 260 265 270 Asp Thr Leu Val Ile Phe Thr Ser Asp Asn Gly Ile Pro Phe Pro Ser 275 280 285 Gly Arg Thr Asn Leu Tyr Trp Pro Gly Thr Ala Glu Pro Leu Leu Val 290 295 300 Ser Ser Pro Glu His Pro Lys Arg Trp Gly Gln Val Ser Glu Ala Tyr 305 310 315 320 Val Ser Leu Leu Asp Leu Thr Pro Thr Ile Leu Asp Trp Phe Ser Ile 325 330 335 Pro Tyr Pro Ser Tyr Ala Ile Phe Gly Ser Lys Thr Ile His Leu Thr 340 345 350 Gly Arg Ser Leu Leu Pro Ala Leu Glu Ala Glu Pro Leu Trp Ala Thr 355 360 365 Val Phe Gly Ser Gln Ser His His Glu Val Thr Met Ser Tyr Pro Met 370 375 380 Arg Ser Val Gln His Arg His Phe Arg Leu Val His Asn Leu Asn Phe 385 390 395 400 Lys Met Pro Phe Pro Ile Asp Gln Asp Phe Tyr Val Ser Pro Thr Phe 405 410 415 Gln Asp Leu Leu Asn Arg Thr Thr Ala Gly Gln Pro Thr Gly Trp Tyr 420 425 430 Lys Asp Leu Arg His Tyr Tyr Tyr Arg Ala Arg Trp Glu Leu Tyr Asp 435 440 445 Arg Ser Arg Asp Pro His Glu Thr Gln Asn Leu Ala Thr Asp Pro Arg 450 455 460 Phe Ala Gln Leu Leu Glu Met Leu Arg Asp Gln Leu Ala Lys Trp Gln 465 470 475 480 Trp Glu Thr His Asp Pro Trp Val Cys Ala Pro Asp Gly Val Leu Glu 485 490 495 Glu Lys Leu Ser Pro Gln Cys Gln Pro Leu His Asn Glu Leu Leu Glu 500 505 510 Gly Glu Thr Ser Thr Leu Arg Thr Ser Phe Thr Arg Asn Ile Val Gly 515 520 525 Arg Asp Gly Leu Cys Val Asp Val Arg Asn Gly Tyr Asp Thr Asp Gly 530 535 540 Thr Pro Leu Gln Leu Trp Pro Cys Gly Thr Gln Arg Asn Gln Arg Trp 545 550 555 560 Thr Phe Asp Ser Asp Asp Thr Ile Arg Ser Met Gly Lys Cys Met Thr 565 570 575 Ala Asn Gly Leu Asn Asn Gly Ser Asn Ile Val Ile Phe Asn Cys Ser 580 585 590 Thr Ala Ala Glu Asn Ala Ile Lys Trp Glu Val Pro Ile Asp Gly Ser 595 600 605 Ile Ile Asn Pro Ser Ser Gly Leu Val Met Thr Ala Pro Arg Ala Ala 610 615 620 Ser Arg Thr Ile Leu Leu Leu Glu Asp Asn Ile Tyr Ala Ala Ser Gln 625 630 635 640 Gly Trp Thr Val Thr Asn Asn Val Lys Pro Ile Val Ala Ser Ile Val 645 650 655 Gly Tyr Lys Glu Met Cys Leu Gln Ser Asn Gly Glu Asn Asn Gly Val 660 665 670 Trp Met Glu Asp Cys Glu Ala Thr Ser Leu Gln Gln Gln Trp Ala Leu 675 680 685 Tyr Gly Asp Arg Thr Ile Arg Val Asn Ser Thr Arg Gly Leu Cys Val 690 695 700 Thr Thr Asn Gly Tyr Asn Ser Lys Asp Leu Ile Ile Ile Leu Lys Cys 705 710 715 720 Gln Gly Leu Pro Ser Gln Arg Trp Phe Phe Asn Ser Asp Gly Ala Ile 725 730 735 Val Asn Pro Lys Ser Arg His Val Met Asp Val Arg Ala Ser Asn Val 740 745 750 Ser Leu Arg Glu Ile Ile Ile Phe Pro Ala Thr Gly Asn Pro Asn Gln 755 760 765 Gln Trp Val Thr Gln Val Leu Pro Ser Pro Gly His His His His His 770 775 780 His 785 701140DNAHomo sapiens 70atggctgcgc ccgcactagg gctggtgtgt ggacgttgcc ctgagctggg tctcgtcctc 60ttgctgctgc tgctctcgct gctgtgtgga gcggcaggga gccaggaggc cgggaccggt 120gcgggcgcgg ggtcccttgc gggttcttgc ggctgcggca cgccccagcg gcctggcgcc 180catggcagtt cggcagccgc tcaccgatac tcgcgggagg ctaacgctcc gggccccgta 240cccggagagc ggcaactcgc gcactcaaag atggtcccca tccctgctgg agtatttaca 300atgggcacag atgatcctca gataaagcag gatggggaag cacctgcgag gagagttact 360attgatgcct tttacatgga tgcctatgaa gtcagtaata ctgaatttga gaagtttgtg 420aactcaactg gctatttgac