HUMAN ANTIBODIES TO HUMAN DELTA LIKE LIGAND 4

Abstract

The present invention provides methods of treating, ameliorating, or inhibiting tumor growth, cancer, or pathological angiogenesis by administering to a subject in need thereof a human antibody or fragment thereof that specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The anti-hDll4 antibody or fragment thereof of the present invention have a high affinity with the K.sub.D of 500 pM or less, as measured by surface plasmon resonance.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. non-provisional application Ser. No. 12/002,245 filed Dec. 14, 2007, which claims the benefit under 35 U.S.C .sctn.119(e) of U.S. provisional application No. 60/874,922 filed Dec. 14, 2006, 60/916,415 filed May 7, 2007, and 60/985,323 filed Nov. 5, 2007, all of which are herein specifically incorporated by reference in their entirety.

BACKGROUND

[0002] The Notch-signaling pathway is a system for cell-to-cell communication used by a wide range of eukaryotes for many biological processes, such as differentiation, proliferation, and homeostasis. Delta like 4 (Dl4) or delta-like ligand 4 (Dll4) (hereinafter "Dll4") is a member of the Delta family of Notch ligands which exhibits highly selective expression by vascular endothelium (Shutter et al. (2000) Genes Develop. 14:1313-1318). Dll4 is a ligand for Notch receptors, including Notch1 and Notch 4. The nucleic acid and amino acid sequences for human Dll4 are shown in SEQ ID NO:1-2, respectively.

[0003] Methods to produce antibodies useful as human therapeutics include generation of chimeric antibodies and humanized antibodies (see, for example, U.S. Pat. No. 6,949,245). See, for example, WO 94/02602 (Abgenix) and U.S. Pat. No. 6,596,541 (Regeneron Pharmaceuticals), which publications are herein specifically incorporated by reference, describing methods of generating nonhuman transgenic mice capable of producing human antibodies.

[0004] Japanese patent application 2003/047470A2 (Asahi Kasei Kogyo) describes antibodies to the extracellular portion of human Notch ligand protein.

BRIEF SUMMARY OF THE INVENTION

[0005] In a first aspect, the invention provides human antibodies, preferably recombinant human antibodies, that specifically bind human delta-like ligand 4 (hDll4). These antibodies are characterized by binding to hDll4 with high affinity and by the ability to neutralize Dll4 activity. The antibodies of the invention are capable of blocking Dll4 binding to its Notch receptor(s), and thus inhibit signaling by Dll4. The antibodies can be full-length (for example, an IgG1 or IgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab').sub.2 or scFv fragment), and may be modified to effect functionality, e.g., to eliminate residual effector functions (Glu which eliminates residual effector functions (Reddy et al. (2000) J. Immunol. 164:1925-1933).

[0006] In one embodiment, the antibody of the invention comprises a heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NO:4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 397, 413, 429, 445, 461, 477, 493, 509, 525, 541, 557, 573, 589, 605, 621, 637, 653, 669, 685, 701, 717, 733, 749, 765, 781, 797, 813, 893, 897, 901, 905, 909, 913, 917, 921, 925, 935, 939, 943, and 947 or a substantially identical sequence thereof. In a preferred embodiment, the HCVR is the amino acid sequence of SEQ ID NO:429 or 901.

[0007] In one embodiment, the antibody of the invention comprises a light chain variable region (LCVR) selected from the group consisting of SEQ ID NO:12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 405, 421, 437, 453, 469, 485, 501, 517, 533, 549, 565, 581, 597, 613, 629, 645, 661, 677, 693, 709, 725, 741, 757, 773, 789, 805, 821, 895, 899, 903, 907, 911, 915, 919, 923, 927, 937, 941, 945, and 949 or a substantially identical sequence thereof. In a preferred embodiment, the LCVR is the amino acid sequence of SEQ ID NO:437 or 903.

[0008] In one embodiment, the antibody of the invention comprises a HCVR selected from the group consisting of SEQ ID NO: 4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 397, 413, 429, 445, 461, 477, 493, 509, 525, 541, 557, 573, 589, 605, 621, 637, 653, 669, 685, 701, 717, 733, 749, 765, 781, 797, 813, 893, 897, 901, 905, 909, 913, 917, 921, 925, 935, 939, 943, and 947 or a substantially identical sequence thereof, and a LCVR selected from the group consisting of SEQ ID NO:12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 405, 421, 437, 453, 469, 485, 501, 517, 533, 549, 565, 581, 597, 613, 629, 645, 661, 677, 693, 709, 725, 741, 757, 773, 789, 805, 821, 895, 899, 903, 907, 911, 915, 919, 923, 927, 937, 941, 945, and 949 or a substantially identical sequence thereof. In a preferred embodiment, the HCVR/LCVR are the amino acid sequence pairs SEQ ID NO:429/437 or 901/903.

[0009] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain complementary determining region 1 (CDR1) selected from the group consisting of SEQ ID NO:6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278 294, 310, 326, 342, 358, 374, 399, 415, 431, 447, 463, 479, 495, 511, 527, 543, 559, 575, 591, 607, 623, 639, 655, 671, 687, 703, 719, 735, 751, 767, 783, 799, 815, 831, 847, 863 and 879, or a substantially identical sequence thereof.

[0010] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR2 selected from the group consisting of SEQ ID NO:8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 401, 417, 433, 449, 465, 481, 497, 513, 529, 545, 561, 577, 593, 609, 625, 641, 657, 673, 689, 705, 721, 737, 753, 769, 785, 801, 817, 833, 849, 865 and 881, or a substantially identical sequence thereof.

[0011] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR3 selected from the group consisting of SEQ ID NO:10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 403, 419, 435, 451, 467, 483, 499, 515, 531, 547, 563, 579, 595, 611, 627, 643, 659, 675, 691, 707, 723, 739, 755, 771, 787, 803, 819, 835, 851, 867 and 883, or a substantially identical sequence thereof.

[0012] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 selected from the group consisting of SEQ ID NO: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278 294, 310, 326, 342, 358, 374, 399, 415, 431, 447, 463, 479, 495, 511, 527, 543, 559, 575, 591, 607, 623, 639, 655, 671, 687, 703, 711119, 735, 751, 767, 783, 799, 815, 831, 847, 863 and 879, or a substantially identical sequence thereof; a heavy chain CDR2 selected from the group consisting of SEQ ID NO: 8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 401, 417, 433, 449, 465, 481, 497, 513, 529, 545, 561, 577, 593, 609, 625, 641, 657, 673, 689, 705, 721, 737, 753, 769, 785, 801, 817, 833, 849, 865 and 881, or a substantially identical sequence thereof; and a heavy chain CDR3 selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 403, 419, 435, 451, 467, 483, 499, 515, 531, 547, 563, 579, 595, 611, 627, 643, 659, 675, 691, 707, 723, 739, 755, 771, 787, 803, 819, 835, 851, 867 and 883, or a substantially identical sequence thereof. In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR1, CDR2 and CDR3 selected from the group consisting of SEQ ID NO:431/433/435; 374/376/378; 783/785/787; and 799/801/803.

[0013] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 407, 423, 439, 455, 471, 487, 503, 519, 535, 551, 567, 583, 599, 615, 631, 647, 663, 679, 695, 711, 727, 743, 759, 775, 791, 807, 823, 839, 855, 871 and 887, or a substantially identical sequence thereof.

[0014] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR2 selected from the group consisting of SEQ ID NO:16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 409. 425, 441, 457, 473, 489, 505, 521, 537, 553, 569, 585, 601, 617, 633, 649, 665, 681, 697, 713, 729, 745, 761, 777, 793, 809, 825, 841, 857, 873 and 889, or a substantially identical sequence thereof.

[0015] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR3 selected from the group consisting of SEQ ID NO:18, 34, 50, 66, 82, 98, 11, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 587, 603, 619, 635, 651, 667, 683, 699, 715, 731, 747, 763, 779, 795, 811, 827, 843, 859, 875 and 891, or a substantially identical sequence thereof.

[0016] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 407, 423, 439, 455, 471, 487, 503, 519, 535, 551, 567, 583, 599, 615, 631, 647, 663, 679, 695, 711, 727, 743, 759, 775, 791, 807, 823, 839, 855, 871 and 887, or a substantially identical sequence thereof; a light chain CDR2 selected from the group consisting of SEQ ID NO: 16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 409. 425, 441, 457, 473, 489, 505, 521, 537, 553, 569, 585, 601, 617, 633, 649, 665, 681, 697, 713, 729, 745, 761, 777, 793, 809, 825, 841, 857, 873 and 889, or a substantially identical sequence thereof; and a light chain CDR3 selected from the group consisting of SEQ ID NO: 18, 34, 50, 66, 82, 98, 11, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555, 571, 587, 603, 619, 635, 651, 667, 683, 699, 715, 731, 747, 763, 779, 795, 811, 827, 843, 859, 875 and 891, or a substantially identical sequence thereof. In a preferred embodiment, the antibody or antibody fragment comprises the light chain CDR1, CDR2 and CDR3 selected from the group consisting of SEQ ID NO:439/441/443; 382/384/386; 791/793/795; and 807/809/811.

[0017] In a second aspect, the invention provides nucleic acid molecules encoding the antibodies, or antigen-binding portions, of the invention. Recombinant expression vectors carrying the antibody-encoding nucleic acids of the invention, and host cells into which such vectors have been introduced, are also encompassed by the invention, as are methods of making the antibodies of the invention by culturing the host cells of the invention.

[0018] In one embodiment, the antibody of the invention comprises a HCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:3, 19, 35, 51, 67, 83, 99, 115, 131, 147, 163, 179, 195, 211, 227, 243, 259, 275, 291, 307, 323, 339, 355, 371, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, 588, 604, 620, 636, 652, 668, 684, 700, 716, 732, 748, 764, 780, 796, 812, 892, 896, 900, 904, 908, 912, 916, 920, 924, 934, 938, 942, and 946 or a substantially similar sequence having at least 95% homology thereof.