agaggctgag aagtttggcg actcctttgt ctttgaaggc 480atgttgagtg agcaagtgaa gaccaatatt caacaggcag ttgcagctgc tccctggtgg 540ttacctgtga aaggcgctaa ctggagacac ccagaagggc ctgactctac tattctgcac 600aggccggatc atccagttct ccatgtgtcc tggaatgatg cggttgccta ctgcacttgg 660gcagggaagc ggctgcccac ggaagctgag tgggaataca gctgtcgagg aggcctgcat 720aatagacttt tcccctgggg caacaaactg cagcccaaag gccagcatta tgccaacatt 780tggcagggcg agtttccggt gaccaacact ggtgaggatg gcttccaagg aactgcgcct 840gttgatgcct tccctcccaa tggttatggc ttatacaaca tagtggggaa cgcatgggaa 900tggacttcag actggtggac tgttcatcat tctgttgaag aaacgcttaa cccaaaaggt 960cccccttctg ggaaagaccg agtgaagaaa ggtggatcct acatgtgcca taggtcttat 1020tgttacaggt atcgctgtgc tgctcggagc cagaacacac ctgatagctc tgcttcgaat 1080ctgggattcc gctgtgcagc cgaccgcctg cccactatgg accatcatca tcatcatcat 114071380PRTHomo sapiens 71Met Ala Ala Pro Ala Leu Gly Leu Val Cys Gly Arg Cys Pro Glu Leu 1 5 10 15 Gly Leu Val Leu Leu Leu Leu Leu Leu Ser Leu Leu Cys Gly Ala Ala 20 25 30 Gly Ser Gln Glu Ala Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly 35 40 45 Ser Cys Gly Cys Gly Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser 50 55 60 Ala Ala Ala His Arg Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val 65 70 75 80 Pro Gly Glu Arg Gln Leu Ala His Ser Lys Met Val Pro Ile Pro Ala 85 90 95 Gly Val Phe Thr Met Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly 100 105 110 Glu Ala Pro Ala Arg Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala 115 120 125 Tyr Glu Val Ser Asn Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly 130 135 140 Tyr Leu Thr Glu Ala Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly 145 150 155 160 Met Leu Ser Glu Gln Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala 165 170 175 Ala Pro Trp Trp Leu Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu 180 185 190 Gly Pro Asp Ser Thr Ile Leu His Arg Pro Asp His Pro Val Leu His 195 200 205 Val Ser Trp Asn Asp Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg 210 215 220 Leu Pro Thr Glu Ala Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His 225 230 235 240 Asn Arg Leu Phe Pro Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His 245 250 255 Tyr Ala Asn Ile Trp Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu 260 265 270 Asp Gly Phe Gln Gly Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly 275 280 285 Tyr Gly Leu Tyr Asn Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp 290 295 300 Trp Trp Thr Val His His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly 305 310 315 320 Pro Pro Ser Gly Lys Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys 325 330 335 His Arg Ser Tyr Cys Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn 340 345 350 Thr Pro Asp Ser Ser Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp 355 360 365 Arg Leu Pro Thr Met Asp His His His His His His 370 375 380 721140DNAHomo sapiens 72atggctgctc cagctcttgg acttgtttgt ggaagatgtc cagagcttgg actcgtgctc 60cttttgcttc ttttgtcact tctctgcgga gctgctggat ctcaagaggc tggaactggt 120gctggtgctg gatctcttgc tggatcttgt ggatgtggaa ctccacaaag accaggtgct 180catggatctt cagctgctgc tcataggtac tctagggaag ctaatgctcc aggtccagtt 240ccaggtgaga gacagcttgc tcactctaag atggtgccaa ttccagctgg cgtgttcact 300atgggaactg atgatccaca gatcaagcag gatggtgagg ctccagctag aagggtgaca 360atcgatgctt tctacatgga tgcttacgag gtgtccaaca ctgagttcga gaagttcgtg 420aactccactg gctaccttac tgaggctgag aagttcggcg attccttcgt tttcgaggga 480atgctctctg agcaggttaa gactaacatc cagcaggctg ttgctgctgc tccatggtgg 540cttccagtta agggtgctaa ttggagacat ccagagggcc cagattccac tattcttcat 600aggccagatc acccagtgct ccacgtttca tggaatgatg ctgtggctta ctgcacttgg 660gctggaaaga gacttccaac tgaagctgag tgggagtact cttgtagggg aggacttcac 720aacaggcttt tcccatgggg aaacaagttg cagccaaagg gacagcacta cgctaatatt 780tggcaaggcg agttcccagt gactaacact ggtgaggatg gattccaagg tactgctcca 840gttgatgctt tcccaccaaa tggatacggc ctctacaaca tcgttggaaa cgcttgggag 900tggacttccg attggtggac tgttcatcac tccgtggaag agactctcaa cccaaaggga 960ccaccatctg gaaaggatag ggttaagaaa ggcggctcct acatgtgcca taggtcttac 1020tgttacaggt acaggtgcgc tgctaggtcc cagaatactc cagattcctc tgcttccaac 1080ctcggattca gatgtgctgc tgataggctc ccaactatgg atcatcatca ccatcaccac 114073380PRTHomo sapiens 73Met Ala Ala Pro Ala Leu Gly Leu Val Cys Gly Arg Cys Pro Glu Leu 1 5 10 15 Gly Leu Val Leu Leu Leu Leu Leu Leu Ser Leu Leu Cys Gly Ala Ala 20 25 30 Gly Ser Gln Glu Ala Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly 35 40 45 Ser Cys Gly Cys Gly Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser 50 55 60 Ala Ala Ala His Arg Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val 65 70 75 80 Pro Gly Glu Arg Gln Leu Ala His Ser Lys Met Val Pro Ile Pro Ala 85 90 95 Gly Val Phe Thr Met Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly 100 105 110 Glu Ala Pro Ala Arg Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala 115 120 125 Tyr Glu Val Ser Asn Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly 130 135 140 Tyr Leu Thr Glu Ala Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly 145 150 155 160 Met Leu Ser Glu Gln Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala 165 170 175 Ala Pro Trp Trp Leu Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu 180 185 190 Gly Pro Asp Ser Thr Ile Leu His Arg Pro Asp His Pro Val Leu His 195 200 205 Val Ser Trp Asn Asp Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg 210 215 220 Leu Pro Thr Glu Ala Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His 225 230 235 240 Asn Arg Leu Phe Pro Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His 245 250 255 Tyr Ala Asn Ile Trp Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu 260 265 270 Asp Gly Phe Gln Gly Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly 275 280 285 Tyr Gly Leu Tyr Asn Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp 290 295 300 Trp Trp Thr Val His His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly 305 310 315 320 Pro Pro Ser Gly Lys Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys 325 330 335 His Arg