[0019] In one embodiment, the antibody of the invention comprises a LCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:11, 27, 43, 59, 75, 91, 107, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 404, 420, 436, 452, 468, 484, 500, 516, 532, 548, 564, 580, 596, 612, 628, 644, 660, 676, 692, 708, 724, 740, 756, 772, 788, 804, 820, 894, 898, 902, 906, 910, 914, 918, 922, 926, 936, 940, 944, and 948 or a substantially similar sequence having at least 95% homology thereof.

[0020] In one embodiment, the antibody of the invention comprises a HCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 3, 19, 35, 51, 67, 83, 99, 115, 131, 147, 163, 179, 195, 211, 227, 243, 259, 275, 291, 307, 323, 339, 355, 371, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, 588, 604, 620, 636, 652, 668, 684, 700, 716, 732, 748, 764, 780, 796, 812, 892, 896, 900, 904, 908, 912, 916, 920, 924, 934, 938, 942, and 946 or a substantially similar sequence having at least 95% homology thereof, and a LCVR encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 11, 27, 43, 59, 75, 91, 107, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 404, 420, 436, 452, 468, 484, 500, 516, 532, 548, 564, 580, 596, 612, 628, 644, 660, 676, 692, 708, 724, 740, 756, 772, 788, 804, 820, 894, 898, 902, 906, 910, 914, 918, 922, 926, 936, 940, 944, and 948 or a substantially similar sequence having at least 95% homology thereof.

[0021] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:5, 21, 37, 53, 69, 85, 101, 117, 133, 149, 165, 181, 197, 213, 229, 245, 261, 277, 293, 309, 325, 341, 357, 373, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, 574, 590, 606, 622, 638, 654, 670, 686, 702, 718, 734, 750, 766, 782, 798, 814, 830, 846, 862 and 878, or a substantially similar sequence having at least 95% homology thereof.

[0022] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:7, 23, 39, 55, 71, 87, 103, 119, 135, 151, 167, 183, 100, 215, 231, 247, 263, 279, 295, 311, 327, 343, 359, 375, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, 592, 608, 624, 640, 656, 672, 688, 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864 and 880, or a substantially similar sequence having at least 95% homology thereof.

[0023] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:9, 25, 41, 57, 73, 89, 105, 121, 137, 153, 169, 185, 201, 217, 233, 249, 265, 281, 297, 313, 329, 345, 361, 377, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, 578, 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 770, 786, 802, 818, 834, 850, 866 and 882, or a substantially similar sequence having at least 95% homology thereof.

[0024] In one embodiment, the invention features a human antibody or antibody fragment comprising a heavy chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:5, 21, 37, 53, 69, 85, 101, 117, 133, 149, 165, 181, 197, 213, 229, 245, 261, 277, 293, 309, 325, 341, 357, 373, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, 574, 590, 606, 622, 638, 654, 670, 686, 702, 718, 734, 750, 766, 782, 798, 814, 830, 846, 862 and 878, or a substantially similar sequence having at least 95% homology thereof; a heavy chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:7, 23, 39, 55, 71, 87, 103, 119, 135, 151, 167, 183, 100, 215, 231, 247, 263, 279, 295, 311, 327, 343, 359, 375, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, 592, 608, 624, 640, 656, 672, 688, 704, 720, 736, 752, 768, 784, 800, 816, 832, 848, 864 and 880, or a substantially similar sequence having at least 95% homology thereof; and a heavy chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 9, 25, 41, 57, 73, 89, 105, 121, 137, 153, 169, 185, 201, 217, 233, 249, 265, 281, 297, 313, 329, 345, 361, 377, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, 578, 594, 610, 626, 642, 658, 674, 690, 706, 722, 738, 754, 770, 786, 802, 818, 834, 850, 866 and 882, or a substantially similar sequence having at least 95% homology thereof. In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR1, CDR2 and CDR3 encoded b a nucleic acid sequence selected from the group consisting of SEQ ID NO:430/432/434; 373/375/377; 782/784/786; and 798/800/802.

[0025] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 237, 253, 269, 285, 301, 317, 333, 349, 365, 381, 406, 422, 438, 454, 470, 486, 502, 518, 534, 550, 566, 582, 598, 614, 630, 646, 662, 678, 694, 710, 726, 742, 758, 774, 790, 806, 822, 838, 854, 870 and 886, or a substantially similar sequence having at least 95% homology thereof.

[0026] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:15, 31, 47, 63, 79, 95, 111, 127, 143, 159, 175, 191, 207, 223, 239, 255, 271, 287, 303, 319, 335, 351, 367, 383, 408, 424, 440, 456, 472, 488, 504, 520, 536, 552, 568, 584, 600, 616, 632, 648, 664, 680, 696, 712, 728, 744, 760, 776, 792, 808, 824, 840, 856, 872, and 888, or a substantially similar sequence having at least 95% homology thereof.

[0027] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:17, 33, 49, 65, 81, 97, 113, 129, 145, 161, 177, 193, 209, 225, 241, 257, 273, 289, 305, 321, 337, 353, 369, 385, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, 586, 602, 618, 634, 650, 666, 682, 698, 714, 730, 746, 762, 778, 794, 810, 826, 842, 858, 874 and 890, or a substantially similar sequence having at least 95% homology thereof.

[0028] In one embodiment, the invention features a human antibody or antibody fragment comprising a light chain CDR1 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 237, 253, 269, 285, 301, 317, 333, 349, 365, 381, 406, 422, 438, 454, 470, 486, 502, 518, 534, 550, 566, 582, 598, 614, 630, 646, 662, 678, 694, 710, 726, 742, 758, 774, 790, 806, 822, 835, 851, 867 and 883, or a substantially similar sequence having at least 95% homology thereof; a light chain CDR2 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 15, 31, 47, 63, 79, 95, 111, 127, 143, 159, 175, 191, 207, 223, 239, 255, 271, 287, 303, 319, 335, 351, 367, 383, 408, 424, 440, 456, 472, 488, 504, 520, 536, 552, 568, 584, 600, 616, 632, 648, 664, 680, 696, 712, 728, 744, 760, 776, 792, 808, 824, 840, 856, 872, and 888, or a substantially similar sequence having at least 95% homology thereof; and a light chain CDR3 encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 17, 33, 49, 65, 81, 97, 113, 129, 145, 161, 177, 193, 209, 225, 241, 257, 273, 289, 305, 321, 337, 353, 369, 385, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, 586, 602, 618, 634, 650, 666, 682, 698, 714, 730, 746, 762, 778, 794, 810, 826, 842, 858, 874 and 890, or a substantially similar sequence having at least 95% homology thereof. In a preferred embodiment, the antibody or antibody fragment comprises the light chain CDR1, CDR2 and CDR3 encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO:438/440/442; 381/383/385; 790/792/794; and 806/808/810.

[0029] In a third aspect, the invention features an isolated antibody or antibody fragment that specifically binds hDll4, comprising a CDR 1, 2 and 3 selected from the group consisting of (a) a heavy chain CDR1 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8 (SEQ ID NO:928), wherein X.sup.1 is Gly; X.sup.2 is Phe or Tyr; X.sup.3 is Thr; X.sup.4 is Phe; X.sup.5 is Ser, Thr or Asn; X.sup.6 is Ser, Asn or Tyr; X.sup.7 is Tyr or Phe; and X.sup.8 is Gly or Ala; (b) a heavy chain CDR2 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8 (SEQ ID NO:929), wherein X.sup.1 is Ile or Leu; X.sup.2 is Trp or Ser; X.sup.3 is Tyr, Ala or Gly; X.sup.4 is Asp, Ser or Tyr; X.sup.5 is Gly or Asp; X.sup.6 is Ser, Gly, Thr or Val; X.sup.7 is Asn or Asp; and X.sup.8 is Lys or Arg; (c) a heavy chain CDR3 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9-X- .sup.10-X.sup.11-X.sup.12-X.sup.13-X.sup.14-X.sup.15-X.sup.16 (SEQ ID NO:930), wherein X.sup.1 is Ala or Ser; X.sup.2 is Arg or Lys; X.sup.3 is Asp or Tyr; X.sup.4 is Ser, Gly or His; X.sup.5 is Asp, Ala or Trp; X.sup.6 is Asn, or Phe; X.sup.7 is Tyr, Arg or Lys; X.sup.8 is His or Ser; X.sup.9 is Gly or Trp; X.sup.10 is Tyr or Phe; X.sup.11 is Glu or Asp; X.sup.12 is Gly, His or Pro; X.sup.13 is Tyr, Trp or absent; X.sup.14 is Phe or absent; X.sup.15 is Asp or absent; and X.sup.16 is Pro or absent.

[0030] In a preferred embodiment, the antibody or antibody fragment comprises heavy chain CDR 1, 2 and 3 selected from the group consisting of (a) a heavy chain CDR1 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8 (SEQ ID NO:928), wherein X.sup.1 is Gly; X.sup.2 is Phe; X.sup.3 is Thr; X.sup.4 is Phe; X.sup.5 is Ser or Asn; X.sup.6 is Ser or Asn; X.sup.7 is Tyr or Phe; and X.sup.8 is Gly or Ala; (b) a heavy chain CDR2 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8 (SEQ ID NO:929), wherein X.sup.1 is Ile or Leu; X.sup.2 is Trp or Ser; X.sup.3 is Tyr or Gly; X.sup.4 is Asp or Ser; X.sup.5 is Gly; X.sup.6 is Ser, Thr or Val; X.sup.7 is Asn or Asp; and X.sup.8 is Lys or Arg; (c) a heavy chain CDR3 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9-X- .sup.10-X.sup.11-X.sup.12-X.sup.13-X.sup.14-X.sup.15-X.sup.16 (SEQ ID NO:930), wherein X.sup.1 is Ala or Ser; X.sup.2 is Arg or Lys; X.sup.3 is Asp; X.sup.4 is Gly or His; X.sup.5 is Asp or Ala; X.sup.6 is Phe; X.sup.7 is Tyr or Arg; X.sup.8 is Ser; X.sup.9 is Gly; X.sup.10 is Tyr; X.sup.11 is Glu; X.sup.12 is Gly or His; X.sup.13 is Tyr or Trp; X.sup.14 is Phe or absent; X.sup.15 is Asp or absent; and X.sup.16 is Pro or absent.

[0031] In a further embodiment, the isolated antibody or antibody fragment further comprises (d) a light chain CDR1 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7 (SEQ ID NO:931), wherein X.sup.1 is Gln; X.sup.2 is Ser; X.sup.3 is Val; X.sup.4 is Arg, Ser or Thr; X.sup.5 is Ser or Gly; X.sup.6 is Ser or Tyr; and X.sup.7 is Tyr or absent; (e) a light chain CDR2 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3 (SEQ ID NO:932), wherein X.sup.1 is Gly or Asp; X.sup.2 is Ala or Thr; and X.sup.3 is Ser; and (f) a light chain CDR3 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X- .sup.9 (SEQ ID NO:933), wherein X.sup.1 is Gln; X.sup.2 is Gln or His; X.sup.3 is Tyr, Arg or Ser; X.sup.4 is Gly, Ser or Ala; X.sup.5 is Ser, Asn or Phe; X.sup.6 is Trp or Ser; X.sup.7 is Pro; X.sup.8 is Trp, Pro or Arg; and X.sup.9 is Thr.

[0032] In a preferred embodiment, the isolated antibody or antibody fragment further comprises (d) a light chain CDR1 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7 (SEQ ID NO:931), wherein X.sup.1 is Gln; X.sup.2 is Ser; X.sup.3 is Val; X.sup.4 is Arg or Ser; X.sup.5 is Ser; X.sup.6 is Ser or Tyr; and X.sup.7 is Tyr or absent; (e) a light chain CDR2 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3 (SEQ ID NO:932), wherein X.sup.1 is Gly or Asp; X.sup.2 is Ala or Thr; and X.sup.3 is Ser; and (f) a light chain CDR3 region comprising an amino acid sequence of the formula X.sup.1-X.sup.2-X.sup.3-X.sup.4-X.sup.5-X.sup.6-X.sup.7-X.sup.8-X.sup.9 (SEQ ID NO:933), wherein X.sup.1 is Gln; X.sup.2 is Gln or His; X.sup.3 is Tyr or Arg; X.sup.4 is Gly or Ser; X.sup.5 is Ser or Asn; X.sup.6 is Trp or Ser; X.sup.7 is Pro; X.sup.8 is Pro or Arg; and X.sup.9 is Thr.

[0033] In a fourth aspect, the invention features a fully human antibody or antibody fragment which binds hDll4 with an IC.sub.50 of less than about 10 nM, as measured in in vitro assay or ELISA-based Dll4 blocking assay (described below). In a preferred embodiment, the antibody of the invention exhibits an IC.sub.50 of about 500 pM or less. In an even more preferred embodiment, the antibody of the invention exhibits an IC.sub.50 of about 100 pM or less.

[0034] In one embodiment, the invention provides a fully human monoclonal antibody which specifically binds and inhibits human Dll4 and exhibits an IC.sub.50 of less than or equal to about 150 pM, 100 pM, 75 pM, or 50 pM, as measured by Notch-inducible luciferase bioassay with hDll4-Fc. As shown in the experimental section below, the anti-hDll4 antibodies of the invention do not cross-react with closely related delta proteins, such as hDll1 and hDll3.

[0035] In one embodiment, the invention provides an isolated human antibody, or an antigen-binding portion thereof, that binds hDll4 with a K.sub.D of less than about 500 pM, preferably less than about 300 pM, even more preferably less than about 100 pM, less than about 50 pM, less than about 10 pM, as determined by surface plasmon resonance (BIACORE.TM.), for example, using dimeric hDll4 (Table 2).

[0036] The invention encompasses anti-hDll4 antibodies having a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or an antibody lacking a fucose moiety present on the oligosaccharide chain, for example, to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, modification of a galactosylation can be made in order to modify complement dependent cytotoxicity (CDC).

[0037] The invention includes anti-hDll4 antibodies which bind specific epitopes of hDll4 and are capable of blocking the biological activity of hDll4. The extracellular domain of Dll4 is composed of an N-terminal domain, a Delta/Serrate/Lag-2 (DSL) domain, and a tandem of eight epidermal growth factor (EGF)-like repeats. Generally, the EGF domains are recognized as occurring at about amino acid residues 218-251 (domain 1), 252-282 (domain 2), 284-322 (domain 3), 324-360 (domain 4), and 362-400 (domain 5), with the DSL domain at about amino acid residues 173-217 and the N-terminal domain at about amino acid residues 27-172 of hDll4 (SEQ ID NO:2).

[0038] In one embodiment, a blocking antibody of the invention binds within amino acids residues 27 to 524 of SEQ ID NO:2. In a more specific embodiment, a blocking antibody of the invention binds an epitope within the N-terminus-DSL domains 27-217 of SEQ ID NO:2; in an even more specific embodiment, the blocking antibody binds an epitope within about amino acid residues 27-172 (N-terminal domain) or 173-217 (DSL domain). In another embodiment, a blocking antibody of the invention binds the EGF-2 epitope within about amino acids residues 252-282 of SEQ ID NO:2.

[0039] In a fifth aspect, the invention features a composition comprising a recombinant human anti-human Dll4 antibody and an acceptable carrier. Further included in the invention are vectors and host cells comprising vectors which contain nucleic acid molecules encoding the human anti-hDll4 antibody of the invention, as well as methods of producing these novel antibodies, comprising growing a host cell comprising nucleic acid encoding the anti-hDll4 antibody of the invention or an antibody fragment, under conditions permitting production of the protein and recovering the protein so produced.

[0040] In a sixth aspect, the invention features methods for inhibiting hDll4 activity using an antibody, or antigen-binding portion thereof, of the invention. In one embodiment, the method comprises contacting hDll4 with the instant antibody or antigen-binding portion thereof, such that hDll4 is inhibited from binding to Notch receptor, for example Notch-1. In another embodiment, the method comprises administering an antibody or antibody fragment of the invention, to a human subject suffering from a disorder which is ameliorated by inhibition of Dll4 activity. The disorder treated is a disease or condition which is improved, ameliorated, inhibited or prevented by removal, inhibition or reduction of Dll4 activity, for example, pathological vascularization associated with tumor angiogenesis and cancer, immunodeficiency diseases, transplant rejection, or inflammation; and neurodegenerative conditions, e.g., associated with prion disease.

[0041] Other objects and advantages will become apparent from a review of the ensuing detailed description.

DETAILED DESCRIPTION

[0042] Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0043] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

DEFINITIONS

[0045] "Delta-like ligand 4", "Dll4", "hDll4" are used interchangeably to refer to the protein encoded by the nucleic acid sequence of SEQ ID NO:1 and the protein having the amino acid sequence of SEQ ID NO:2.

[0046] The term "antibody", as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementary determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0047] The term "high affinity" antibody refers to those antibodies having a binding affinity to hDll4 of at least 10.sup.-8 M; preferably 10.sup.-9 M; even more preferably 10.sup.-10 M, as measured by surface plasmon resonance, e.g., BIACORE.TM. or solution-affinity ELISA.

[0048] By the term "slow off rate" or "Koff" is meant an antibody that dissociates from hDll4 with a rate constant of 1.times.10.sup.-3 s.sup.-1 or less, preferably 1.times.10.sup.-4s.sup.-1 or less, as determined by surface plasmon resonance, e.g., BIACORE.TM..

[0049] A "neutralizing" or "blocking" antibody, is intended to refer to an antibody whose binding to Dll4 results in inhibition of the biological activity of Dll4. This inhibition of the biological activity of Dll4 can be assessed by measuring one or more indicators of Dll4 biological activity. These indicators of Dll4 biological activity can be assessed by one or more of several standard in vitro or in vivo assays known in the art (see examples below). Preferably, the ability of an antibody to neutralize Dll4 activity is assessed by inhibition of Dll4 binding to a Notch receptor.

[0050] The term "antigen-binding portion" of an antibody (or simply "antibody portion" or "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hDll4). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab').sub.2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature 241:544-546), which consists of a VH domain; and (vi) an isolated CDR. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger et al. (1993) Proc. Natl. Acad Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123).

[0051] Still further, an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov et al. (1994) Mol. Immunol. 31:1047-1058). Antibody portions, such as Fab and F(ab').sub.2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.

[0052] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0053] The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0054] An "isolated antibody", as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hDll4 is substantially free of antibodies that specifically bind antigens other than hDll4). An isolated antibody that specifically binds hDll4 may, however, have cross-reactivity to other antigens, such as hDll4 molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0055] The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE.TM. system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).

[0056] The term "K.sub.D", as used herein, is intended to refer to the dissociation constant of a particular antibody-antigen interaction.

[0057] The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specific binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics, and/or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In preferred embodiments, an antibody is said to specifically bind an antigen when the equilibrium dissociation constant is less than or equal to 10.sup.-8 M, more preferably when the equilibrium dissociation constant is less than or equal to 10.sup.-9 M, and most preferably when the dissociation constant is less than or equal to 10.sup.-10 M.

[0058] A protein or polypeptide is "substantially pure," "substantially homogeneous" or "substantially purified" when at least about 60 to 75% of a sample exhibits a single species of polypeptide. The polypeptide or protein may be monomeric or multimeric. A substantially pure polypeptide or protein will typically comprise about 50%, 60, 70%, 80% or 90% W/W of a protein sample, more usually about 95%, and preferably will be over 99% pure. Protein purity or homogeneity may be indicated by a number of means well known in the art, such as polyacrylamide gel electrophoresis of a protein sample, followed by visualizing a single polypeptide band upon staining the gel with a stain well known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well known in the art for purification.

[0059] The term "polypeptide analog or variant" as used herein refers to a polypeptide that is comprised of a segment of at least 25 amino acids that has substantial identity to a portion of an amino acid sequence and that has at least one of the following properties: (1) specific binding to hDll4 under suitable binding conditions, or (2) ability to block Dll4 binding to a Notch receptor. Typically, polypeptide analogs or variants comprise a conservative amino acid substitution (or insertion or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50, 60, 70, 80, 90, 100, 150 or 200 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide.