Ser Tyr Cys Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn 340 345 350 Thr Pro Asp Ser Ser Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp 355 360 365 Arg Leu Pro Thr Met Asp His His His His His His 370 375 380 741129DNAHomo sapiens 74aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacag ccaggaggcc gggaccggtg cgggcgcggg 120gtcccttgcg ggttcttgcg gctgcggcac gccccagcgg cctggcgccc atggcagttc 180ggcagccgct caccgatact cgcgggaggc taacgctccg ggccccgtac ccggagagcg 240gcaactcgcg cactcaaaga tggtccccat ccctgctgga gtatttacaa tgggcacaga 300tgatcctcag ataaagcagg atggggaagc acctgcgagg agagttacta ttgatgcctt 360ttacatggat gcctatgaag tcagtaatac tgaatttgag aagtttgtga actcaactgg 420ctatttgaca gaggctgaga agtttggcga ctcctttgtc tttgaaggca tgttgagtga 480gcaagtgaag accaatattc aacaggcagt tgcagctgct ccctggtggt tacctgtgaa 540aggcgctaac tggagacacc cagaagggcc tgactctact attctgcaca ggccggatca 600tccagttctc catgtgtcct ggaatgatgc ggttgcctac tgcacttggg cagggaagcg 660gctgcccacg gaagctgagt gggaatacag ctgtcgagga ggcctgcata atagactttt 720cccctggggc aacaaactgc agcccaaagg ccagcattat gccaacattt ggcagggcga 780gtttccggtg accaacactg gtgaggatgg cttccaagga actgcgcctg ttgatgcctt 840ccctcccaat ggttatggct tatacaacat agtggggaac gcatgggaat ggacttcaga 900ctggtggact gttcatcatt ctgttgaaga aacgcttaac ccaaaaggtc ccccttctgg 960gaaagaccga gtgaagaaag gtggatccta catgtgccat aggtcttatt gttacaggta 1020tcgctgtgct gctcggagcc agaacacacc tgatagctct gcttcgaatc tgggattccg 1080ctgtgcagcc gaccgcctgc ccactatgga ccatcatcat catcatcat 112975375PRTHomo sapiens 75Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Ser Gln Glu Ala 20 25 30 Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly Ser Cys Gly Cys Gly 35 40 45 Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser Ala Ala Ala His Arg 50 55 60 Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val Pro Gly Glu Arg Gln 65 70 75 80 Leu Ala His Ser Lys Met Val Pro Ile Pro Ala Gly Val Phe Thr Met 85 90 95 Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly Glu Ala Pro Ala Arg 100 105 110 Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala Tyr Glu Val Ser Asn 115 120 125 Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly Tyr Leu Thr Glu Ala 130 135 140 Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly Met Leu Ser Glu Gln 145 150 155 160 Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala Ala Pro Trp Trp Leu 165 170 175 Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu Gly Pro Asp Ser Thr 180 185 190 Ile Leu His Arg Pro Asp His Pro Val Leu His Val Ser Trp Asn Asp 195 200 205 Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg Leu Pro Thr Glu Ala 210 215 220 Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His Asn Arg Leu Phe Pro 225 230 235 240 Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His Tyr Ala Asn Ile Trp 245 250 255 Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu Asp Gly Phe Gln Gly 260 265 270 Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly Tyr Gly Leu Tyr Asn 275 280 285 Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp Trp Trp Thr Val His 290 295 300 His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly Pro Pro Ser Gly Lys 305 310 315 320 Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys His Arg Ser Tyr Cys 325 330 335 Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn Thr Pro Asp Ser Ser 340 345 350 Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp Arg Leu Pro Thr Met 355 360 365 Asp His His His His His His 370 375 761129DNAHomo sapiens 76aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgactc tcaagaggct ggaactggtg ctggtgctgg 120atctcttgct ggatcttgtg gatgtggaac tccacaaaga ccaggtgctc atggatcttc 180agctgctgct cataggtact ctagggaagc taatgctcca ggtccagttc caggtgagag 240acagcttgct cactctaaga tggtgccaat tccagctggc gtgttcacta tgggaactga 300tgatccacag atcaagcagg atggtgaggc tccagctaga agggtgacaa tcgatgcttt 360ctacatggat gcttacgagg tgtccaacac tgagttcgag aagttcgtga actccactgg 420ctaccttact gaggctgaga agttcggcga ttccttcgtt ttcgagggaa tgctctctga 480gcaggttaag actaacatcc agcaggctgt tgctgctgct ccatggtggc ttccagttaa 540gggtgctaat tggagacatc cagagggccc agattccact attcttcata ggccagatca 600cccagtgctc cacgtttcat ggaatgatgc tgtggcttac tgcacttggg ctggaaagag 660acttccaact gaagctgagt gggagtactc ttgtagggga ggacttcaca acaggctttt 720cccatgggga aacaagttgc agccaaaggg acagcactac gctaatattt ggcaaggcga 780gttcccagtg actaacactg gtgaggatgg attccaaggt