[0060] Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and (4) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various mutations of a sequence other than the naturally-occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton 1984 W. H. Freeman and Company, New York; Introduction to Protein Structure (Branden & Tooze, eds., 1991, Garland Publishing, NY); and Thornton et at. 1991 Nature 354:105, which are each incorporated herein by reference.

[0061] Non-peptide analogs are commonly used in the pharmaceutical industry as drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed "peptide mimetics" or "peptidomimetics" (see, for example, Fauchere (1986) J. Adv. Drug Res. 15:29; and Evans et al. (1987) J. Med. Chem. 30:1229, which are incorporated herein by reference. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may also be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo et al. (1992) Ann. Rev. Biochem. 61:387, incorporated herein by reference), for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.

[0062] The term "percent sequence identity" in the context of nucleic acid sequences refers to the residues in two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides or more, usually at least about 18 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36, 48 or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (1990) Methods Enzymol. 183:63-98 and (2000) Methods Mol. Biol. 132:185-219, each herein incorporated by reference). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1, herein incorporated by reference.

[0063] A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. Generally, the art uses the terms "percent sequence identity", "percent sequence similarity" and "percent sequence homology" interchangeably. In this application, these terms shall have the same meaning with respect to nucleic acid sequences.

[0064] The term "substantial similarity", or "substantial sequence similarity," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 90%, preferably at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above.

[0065] As applied to polypeptides, the term "substantial identity" or "substantially identical" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 80% sequence identity, preferably at least 90% or 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331, herein incorporated by reference. Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; and 6) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45, herein incorporated by reference. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0066] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as "Gap" and "Bestfit" which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389 402, each of which is herein incorporated by reference.

[0067] The length of polypeptide sequences compared for homology will generally be at least about 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.

Preparation of Human Antibodies

[0068] Methods for generating human antibodies include, for example, VELOCIMMUNE.RTM. (Regeneron Pharmaceuticals), XENOMOUSE.TM. technology (Abgenix), the "minilocus" approach, and phage display. The VELOCIMMUNE.RTM. technology (U.S. Pat. No. 6,596,541) encompasses a method of generating a high specificity fully human antibody to a select antigen. This technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody. In specific embodiment, the cell is a CHO cell.

[0069] The XENOMOUSE.TM. technology (Green et al. (1994) Nature Genetics 7:13-21) generates a mouse having both human variable and constant regions from both the heavy chain and kappa light chain loci. In an alternative approach, others have utilized a `minilocus" approach in which an exogenous Ig locus is mimicked through inclusion of individual genes from the Ig locus (see, for example, U.S. Pat. No. 5,545,807). The DNA encoding the variable regions can be isolated with or without being operably linked to the DNA encoding the human heavy and light chain constant region.

[0070] Other methods of generating human antibodies, including isolation from a human donor, are known. See, for example, U.S. Pat. No. 6,787,637, herein specifically incorporated by reference in its entirety.

[0071] Antibodies may be therapeutically useful in blocking a ligand-receptor interaction or inhibiting receptor component interaction, rather than by killing cells through fixation of complement and participation in CDC. The constant region of an antibody is important in the ability of an antibody to fix complement and participate in CDC or direct cell killing through antibody-dependent cellular cytoxicity (ADCC). Thus, the isotype of an antibody may be selected on the basis of the desirability for the antibody to fix complement.

[0072] Human immunoglobulins can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-heavy chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a single light and heavy chain. These forms have been difficult to separate, even after affinity purification.

[0073] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. In fact, a single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. 1993 Molecular Immunology 30:105) to levels typically observed using a human IgG1 hinge. The instant invention encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production to improve the yield, or modulate effector functions.

[0074] Antibodies of the invention are preferably prepared with the use of VELOCIMMUNE.RTM. technology. A transgenic mouse in which the endogenous immunoglobulin heavy and light chain variable regions are replaced with the corresponding human variable regions is challenged with the antigen of interest, and lymphatic cells (such as B-cells) recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloid-type cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimeric antibodies may be isolated directly from antigen-specific lymphocytes. In various embodiments, the transgenic mouse comprises 12 functional human variable heavy chain genes and 11 functional human variable kappa light chain genes; 25 to 30 human variable heavy chain genes and from 18 to 20 human variable kappa light chain genes; 43 to 48 human variable heavy chain genes and 20 to 22 human variable kappa light chain genes; or about 80 human variable heavy chain genes and about 40 human variable kappa light chain genes.

[0075] In general, the antibodies of the instant invention possess very high affinities, typically possessing K.sub.D of from about 10.sup.-9 through about 10.sup.-11 M, when measured by binding to antigen either immobilized on solid phase or in solution phase. The mouse constant regions are replaced with desired human constant regions to generate the fully human antibodies of the invention, for example wild-type or modified IgG1 or IgG4 (for example, SEQ ID NO:950, 951, or 952). While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.

[0076] Cancer, infectious diseases, autoimmunity, immunodeficiency, transplants, inflammation, injury and degenerative conditions can be treated by modulation of the immune system. In cases of disease due to inappropriate function or hyperactivity of the immune system, such as autoimmunity or inflammation, can be ameliorated through inhibition of immune cell function or reduction of immune cell numbers. This can be accomplished by blockade of positive signals or stimulation of negative signals on immune cell populations critical to the disease process, such as T, B or NK cells, neutrophils, macrophages, antigen presenting cells, mast cells or other cell types. Overactivity can also be inhibited through elimination of various immune cell populations by stimulation of apoptosis, targeting of specific surface receptors with depleting antibodies or antibody-drug conjugates, or the blockade or alteration of the differentiation of immune cell lineages or specific cell types. Inefficient or reduced immune function can cause or exacerbate disorders such as cancer, infectious disease, and other immunodeficiencies. Hypoactivity of the immune system can be improved through activation of immune cells by stimulation of positive signals by crosslinking or agonistic antibodies or blockade of negative signals. Immune cell populations can be increased by stimulation of development of some or all immune cell lineages, prevention of apoptosis, or elimination of inhibitory signals. In a specific application, the antibodies of the invention are useful for treatment, inhibition or amelioration of a condition or disease such as, for example, cancer, immunodeficiency, transplant rejection, or inflammation.

Epitope Mapping and Related Technologies

[0077] To screen for antibodies which bind to a particular epitope (e.g., those which block binding of IgE to its high affinity receptor), a routine cross-blocking assay such as that described in Harlow and Lane (1990) supra can be performed. Other methods include alanine scanning mutants, peptide blots (Reineke (2004) Methods Mol Biol 248:443-63) (herein specifically incorporated by reference in its entirety), or peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer (2000) Protein Science 9: 487-496) (herein specifically incorporated by reference in its entirety).

[0078] The term "epitope" refers to a site on an antigen to which B and/or T cells respond. B-cell epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation.

[0079] Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (U.S. patent Publication No. 2004/0101920, herein specifically incorporated by reference in its entirety). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma clones that produce mAbs having the desired characteristics. MAP may be used to sort the hDll4 antibodies of the invention into groups of antibodies binding different epitopes.

[0080] Agents useful for altering the structure of the immobilized antigen are enzymes, such as, for example proteolytic enzymes, for example, trypsin, endoproteinase Glu-C, endoproteinase Asp-N, chymotrypsin, etc. Agents useful for altering the structure of the immobilized antigen may also be chemical agents, such as, succinimidyl esters and their derivatives, primary amine-containing compounds, hydrazines and carbohydrazines, free amino acids, etc.

[0081] The antigen protein may be immobilized on either biosensor chip surfaces or polystyrene beads. The latter can be processed with, for example, an assay such as multiplex LUMINEX.TM. detection assay (Luminex Corp., Austin, Tex.). Because of the capacity of LUMINEX.TM. to handle multiplex analysis with up to 100 different types of beads, LUMINEX.TM. provides almost unlimited antigen surfaces with various modifications, resulting in improved resolution in antibody epitope profiling over a biosensor assay.

Therapeutic Administration and Formulations

[0082] The administration of therapeutic entities in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, Pa.). These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN.TM.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. 52:238-311 and the citations therein for additional information related to excipients and carriers well known to pharmaceutical chemists.

EXAMPLES

Example 1

Generation of Human Antibodies to Human Dll4

[0083] Mice may be immunized by any method known in the art (see, for example, Harlow and Lane supra). In one embodiment, hDll4 antigen is administered directly to VELOCIMMUNE.RTM. mice comprising DNA loci encoding human Ig heavy chain variable regions and kappa light chain variable regions, with an adjuvant to stimulate the immune response. Such an adjuvant includes complete and incomplete Freund's adjuvant, MPL+TDM adjuvant system (Sigma), or RIBI (muramyl dipeptides) (see O'Hagan 2000 Vaccine Adjuvant, by Human Press, Totawa, NJ). The antibody immune response is monitored by standard antigen specific immunoassay. When a desired immune response is achieved, antibody-expressing B cells were harvested and fused with mouse myeloma cells to preserve their viability, forming hybridoma cell lines. Such hybridoma cell lines are screened and selected to identify cell lines that produce antigen-specific antibodies using assays as described below.

[0084] Alternatively, antigen-specific hybridoma cells may be isolated by flow cytometry. Briefly, after fusion to myeloma cells, pooled hybridoma cells were grown for 10 days in HAT medium. The cells were then harvested and stained with biotin-labeled Dll4 at 2 mg/ml for one hour, followed by addition of phycoerythrin-streptavidin. The fluorescence-labeled cells were sorted by flow cytometry (single cell per well into 96 well plates containing hybridoma growth medium), cultured for 8-10 days, and conditioned media screened for the presence of functionally desirable monoclonal antibodies, as described below.

[0085] Anti-hDll4 Antibodies Generated Via Direct Isolation of Splenocytes.

[0086] Antigen-specific antibodies may also be isolated directly from antigen-immunized B cells without fusion to myeloma cells, as described in U.S. Patent Publication 2007/0280945A1, herein specifically incorporated by reference in its entirety. Stable recombinant antibody-expressing CHO cell lines were established from the isolated proper recombinants.