actgctccag ttgatgcttt 840cccaccaaat ggatacggcc tctacaacat cgttggaaac gcttgggagt ggacttccga 900ttggtggact gttcatcact ccgtggaaga gactctcaac ccaaagggac caccatctgg 960aaaggatagg gttaagaaag gcggctccta catgtgccat aggtcttact gttacaggta 1020caggtgcgct gctaggtccc agaatactcc agattcctct gcttccaacc tcggattcag 1080atgtgctgct gataggctcc caactatgga tcatcatcac catcaccac 112977375PRTHomo sapiens 77Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Ser Gln Glu Ala 20 25 30 Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly Ser Cys Gly Cys Gly 35 40 45 Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser Ala Ala Ala His Arg 50 55 60 Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val Pro Gly Glu Arg Gln 65 70 75 80 Leu Ala His Ser Lys Met Val Pro Ile Pro Ala Gly Val Phe Thr Met 85 90 95 Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly Glu Ala Pro Ala Arg 100 105 110 Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala Tyr Glu Val Ser Asn 115 120 125 Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly Tyr Leu Thr Glu Ala 130 135 140 Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly Met Leu Ser Glu Gln 145 150 155 160 Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala Ala Pro Trp Trp Leu 165 170 175 Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu Gly Pro Asp Ser Thr 180 185 190 Ile Leu His Arg Pro Asp His Pro Val Leu His Val Ser Trp Asn Asp 195 200 205 Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg Leu Pro Thr Glu Ala 210 215 220 Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His Asn Arg Leu Phe Pro 225 230 235 240 Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His Tyr Ala Asn Ile Trp 245 250 255 Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu Asp Gly Phe Gln Gly 260 265 270 Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly Tyr Gly Leu Tyr Asn 275 280 285 Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp Trp Trp Thr Val His 290 295 300 His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly Pro Pro Ser Gly Lys 305 310 315 320 Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys His Arg Ser Tyr Cys 325 330 335 Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn Thr Pro Asp Ser Ser 340 345 350 Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp Arg Leu Pro Thr Met 355 360 365 Asp His His His His His His 370 375 781141DNAHomo sapiens 78aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgacag ccaggaggcc gggaccggtg cgggcgcggg 120gtcccttgcg ggttcttgcg gctgcggcac gccccagcgg cctggcgccc atggcagttc 180ggcagccgct caccgatact cgcgggaggc taacgctccg ggccccgtac ccggagagcg 240gcaactcgcg cactcaaaga tggtccccat ccctgctgga gtatttacaa tgggcacaga 300tgatcctcag ataaagcagg atggggaagc acctgcgagg agagttacta ttgatgcctt 360ttacatggat gcctatgaag tcagtaatac tgaatttgag aagtttgtga actcaactgg 420ctatttgaca gaggctgaga agtttggcga ctcctttgtc tttgaaggca tgttgagtga 480gcaagtgaag accaatattc aacaggcagt tgcagctgct ccctggtggt tacctgtgaa 540aggcgctaac tggagacacc cagaagggcc tgactctact attctgcaca ggccggatca 600tccagttctc catgtgtcct ggaatgatgc ggttgcctac tgcacttggg cagggaagcg 660gctgcccacg gaagctgagt gggaatacag ctgtcgagga ggcctgcata atagactttt 720cccctggggc aacaaactgc agcccaaagg ccagcattat gccaacattt ggcagggcga 780gtttccggtg accaacactg gtgaggatgg cttccaagga actgcgcctg ttgatgcctt 840ccctcccaat ggttatggct tatacaacat agtggggaac gcatgggaat ggacttcaga 900ctggtggact gttcatcatt ctgttgaaga aacgcttaac ccaaaaggtc ccccttctgg 960gaaagaccga gtgaagaaag gtggatccta catgtgccat aggtcttatt gttacaggta 1020tcgctgtgct gctcggagcc agaacacacc tgatagctct gcttcgaatc tgggattccg 1080ctgtgcagcc gaccgcctgc ccactatgga ccatcatcat catcatcata aggatgaact 1140t 114179379PRTHomo sapiens 79Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Ser Gln Glu Ala 20 25 30 Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly Ser Cys Gly Cys Gly 35 40 45 Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser Ala Ala Ala His Arg 50 55 60 Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val Pro Gly Glu Arg Gln 65 70 75 80 Leu Ala His Ser Lys Met Val Pro Ile Pro Ala Gly Val Phe Thr Met 85 90 95 Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly Glu Ala Pro Ala Arg 100 105 110 Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala Tyr Glu Val Ser Asn 115 120 125 Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly Tyr Leu Thr Glu Ala 130 135 140 Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly Met Leu Ser Glu Gln 145 150 155 160 Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala Ala Pro Trp Trp Leu 165 170 175 Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu Gly Pro Asp Ser Thr 180 185 190 Ile Leu His Arg Pro Asp His Pro Val Leu His Val Ser Trp Asn Asp 195 200 205 Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg Leu Pro Thr Glu Ala 210 215 220 Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His Asn Arg Leu Phe Pro 225 230 235 240 Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His Tyr Ala Asn Ile Trp 245 250 255 Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu Asp Gly Phe Gln Gly 260 265 270 Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly Tyr Gly Leu Tyr Asn 275 280 285 Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp Trp Trp Thr Val His 290 295 300 His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly Pro Pro Ser Gly Lys 305 310 315 320 Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys His Arg Ser Tyr Cys 325 330 335 Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn Thr Pro Asp Ser Ser 340 345 350 Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp Arg Leu Pro Thr Met 355 360 365 Asp His His His His His His Lys Asp Glu Leu 370 375 801141DNAHomo sapiens 80aacaatggct tcctccgcta ctactaaatc tttccttatt cttttcttta tgatacttgc 60aactacttca tcaacatgtg cagtcgactc tcaagaggct ggaactggtg ctggtgctgg 120atctcttgct ggatcttgtg gatgtggaac tccacaaaga ccaggtgctc atggatcttc 180agctgctgct cataggtact ctagggaagc taatgctcca ggtccagttc caggtgagag 240acagcttgct cactctaaga tggtgccaat tccagctggc gtgttcacta tgggaactga 300tgatccacag atcaagcagg atggtgaggc tccagctaga agggtgacaa tcgatgcttt 360ctacatggat gcttacgagg tgtccaacac tgagttcgag aagttcgtga actccactgg 420ctaccttact gaggctgaga agttcggcga ttccttcgtt ttcgagggaa tgctctctga 480gcaggttaag actaacatcc agcaggctgt tgctgctgct ccatggtggc ttccagttaa 540gggtgctaat tggagacatc cagagggccc agattccact attcttcata ggccagatca 600cccagtgctc cacgtttcat ggaatgatgc tgtggcttac tgcacttggg ctggaaagag 660acttccaact gaagctgagt gggagtactc ttgtagggga ggacttcaca acaggctttt 720cccatgggga aacaagttgc agccaaaggg acagcactac gctaatattt ggcaaggcga 780gttcccagtg actaacactg gtgaggatgg attccaaggt actgctccag ttgatgcttt 840cccaccaaat ggatacggcc tctacaacat cgttggaaac gcttgggagt ggacttccga 900ttggtggact gttcatcact ccgtggaaga gactctcaac ccaaagggac caccatctgg 960aaaggatagg gttaagaaag gcggctccta catgtgccat aggtcttact gttacaggta 1020caggtgcgct gctaggtccc agaatactcc agattcctct gcttccaacc tcggattcag 1080atgtgctgct gataggctcc caactatgga tcatcatcac catcaccaca aggatgaact 1140t 114181379PRTHomo sapiens 81Met Ala Ser Ser Ala Thr Thr Lys Ser Phe Leu Ile Leu Phe Phe Met 1 5 10 15 Ile Leu Ala Thr Thr Ser Ser Thr Cys Ala Val Asp Ser Gln Glu Ala 20 25 30 Gly Thr Gly Ala Gly Ala Gly Ser Leu Ala Gly Ser Cys Gly Cys Gly 35 40 45 Thr Pro Gln Arg Pro Gly Ala His Gly Ser Ser Ala Ala Ala His Arg 50 55 60 Tyr Ser Arg Glu Ala Asn Ala Pro Gly Pro Val Pro Gly Glu Arg Gln 65 70 75 80 Leu Ala His Ser Lys Met Val Pro Ile Pro Ala Gly Val Phe Thr Met 85 90 95 Gly Thr Asp Asp Pro Gln Ile Lys Gln Asp Gly Glu Ala Pro Ala Arg 100 105 110 Arg Val Thr Ile Asp Ala Phe Tyr Met Asp Ala Tyr Glu Val Ser Asn 115 120 125 Thr Glu Phe Glu Lys Phe Val Asn Ser Thr Gly Tyr Leu Thr Glu Ala 130 135 140 Glu Lys Phe Gly Asp Ser Phe Val Phe Glu Gly Met Leu Ser Glu Gln 145 150 155 160 Val Lys Thr Asn Ile Gln Gln Ala Val Ala Ala Ala Pro Trp Trp Leu 165 170 175 Pro Val Lys Gly Ala Asn Trp Arg His Pro Glu Gly Pro Asp Ser Thr 180 185 190 Ile Leu His Arg Pro Asp His Pro Val Leu His Val Ser Trp Asn Asp 195 200 205 Ala Val Ala Tyr Cys Thr Trp Ala Gly Lys Arg Leu Pro Thr Glu Ala 210 215 220 Glu Trp Glu Tyr Ser Cys Arg Gly Gly Leu His Asn Arg Leu Phe Pro 225 230 235 240 Trp Gly Asn Lys Leu Gln Pro Lys Gly Gln His Tyr Ala Asn Ile Trp 245 250 255 Gln Gly Glu Phe Pro Val Thr Asn Thr Gly Glu Asp Gly Phe Gln Gly 260 265 270 Thr Ala Pro Val Asp Ala Phe Pro Pro Asn Gly Tyr Gly Leu Tyr Asn 275 280 285 Ile Val Gly Asn Ala Trp Glu Trp Thr Ser Asp Trp Trp Thr Val His 290 295 300 His Ser Val Glu Glu Thr Leu Asn Pro Lys Gly Pro Pro Ser Gly Lys 305 310 315 320 Asp Arg Val Lys Lys Gly Gly Ser Tyr Met Cys His Arg Ser Tyr Cys 325 330 335 Tyr Arg Tyr Arg Cys Ala Ala Arg Ser Gln Asn Thr Pro Asp Ser Ser 340 345 350 Ala Ser Asn Leu Gly Phe Arg Cys Ala Ala Asp Arg Leu Pro Thr Met 355 360 365 Asp His His His His His His Lys Asp Glu Leu 370 375

Claims

1. A fusion protein comprising i) a mammalian sulfatase, or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof, or a fusion protein comprising i) a mammalian sulfatase modifying factor 1 (SUMF1), or an enzymatically active fragment or variant thereof, and ii) a plant lectin or a binding subunit thereof; or a polynucleotide encoding said fusion protein; or a human SUMF1 protein expressed in plant cells comprising transforming a plant cell with an expression vector comprising a nucleotide sequence for translational expression of the SUMF1 enzymatically active fragment or variant thereof, produced in a plant or plant cell.

2. The fusion protein according to claim 1, wherein the mammalian sulfatase is N-acetylgalactosamine-6-sulfatase, N-acetylglucosamine-6-sulfatase, N-sulphoglucosamine sulphohydrolase, sulfamidase, extracellular sulfatase Sulf-1 (hSulf1), extracellular sulfatase Sulf-2 (hSulf2), iduronate 2-sulfatase, arylsulfatase A (ASA), arylsulfatase B (ASB), steryl-sulfatase, arylsulfatase D (ASD), arylsulfatase E (ASE), arylsulfatase F (ASF), arylsulfatase G (ASG), arylsulfatase H (ASH), arylsulfatase I (ASI), arylsulfatase J (ASJ), or arylsulfatase K (ASK).