Example 2

Antigen Binding Affinity Determination

[0087] Equilibrium dissociation constants (K.sub.D values) for antigen binding to the selected antibodies described above were determined by surface kinetics on a real-time biosensor surface plasmon resonance assay (BIACORE.TM. 2000). The antibody was captured on a goat anti-mouse IgG polyclonal antibody surface created through direct chemical coupling to a BIACORE.TM. chip to form a captured antibody surface. Varying concentrations of monomeric hDll4 or dimeric hDll4-hFc were injected over the captured antibody surfaces, and antigen-antibody binding and dissociation monitored in real time. Kinetic analysis was performed to calculate K.sub.D, dissociation rate constants, and half-life of antigen/antibody complex dissociation (Table 1). A similar method was applied to measure single B cell-derived monoclonal antibodies modified to contain a human IgG constant domain. Antibodies were presented by goat anti-hFc polyclonal antibody reagent (Jackson Immuno Research Lab) immobilized on BIACORE.TM. chip, and exposed to either dimeric Dll4-mFc or monomeric Dll4 protein (Table 2).

[0088] Antibody-antigen binding affinity may also be assessed using an ELISA based solution competition assay. Briefly, on a 96-well microtiter plate, antibodies (purified proteins or in conditioned medium) were premixed with serial dilutions of antigen protein (monomeric or dimeric) ranging from 0 to 10 .mu.g/ml with a constant concentration of antibody. After a 2 hr incubation of antigen with antibody, the solutions were transferred to a microtiter plate precoated with antigen for measurement of free antibody (MAXISORB.TM., VWR, West Chester, Pa.). The plate was coated with 1 .mu.g/ml hDll4-hFc protein in PBS solution overnight at 4.degree. C. and nonspecific binding sites blocked with BSA for 2 hrs. After a 1 hr incubation following transfer, the plate was washed and the plate-bound antibodies were detected with an HRP-conjugated goat anti-mouse IgG polyclonal antibody reagent (Jackson Immuno Laboratory) and developed using colorimetric substrates (OPTEIA.TM.; BD Biosciences Pharmingen, San Diego, Calif.). The enzymatic reaction was stopped with 1 M phosphoric acid, optical absorptions at 450 nm were recorded and the data were analyzed using a sigmoidal dose-response model and an IC.sub.50 values were reported (Table 1).

TABLE-US-00001 TABLE 1 Antibody K.sub.D DII4 (nM) K.sub.D DII4-Fc (nM) IC.sub.50 DII4-Fc (nM) 13B6 2.79 0.188 0.06 15E10 0.55 0.023 0.58 22G12 1.29 0.076 0.03 24C8 0.52 0.047 0.01 VAV 2H4-19 1.51 0.611 0.10 VAV 4H10-9 13.70 0.662 0.30 VAV 7B9-9 0.88 0.021 0.27 VAW 10E4-9 89.00 0.468 0.06 VAW 10G11-2 31.30 1.430 1.66 VAW 1C6-1 45.80 0.092 0.25 VAW 1G2-4 83.80 0.035 0.40 VAW 1H2-2 67.00 0.148 0.30 VAW 2H3-2 0.30 0.150 0.26 VAW 3A7-2 1.64 0.162 0.02 VAW 3A9-5 NA 2.510 16.00 VAW 3F12-8 8.12 0.648 0.07 VAW 6B8-12 0.89 0.060 0.43 VAW 6C6-2 91.70 0.092 0.50 VAW 6G12-10 3.74 0.527 0.19 VAW 7C10-11 17.10 0.853 0.28 VAW 8A10-14 1.41 0.648 0.08 VAW 8G1-12 6.09 8.300 8.60 VAW 9B11-2 62.20 0.048 0.00 VAW 9F12-6 16.00 1.350 0.02 VAW 9G10-1 56.10 0.555 0.10

TABLE-US-00002 TABLE 2 Antibody K.sub.D DII4 (nM) K.sub.D DII4-Fc (nM) 314266-06F12-B7 2.17 0.075 318518-01A04-D5 0.237 0.244 318518-01A10-D8 0.399 0.018 318518-01B09-C3 0.833 0.180 318518-01B11-D4 0.382 0.088 318518-01E07-H2 0.165 0.238 318518-01G04-F3 0.501 0.107 318518-01G05-B5 1.06 0.196 318518-02A07-B3 0.208 0.148 318518-02B06-E2 2.15 0.193 318518-02B08-F7 N/A N/A 318518-02C04-D1 0.478 0.331 318518-02F05-D10 1.28 0.035 318518-02G03-F2 1.31 0.042 318518-02G04-B11 0.813 0.048 318518-02G08-F11 N/A N/A 318518-03A03-B2 0.136 0.124 318518-03C10-F2 1.18 0.131 318518-03D04-B5 0.904 0.136 318518-03D07-G11 3.74 0.163 318518-03F04-A6 0.501 0.088 318518-03F06-A3 0.556 0.037 318518-03H03-F3 8.89 0.084 318518-14A06-E7 4.54 0.282 318518-14A07-C4 0.235 0.035 318518-14D08-G1 0.541 0.046 318518-14H08-A2 6.67 0.128 318518-1H08-E9 0.225 0.050

Example 3

Inhibition of Dll4 and Notch Interaction

[0089] The ability of the antibodies to block Dll4 binding to Notch was evaluated with an ELISA-based immunoassay. Briefly, Notch-hFc recombinant protein was coated on a 96-well plate in PBS buffer overnight at 4.degree. C. at 1 mg/ml, and the nonspecific binding sites were blocked with BSA. This plate was used to measure free biotin-Dll4-hFc from antibody titration sample solutions. To make the antibody titration samples, a constant amount of biotin-Dll4-hFc at 25 pM was pre-mixed with varied amounts of antibody, either in crude hybridoma condition medium or as purified antibody protein, ranging from 0 to .about.50 nM in serial dilutions, followed by 2 hr incubation at room temperature to allow antibody-antigen binding to reach equilibrium. The equilibrated sample solutions were then transferred to the Notch-hFc coated plates for the measurement of free biotin-Dll4-hFc. After 1 hour binding, the plate was washed and bound biotin-Dll4-hFc was detected using HRP conjugated streptavidin (Poly HRP streptavidin, Pierce Endogen), and developed using TMB substrate (BD Pharmigen). Data was analyzed using Graph Pad Prism software and IC.sub.50 values were determined as the amount of antibody required to achieve 50% reduction of biotin-Dll4-hFc bound to the plate-coated Notch-Fc (Table 3) (*conditioned media).

TABLE-US-00003 TABLE 3 Antibody IC.sub.50 (nM) VAV 2H4-19 0.01 VAW 3A7-2 0.017 VAW 9G10-1 0.019 VAW 10E4-9 0.032 VAW 8A10-11 0.04 VAW 9F12-6 0.059 VAW 3F12-8 0.066 VAW 1C6-1 0.086 VAW 1G2-4 0.11 VAW 6C6-2 0.119 VAV 7B9-4 0.123 VAW 1H2-2 0.154 VAW 2H3-2 0.168 VAW 6B8-12 0.255 VAW 6G12-10 0.257 VAW 7C10-11 0.273 VAV 4H10-9 0.599 VAW 10G11-2 0.931 VAW 3A9-5 3.8 VAW 8G1-12 10.7 VAW 9B11-2 0.069 15E10* 0.04 22G12 0.10 13B6 0.11 24C8 0.031 314266-06F12-B7 0.07 318518-01A04-D5 0.11 318518-01A10-D8 0.05 318518-01B09-C3 0.03 318518-01B11-D4 0.03 318518-01E07-H2 1.17 318518-01G04-F3 0.02 318518-01G05-B5 1.08 318518-02A07-B3 0.03 318518-02B06-E2 0.09 318518-02B08-F7 N/A 318518-02C04-D1 0.60 318518-02F05-D10 0.16 318518-02G03-F2 0.07 318518-02G04-B11 1.09 318518-02G08-F11 N/A 318518-03A03-B2 0.57 318518-03C10-F2 0.12 318518-03D04-B5 0.04 318518-03D07-G11 0.45 318518-03F04-A6 0.01 318518-03F06-A3 0.02 318518-03H03-F3 0.17 318518-14A06-E7 0.04 318518-14A07-C4 0.02 318518-14D08-G1 0.14 318518-14H08-A2 0.25 318518-1H08-E9 0.03

[0090] The ability of selected purified anti-hDll4 antibodies to block Dll4 binding to Notch was also evaluated with the ELISA-based immunoassay described above, modified by replacing 25 pM of biotin-Dll4-hFc with 30 pM of biotin-Dll4-hFc, and reducing antibody-antigen incubation duration from 2 hrs to 1 hr. For convenience, antibody 318518-01A10-D8 was renamed "REGN281" (HCVR/LCVR SEQ ID NOs:429/437 and hIgG1 SEQ ID NO:950). Derived antibodies tested included REGN421 (HCVR/LCVR SEQ ID NO:901/903, hIgG1 SEQ ID NO:950); and REGN422 (HCVR/LCVR SEQ ID NO:901/903, with modified hIgG4 SEQ ID NO:952). Results are shown in Table 4.

TABLE-US-00004 TABLE 4 Antibody IC.sub.50 (nM) REGN281 0.042 REGN421 0.045 REGN422 0.039

[0091] Ability of antibody to neutralize Dll4 mediated cellular function was also tested in vitro using Dll4 expressing human umbilical vein endothelial cells (HUVEC). Inhibition of Notch mediated hHes1 and EphB2 gene expression in HUVEC with the derived antibodies was monitored as follows: low passage HUVEC were cultured in MCDB-131 media (Vec Technologies). One day prior to analysis, HUVEC cells were seeded at a density of 2.times.10.sup.5 cells/well in 24-well plates in 1 ml total media volume. The test antibody or other inhibitor was added directly to the individual sample wells in triplicate followed by 5-hour culture at 37.degree. C. At the end of the culture period, media was removed and total RNA was isolated using QIAZOL.TM. and the RNEASY.TM. lipid tissue kit (Qiagen). mRNA level quantification was performed by the use of PCR and the fluorogenic 5' nuclease assay (TAQMAN.RTM. assay, Appied Biosystems). For each sample, cDNA was synthesized from 1-2 mg of total RNA. cDNA generated from an equivalent amount of starting RNA (typically 25 ng) was loaded in triplicate on ABI PRISM.TM. optical reaction plates. For each RNA sample a "no RT" control was also run in which no reverse transcriptase was added to allow for subtraction of any potential genomic DNA contributions to the signal. 2.times. Mastermix (TAQMAN.RTM. 2.times.PCR Mastermix; ABI) was added to each reaction to a final concentration of 1.times.. Additionally, TAQMAN.RTM. probe and primers for the gene of interest were added to each reaction. Each primer was used at a final concentration of 900 nM and the probe was added at a final concentration of 200 nM. Human genomic DNA was used as a standard. The assays were performed under standard TAQMAN.RTM. conditions on a ABI 7900HT instrument. Levels of Hes1 and EphrinB2 were measured and normalized to an endogenous control gene (cyclophilin) (Table 5). Probes and primers: human Hes1 probe (SEQ ID NO:387); Oligos: hHes1-869F (SEQ ID NO:388); hHes1-940R (SEQ ID NO:389), human ephrinB2 probe: hEphB2-773T (SEQ ID NO:390); Oligos: hEphB2-752F (SEQ ID NO:391) hEphB2-812R (SEQ ID NO:392); human cyclophilin: probe: hCyclophilin-343T (SEQ ID NO:393); Oligos: hCyclophilin-323F (SEQ ID NO:394); hCyclophilin-389R (SEQ ID NO:395).

TABLE-US-00005 TABLE 5 EphrinB2 Hes1 Antibody Expression IC.sub.50 (nM) Expression IC.sub.50 (nM) 22G12 0.379 0.381 15E10 2.56 4.49 VAW 3A7-2 0.409 0.533 314266-06F12-B7 0.239 0.405 318518-01A10-D8 0.305 0.329 318518-01G04-F3 0.088 0.172 318518-01H08-E9 0.413 0.548 318518-02A07-B3 0.398 0.128 318518-03F04-A6 0.158 0.115 318518-03F06-A3 0.304 0.692 318518-014A07-C4 0.175 0.312 318518-014D08-G1 0.510 0.568 hDII4-hFc 0.843 0.974

[0092] HUVEC Proliferation Assay.

[0093] The ability of antibody to block Dll4 mediated growth inhibition of Human umbilical vein endothelial cells (HUVEC) cells was tested in an in vitro cell proliferation assay. Low passage HUVEC cells were obtained and cultured in MCDB-131 media (Vec Technologies). One day prior to analysis 12-well tissue culture plates were coated with hDll4-hFc in PBS at 4.degree. C. overnight (0.2 .mu.g/ml; 0.5 ml PBS/well). Plates were washed 1.times. with PBS and HUVEC cells were seeded at a density of 4.times.10.sup.3 cells/well in 1.0 ml total media volume. Immediately following addition of cells anti-hDll4 antibodies were added in 0.5 ml total volume over a range of concentrations to generate an inhibition curve. Cells were grown for 96-hours at 37.degree. C. Cell number was quantitated using the CCK-8 reagent (Dojindo). All assays were run in triplicate. (Table 6, NB, not blocking).

TABLE-US-00006 TABLE 6 Antibody IC.sub.50 (nM) 15E10 0.284 VAW9B11-2 1.868 VAW8D8-12 NB 13B6 5.01 VAW2H4-19 NB VAW3A7-2 0.198 VAW8A10-14 0.214 22G12 0.888 318518-06F12-B7 2.067 318518-01A10-D8 0.096 318518-01G04-F3 0.106 318518-01H08-E9 0.188 318518-02A07-B3 0.200 318518-03F04-A6 0.184 318518-03F06-A3 0.188 318518-014A07-C4 0.159 318518-014D08-G1 0.165

[0094] Notch-Inducible Luciferase Assay.

[0095] A bioassay was developed to determine the ability of selected purified antibodies to neutralize Dll4-mediated cellular function in vitro using an engineered HEK293 cell line (ATCC) that constitutively expresses human Notch 1 and contains a Notch-responsive promoter driving luciferase. Inhibition of Notch-inducible luciferase activity was determined as follows: 1 day prior to assay, each well of an opaque 96 well tissue culture plate was coated with 100 .mu.l of either 1 nM or 1.5 nM hDll4-hFc in PBS overnight at 4.degree. C. Cells were seeded onto the coated plates at 2.times.10.sup.4 cells/well in media. Purified antibody protein, in serial dilutions starting from 2 nM in cell media, was incubated with the cells at 37.degree. C. for 24 hrs. Luciferase activity was determined by adding an equal well volume of STEADY-GLO.RTM. Substrate (Promega) (Table 7).

TABLE-US-00007 TABLE 7 IC.sub.50 (pM) Antibody 1 nM hDII4-hFc 1.5 nM hDII4-hFc REGN281 50.5 78.7 REGN421 54.4 87.3 REGN422 88.2 131.1

Example 4

Inhibition of Notch1 Cleavage

[0096] The ability of selected anti-hDll4 antibodies to inhibit Notch1 cleavage was tested by examination of total cleaved Notch1 protein by SDS-Page/Western blotting. Low passage HUVEC cells were cultured as described above. One day prior to analysis 6-well plates were coated with hDll4-hFc in PBS at 4.degree. C. overnight (0.2 .mu.g/ml; 1.0 ml PBS/well). Plates were washed 1.times. with PBS and HUVEC cells were seeded at 7.5.times.10.sup.5 cells/well in 2.0 ml total media volume. Immediately following cell seeding, anti-hDll4 antibody was added to each well at 10 nM final concentration. Cells were grown for 24 hours at 37.degree. C. following which whole cell extracts were prepared and analyzed by SDS-PAGE. Levels of cleaved Notch1 were determined using an anti-cleaved Notch1 (Val1744) antibody (Cell Signaling) and standard western blotting techniques. The anti-hDll4 antibodies were able to entirely block the Notch1 cleavage induced by plate coated hDll4-hFc (data not shown).

Example 5

ADCC and CDC Assays

[0097] Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by two test antibodies (REGN421, REGN422) was assessed using a panel of eight target cell lines with varying hDll4 expression levels. The eight target cell lines were (1) HUVECs; (2) HUVECs stimulated with 10 nM VEGF for 24 hours; (3) Colo205; (4) engineered C6 rat glioma cells expressing eGFP; (5) engineered C6 rat glioma cells expressing hDll4; (6) engineered HT1080 cells expressing eGFP; (7) engineered HT1080 cells expressing hDll4; and (8) HT29. Human Dll4 or eGFP was integrated into the 06 cell or HT1080 genome through retroviral transfection. Briefly, cells from each target cell line (10,000 cells/well in 50 .mu.l) were first mixed with an equal volume of serially diluted REGN421 or REGN422, resulting in a final antibody concentration ranging from 0.169 pM to 10 nM, and incubated for 10 min at room temperature in a 96-well plate format (control=wells without antibody). Separately, human peripheral blood mononuclear cells (PBMCs, effector cells) were prepared following a conventional Ficoll-Hypaque gradient centrifugation enrichment procedure. Approximately 300,000 PBMCs were added to each mixture of antibody and target cells to give a final ratio of effector to target cells of approximately 30:1. The 96-well plates were then incubated for 4 h at 37.degree. C., 5% CO.sub.2 followed by centrifugation at 250.times.g. Supernatants were harvested and assayed for lactate dehydrogenase (LDH) activity using the CYTOTOX 96.RTM. Non-Radioactive Cytotoxicity Assay system (Promega). Results are shown in Table 8. REGN421-induced dose dependent cell lysis was only observed in 06 cells expressing hDll4 (col. 5), which exhibited the highest hDll4 expression among all cell lines (as determined by immunoprecipitation/Western blot and flow cytometry). The maximum cell cytotoxicity in the 06-h Dll4 cell line ranged from 20% to 60%. No REGN421-induced cell lysis was observed in the remaining seven target cell lines. REGN422 did not induce cell lysis in any of the target cell lines.

TABLE-US-00008 TABLE 8 % Maximum Cytotoxicity Ab 1 2 3 4 5 6 7 8 REGN421 0 0 0 0 20-60 0 0 0 REGN422 0 0 0 0 0 0 0 0

[0098] Complement-dependent cytotoxicity (CDC) induced by REGN421 was assessed using the same panel of cells lines described above. Briefly, cells from each of the target cell lines (50,000 cells/well in 50 .mu.l) were first mixed with an equal volume of serially diluted REGN421, resulting in a final antibody concentration ranging from 0.169 pM to 10 nM, and incubated for 10 min at room temperature in a 96-well plate format. Normal human serum, with complement components (Quidel Corp., San Diego, Calif.) was added to each well to give a final serum concentration of 5%. The plates were then incubated at 37.degree. C., 5% CO.sub.2 for 2 hours followed by addition of CELLTITER-BLUE.RTM. reagent (Promega) (controls=wells without antibody and wells with antibody but no serum). The plates were incubated overnight and cell survival (CDC levels) assayed. As a positive control, Daudi cells were treated with rituximab. REGN421 exhibited no CDC toward any of the target cell lines tested (data not shown).

Example 6

Epitope Mapping and Specificity

[0099] In order to determine epitope binding specificity, a series of seven chimeric Dll4 proteins were generated in which specific human Dll4 domains were substituted into a mouse Dll4 protein as follows: #1 contained the human N-terminal and DSL domains (S27-0218); #2 contained human N-terminal, DSL and EGF-1 domains (S27-N252); #3 contained human N-terminal, DSL, EGF-1 and EGF-2 domains (S27-0283); #4 contained human N-terminal, DSL, EGF-1, EGF-2, EGF-3, EGF-4 and EGF-5; #5 contained human N-terminal domain (S27-R172); #6 contained human DSL domain (V173-Q218); and #7 contained human EGF-2 domain (E252-D282). The chimeric proteins were fused to a mouse IgG2a-Fc fragment and expressed in CHO-K1 cell. The conditioned media were harvested and protein expression confirmed by western blot.