3. The fusion protein according to claim 1, wherein the mammalian sulfatase comprises the amino acid sequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, or 34, or an enzymatically active fragment or variant thereof.

4. The fusion protein according to claim 1, wherein the plant lectin is a lectin from Table 2 or Table 3 of the specification.

5. The fusion protein according to claim 1, wherein the plant lectin is the non-toxic subunit of ricin (RTB) or nigrin (NBB).

6. The fusion protein according to claim 1, wherein the fusion protein comprises an endoplasmic reticulum (ER) retention sequence.

7. The fusion protein according to claim 6, wherein the ER retention sequence comprises KDEL.

8. The fusion protein according to claim 1, wherein the mammalian sulfatase is linked to the plant lectin by a linker sequence of amino acids.

9-10. (canceled)

11. A method for treating or preventing a disease or condition associated with a sulfatase enzyme or a sulfatase modifying factor 1 (SUMF1) protein in a person or animal, comprising administering to the person or animal a therapeutically effective amount of a SUMF1 protein or a fusion protein of claim 1.

12. The method according to claim 11, wherein the disease or condition is mucoposysaccharidosis IVA (MPS-IVA), Morquio A syndrome, mucoposysaccharidosis IIID (MPS-IIID), Sanfilippo D syndrome, mucopolysaccharidosis IIIA (MPS-IIIA), Sanfilippo A syndrome, mucopolysaccharidosis II (MPS-II), Hunter syndrome, metachromatic leukodystrophy (MLD), mucopolysaccharidosis VI (MPS-VI), Maroteaux-Lamy syndrome, X-linked ichthyosis (XLI), or chondrodysplasia punctata 1 (CDPX1).

13. The method according to claim 12, wherein the fusion protein is administered by intravenous infusion or injection, or by inhalation via nasal cavity or lung, or orally, ocularly, vaginally, anally, rectally, or transmembraneously or transdermally, subcutaneously, intradermally, intravenously, intramuscularly, intraperitoneally, or intrasternally, such as by injection.

14. (canceled)

15. The fusion protein according to claim 1, wherein the SUMF1 comprises the amino acid sequence of SEQ ID NO:36, or an enzymatically active fragment or variant thereof.

16-25. (canceled)

26. A method for producing a sulfatase fusion protein and/or a mammalian SUMF1 protein and/or a SUMF1 fusion protein of claim 1, and/or a mammalian sulfatase, or an enzymatically active fragment or variant of any of the proteins, comprising expressing in a plant or plant cell a polynucleotide encoding a mammalian sulfatase fusion protein and/or a polynucleotide encoding a sulfatase modifying factor 1 (SUMF1) protein or a SUMF1 fusion protein, and/or a polynucleotide encoding a mammalian sulfatase, or an enzymatically active fragment or variant of any of the proteins.

27-28. (canceled)

29. The method according to claim 26, wherein the SUMF1 protein or the SUMF1 fusion protein comprises an ER retention signal.

30. The method according to claim 29, wherein the ER retention signal comprises KDEL sequence.

31-38. (canceled)

39. The method according to claim 26, wherein the plant or plant cell is transiently or stably transformed with one or both of the polynucleotides.

40. (canceled)

41. The human SUMF1 protein of claim 1, wherein the SUMF1 protein shows enzymatic and biological activity with capacity to activate human sulfatases expressed in plant cells.

42. (canceled)

43. The human SUMF1 protein of claim 41, wherein the SUMF1 protein activates a sulfatase in plant cells by catalyzing the conversion of a relevant cysteine to a FGly residue required for activating enzymatic activity of the sulfatase.

44-66. (canceled)

67. The fusion protein according to claim 1, wherein the fusion protein comprises the amino acid sequence of any of SEQ ID NOs:39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, or 69, or an enzymatically active fragment or variant thereof; or wherein the fusion protein comprises the amino acid sequence of any of SEQ ID NOs:71, 73. 75, 77, 79, or 81, or an enzymatically active fragment or variant thereof.

68-93. (canceled)