[0100] Binding specificity of test antibodies to hDll4, mDll4, and chimeric proteins #1, #2, #3, and #4 were tested as follows: purified antibodies 22G12, VAW3A7-2, and 15E10 were amine coupled between 5000-6000 RU on CMS chip. Conditioned media from CHO K1 cells containing the chimeric Dll4 proteins, hDll4-mFc, and mDll4-mFc were injected sequentially followed by surface regeneration over antibody-coupled surfaces. A blank amine coupled flowcell surface was used as a control for nonspecific binding of the conditioned media. Results are summarized in Table 9. 22G12 bound an epitope between S27-0218 of hDll4; VAW3A7-2 bound an epitope between 0283-E400 hDll4; and 15E10 bound an epitope between E252-D282 of hDll4.

TABLE-US-00009 TABLE 9 Chimeric Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 22G12 + - + + + + VAW3A7-2 + - - - - + 15E10 + - - - + +

[0101] Binding specificity of purified test mAb to hDll4, mDll4 and the chimeric proteins (described above) was determined (REGN279=314266-6F12-B7; REGN287=318518-1G04-F3; REGN289=318518-1H08-E9; REGN290=318518-2A07-B3; REGN306=318518-3F06-A3). Briefly, each Dll4 protein was captured (70-130 RU) on goat anti-mouse IgG antibody surfaces, followed by injection of test mAb at a concentration of 100 .mu.g/ml. An antibody that bound mDll4-mFc was used as a positive control (positive control=6C10). The results (Table 10) show that REGN279 bound an epitope between S27-0218 of hDll4; REGN287 bound between 0283-E400 of hDll4; REGN289, REGN290 and REGN306 bound between S27-E400 of hDll4.

TABLE-US-00010 TABLE 10 Chimeric human-mouse DII4 Fusion Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 #5 #6 #7 REGN279 + - + + + + + - - REGN287 + - - - - + - - - REGN289 + - + + + + - + - REGN290 + - + + + + - + - REGN306 + - + + + + - + - Control + + + + + + + + +

[0102] Further epitope binding specificity determinations were conducted as described above with the following purified test antibodies: REGN281=318518-1A10-D8; REGN305=318518-3F04-A6; REGN309=318518-14A07-C4; REGN310=318518-14D08-G1; REGN421, and REGN422. Briefly, each of the Dll4 proteins was captured (240-470 RU) on goat anti-mouse IgG antibody surfaces, followed by injection of test antibody at a concentration of 100 .mu.g/ml (Table 11).

TABLE-US-00011 TABLE 11 Chimeric human-mouse DII4 Fusion Proteins Antibody hDII4-mFc mDII4-mFc #1 #2 #3 #4 #5 #6 #7 REGN281 + - + + + + + + - REGN305 + - - - - + - - - REGN309 + - + + + - + + - REGN310 + - - - + + - + + REGN421 + - + + + + + + - REGN422 + - + + + + + + -

[0103] Western Blot Analysis.

[0104] Binding specificity of selected antibodies to chimeric, mouse and human Dll4 was determined by Western blot. Briefly, hDll4-mFc (200 ng per lane), mDll4-mFc (200 ng per lane), and chimeric proteins #1-#7 (approximate 150 ng per lane) were subjected to electrophoresis on duplicate SDS-PAGE gels using non-reducing sample buffer. Each gel was then transferred to a PVDF membrane. Blots were first exposed to REGN421 at 0.2 .mu.g/ml and then to HRP-conjugated anti-hIgG antibody (Pierce). Control blots were exposed to HRP-conjugated anti-mFc antibody (Pierce). Results: REGN421 recognized hDll4-mFc and chimeric proteins containing the human N-terminal domain (#5), a human DSL domain (#6), or both (#1, #2, #3, and #4). REGN421 did not recognize a chimeric protein containing a human EGF-2 domain (#7).

[0105] Protease digestion analysis. Binding between REGN281 and hDll4 was further assessed by protective protease digestion and liquid chromatography/mass spectrometry (LC/MS) using an HPLC1100 (Agilent) and LCQ Classical Ion Trap Mass Spectrometer (Thermo). Briefly, a mixture of hDll4 and REGN281, in a molar ratio of 1:5, or hDll4 alone, was incubated with protease overnight at either 25.degree. C. (for GluC protease) or 37.degree. C. (for trypsin). Each of the resulting proteolytic digest mixtures was then subjected to LC/MS. Unique peptide peaks present in proteolytic digests performed in the absence of REGN281, which either diminished or disappeared in proteolytic digests performed in the presence of REGN281, indicate potential REGN281 binding sites on hDll4 that were protected from protease digestion by the binding of REGN281 to hDll4. These unique peptide peaks were analyzed by mass spectrometry. The observed mass, predicted mass, and the N-terminal sequences of the peptides are shown in Table 12.

TABLE-US-00012 TABLE 12 Observed Predicted hDII4 Peptide Peak Mass Mass (SEQ ID NO: 2) Protease Domain G1 521 521.5 Phe37-Glu40 GluC N-terminal G2 1362.8 1363.4 Ala121-Glu132 GluC N-terminal T1 758 760.8 Pro49-Arg55 Trypsin N-terminal T2 587.1 587.2 Tyr169-Arg172 Trypsin N-terminal T3 1607.4 1607.6 Val173-Arg186 Trypsin DSL T4 1399 1400.7 Gly42-Arg55 Trypsin N-terminal T5 569.2 569.3 Thr56-Arg59 Trypsin N-terminal T7 2615 2613.4 Ile143-Arg166 Trypsin N-terminal T8 1807.2 1806.9 Ser27-Arg41 Trypsin N-terminal

Example 7

Binding Affinity of Purified Antibodies to Human and Monkey Dll4

[0106] The binding affinities of selected purified antibodies to hDll4, M. facscicularis Dll4 (mfDll4, SEQ IN NO:956), and M. mulatta Dll4 (mmDll4, SEQ ID NO:957) monomers were determined using a BIACORE.TM. 2000 & 3000. Goat anti-hFc polyclonal antibody reagent immobilized on a BIACORE.TM. chip was used to present REGN281, REGN421, and REGN422. Varying concentrations of each proteins, hDll4 (from 12.5 nM to 100 nM), mfDll4 (from 3.13. nM to 100 nM), or mmDll4 (from 12.5 nM to 100 nM) were used as analyte, and injected over the antibody surfaces. Antigen-antibody binding and dissociation of bound complex were monitored in real time (Table 13).

TABLE-US-00013 .gamma.TABLE 13 ka (M-1s-1) kd (s-1) K.sub.D (nM) hDII4 mfDII4 mmDII4 hDII4 mfDII4 mmDII4 hDII4 mfDII4 mmDII4 REGN281 1.56 .times. 10.sup.5 6.64 .times. 10.sup.4 9.27 .times. 10.sup.4 2.30 .times. 10.sup.-5 2.04 .times. 10.sup.-5 3.05 .times. 10.sup.-5 0.148 0.307 0.329 REGN421 1.63 .times. 10.sup.5 7.28 .times. 10.sup.4 9.70 .times. 10.sup.4 2.17 .times. 10.sup.-5 2.02 .times. 10.sup.-5 3.23 .times. 10.sup.-5 0.133 0.278 0.333 REGN422 1.64 .times. 10.sup.5 8.01 .times. 10.sup.4 9.27 .times. 10.sup.4 2.36 .times. 10.sup.-5 2.88 .times. 10.sup.-5 3.41 .times. 10.sup.-5 0.144 0.360 0.375

[0107] The binding affinities of anti-hDll4 antibodies toward hDll4 and mmDll4 dimers were also determined using a BIACORE.TM. 2000 and the method describe above, except that hDll4 was replaced with hDll4-mFc (from 3.13 nM to 100 nM), or mmDll4 with mmDll4-mFc (from 0.78 nM to 25 nM) as analyte (Table 14).

TABLE-US-00014 TABLE 14 ka (M-1s-1) kd (s-1) K.sub.D (nM) hDII4-mFc mmDII4-mFc hDII4-mFc mmDII4-mFc hDII4-mFc mmDII4-mFc REGN281 3.02 .times. 10.sup.5 3.16 .times. 10.sup.5 4.96 .times. 10.sup.-6 4.64 .times. 10.sup.-6 0.0163 0.0147 REGN421 3.43 .times. 10.sup.5 3.35 .times. 10.sup.5 4.70 .times. 10.sup.-6 3.80 .times. 10.sup.-6 0.0137 0.013 REGN422 3.46 .times. 10.sup.5 4.23 .times. 10.sup.5 4.60 .times. 10.sup.-6 4.15 .times. 10.sup.-6 0.0133 0.0098

Example 8

Cross-Reactivity of Antibodies with hDll1, hDll3, mDll4, or Mf Dll4

[0108] Cross-reactivity of the antibodies to human delta-like ligand1 (SEQ ID NO:953) and human delta-like ligand 3 (SEQ ID NO:954) proteins was determined. REGN281, REGN421 and REGN422 were presented by a goat anti-human kappa (hK) polyclonal antibody reagent (Southern Biotech) immobilized on a BIACORE.TM. chip, and either hDll4-hFc or hDll1-hFc protein at 100 .mu.g/ml were used as analyte injected over the antibody surfaces. All three anti-hDll4 antibodies only bound to hDll4-hFc, and did not bind hDll1-hFc.

[0109] An alternative BIACORE.TM. format was used to assess cross-reactivity between anti-hDll4 antibody and either hDll1-hFc or hDll3-hFc. Briefly, ligands hDll4-hFc, hDll1-hFc, and hDll3-hFc were each covalently linked to a CM-5 chip, through amine coupling, to an RU range of about 8,000 to 10,000. REGN421, at 300 .mu.g/ml, was injected over the surface of each chip. REGN421 bound only to hDll4-hFc; no binding was observed to either hDll1-hFc or hDll3-hFc. The same result was observed for REGN422 instead of REGN421.

[0110] OCTET.TM.-based binding assays were employed to determine the binding between selected purified anti-hDll4 antibodies and hDll4-hFc, hDll3-hFc, hDll1-hFc, mfDll4-mmh, or mDll4-mFc. Briefly, strepavidin high binding FA biosensors (ForteBio, Inc., Menlo Park, Calif.) were first incubated with biotin-anti-hK at 5 .mu.g/ml for 10 min at 30.degree. C., to achieve saturation. Biotin-anti-hK-bound biosensors were then incubated with antibodies REGN281, REGN421 or REGN422, at 20 .mu.g/ml for 10 min at 30.degree. C., to achieve saturation. The antibody-bound biosensors were then incubated with either hDll4-hFc or hDll3-hFc, hDll1-hFc, or mDll4-mFc, at 200 nM, or mfDll4-mmh at 100 nM, for 10 min at 30.degree. C. Changes in the thickness of the biological layer after each incubation were measured. Human Dll4-hFc and mfDll4-mmh bound to anti-hDll4 antibody-bound biosensors, whereas hDll3-hFc, hDll1-hFc, and mDll4-mFc did not bind to anti-hDll4 antibody-bound biosensors.

Example 9

Effect of Anti-hDll4 Antibody on Tumor Growth

[0111] The effect of REGN421 on tumor growth was evaluated on tumors implanted in Severe Combined Immunodeficiency (SCID) mice expressing a humanized Dll4 protein (SCID.times.hDll4). Briefly, the humanized Dll4 mouse was made by replacing the entire extracellular domain of the mouse Dll4 gene with the corresponding extracellular region of the human Dll4 gene (7 kb) in embryonic stem (ES) cells. Homozygous hDll4 mice were generated and bred into SCID background. Each mouse was then implanted subcutaneously (SC) with 2.5.times.10.sup.6 human HT1080 tumor cells. After the tumors were established in the mice (.about.100-150 mm.sup.3 18 days after implantation), mice were measured and treated with hFc, hDll4-Fc or REGN421. A total of 7 mice were divided into three groups. The first group (n=3) was treated subcutaneously with hFc at 25 mg/kg; the second group (n=1) was treated with hDll4-Fc at 25 mg/kg; and the third group (n=3) was treated with REGN421 at 10 mg/kg. The treatments were repeated every 48 hours starting at day 18. In vivo tumor measurements were obtained three days before the initial treatment (day 15), on the same day of each treatment (days 18, 20, and 22), and on day 25. Tumor size was calculated using the formula l.times.w.sup.2/2. Results are shown in Table 15. On day 25, mice were euthanized and each tumor was removed and measured ex vivo and calculated (length.times.width.times.depth) (Table 16).

[0112] In addition, a group of SCID mice expressing endogenous mDll4 (n=2) was implanted with tumor cells and treated with hDll4-Fc (25 mg/kg) following the same dosing schedule.

TABLE-US-00015 TABLE 15 Tumor Size (mm.sup.3) Mouse Treatment Day 15 Day 18 Day 20 Day 22 Day 25 SCID hDII4-hFc 162.0 232.8 320.0 336.0 253.1 SCID hDII4-hFc 22.5 117.0 117.0 108.0 68.8 SCIDxhDII4 hDII4-hFc 288.0 320.0 352.0 446.0 320.0 SCIDxhDII4 hFc 162.0 288.0 320.0 500.0 550.0 SCIDxhDII4 hFc 162.0 220.5 352.0 662.0 661.5 SCIDxhDII4 hFc 93.8 135.0 179.6 352.0 726.0 SCIDxhDII4 REGN421 144.0 245.0 320.0 162.0 144.0 SCIDxhDII4 REGN421 87.5 162.0 153.0 225.0 135.0 SCIDxhDII4 REGN421 144.0 196.0 272.0 162.0 152.5

TABLE-US-00016 TABLE 16 Mouse Treatment Tumor Size (mm.sup.3) SCID hDII4-hFc 308.0 SCID hDII4-hFc 105.0 SCID .times. hDII4 hDII4-hFc 480.0 SCID .times. hDII4 hFc 924.0 SCID .times. hDII4 hFc 1020.0 SCID .times. hDII4 hFc 792.0 SCID .times. hDII4 REGN421 168.0 SCID .times. hDII4 REGN421 84.0 SCID .times. hDII4 REGN421 189.0

Sequence CWU 1

1

95712058DNAHomo sapiens 1atggcggcag cgtcccggag cgcctctggc tgggcgctac tgctgctggt ggcactttgg 60cagcagcgcg cggccggctc cggcgtcttc cagctgcagc tgcaggagtt catcaacgag 120cgcggcgtac tggccagtgg gcggccttgc gagcccggct gccggacttt cttccgcgtc 180tgccttaagc acttccaggc ggtcgtctcg cccggaccct gcaccttcgg gaccgtctcc 240acgccggtat tgggcaccaa ctccttcgct gtccgggacg acagtagcgg cggggggcgc 300aaccctctcc aactgccctt caatttcacc tggccgggta ccttctcgct catcatcgaa 360gcttggcacg cgccaggaga cgacctgcgg ccagaggcct tgccaccaga tgcactcatc 420agcaagatcg ccatccaggg ctccctagct gtgggtcaga actggttatt ggatgagcaa 480accagcaccc tcacaaggct gcgctactct taccgggtca tctgcagtga caactactat 540ggagacaact gctcccgcct gtgcaagaag cgcaatgacc acttcggcca ctatgtgtgc 600cagccagatg gcaacttgtc ctgcctgccc ggttggactg gggaatattg ccaacagcct 660atctgtcttt cgggctgtca tgaacagaat ggctactgca gcaagccagc agagtgcctc 720tgccgcccag gctggcaggg ccggctgtgt aacgaatgca tcccccacaa tggctgtcgc 780cacggcacct gcagcactcc ctggcaatgt acttgtgatg agggctgggg aggcctgttt 840tgtgaccaag atctcaacta ctgcacccac cactccccat gcaagaatgg ggcaacgtgc 900tccaacagtg ggcagcgaag ctacacctgc acctgtcgcc caggctacac tggtgtggac 960tgtgagctgg agctcagcga gtgtgacagc aacccctgtc gcaatggagg cagctgtaag 1020gaccaggagg atggctacca ctgcctgtgt cctccgggct actatggcct gcattgtgaa 1080cacagcacct tgagctgcgc cgactccccc tgcttcaatg ggggctcctg ccgggagcgc 1140aaccaggggg ccaactatgc ttgtgaatgt ccccccaact tcaccggctc caactgcgag 1200aagaaagtgg acaggtgcac cagcaacccc tgtgccaacg ggggacagtg cctgaaccga 1260ggtccaagcc gcatgtgccg ctgccgtcct ggattcacgg gcacctactg tgaactccac 1320gtcagcgact gtgcccgtaa cccttgcgcc cacggtggca cttgccatga cctggagaat 1380gggctcatgt gcacctgccc tgccggcttc tctggccgac gctgtgaggt gcggacatcc 1440atcgatgcct gtgcctcgag tccctgcttc aacagggcca cctgctacac cgacctctcc 1500acagacacct ttgtgtgcaa ctgcccttat ggctttgtgg gcagccgctg cgagttcccc 1560gtgggcttgc cgcccagctt cccctgggtg gccgtctcgc tgggtgtggg gctggcagtg 1620ctgctggtac tgctgggcat ggtggcagtg gctgtgcggc agctgcggct tcgacggccg 1680gacgacggca gcagggaagc catgaacaac ttgtcggact tccagaagga caacctgatt 1740cctgccgccc agcttaaaaa cacaaaccag aagaaggagc tggaagtgga ctgtggcctg 1800gacaagtcca actgtggcaa acagcaaaac cacacattgg actataatct ggccccaggg 1860cccctggggc gggggaccat gccaggaaag tttccccaca gtgacaagag cttaggagag 1920aaggcgccac tgcggttaca cagtgaaaag ccagagtgtc ggatatcagc gatatgctcc 1980cccagggact ccatgtacca gtctgtgtgt ttgatatcag aggagaggaa tgaatgtgtc 2040attgccacgg aggtataa 20582685PRTHomo sapiens 2Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu1 5 10 15 Val Ala Leu Trp Gln Gln Arg Ala Ala Gly Ser Gly Val Phe Gln Leu 20 25 30 Gln Leu Gln Glu Phe Ile Asn Glu Arg Gly Val Leu Ala Ser Gly Arg 35 40 45 Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val Cys Leu Lys His 50 55 60 Phe Gln Ala Val Val Ser Pro Gly Pro Cys Thr Phe Gly Thr Val Ser65 70 75 80 Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val Arg Asp Asp Ser Ser 85 90 95 Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro 100 105 110 Gly Thr Phe Ser Leu Ile Ile Glu Ala Trp His Ala Pro Gly Asp Asp 115 120 125 Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala Leu Ile Ser Lys Ile Ala 130 135 140 Ile Gln Gly Ser Leu Ala Val Gly Gln Asn Trp Leu Leu Asp Glu Gln145 150 155 160 Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg Val Ile Cys Ser 165 170 175 Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys Lys Lys Arg Asn 180 185 190 Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly Asn Leu Ser Cys 195 200 205 Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro Ile Cys Leu Ser 210 215 220 Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Ala Glu Cys Leu225 230 235 240 Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys Ile Pro His 245 250 255 Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp Gln Cys Thr Cys 260 265 270 Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys 275 280 285 Thr His His Ser Pro Cys Lys Asn Gly Ala Thr Cys Ser Asn Ser Gly 290 295 300 Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr Thr Gly Val Asp305 310 315 320 Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro Cys Arg Asn Gly 325 330 335 Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His Cys Leu Cys Pro Pro 340 345 350 Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr Leu Ser Cys Ala Asp 355 360 365 Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly Ala 370 375 380 Asn Tyr Ala Cys Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu385 390 395 400 Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Ala Asn Gly Gly Gln 405 410 415 Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg Cys Arg Pro Gly Phe 420 425 430 Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys Ala Arg Asn Pro 435 440 445 Cys Ala His Gly Gly Thr Cys His Asp Leu Glu Asn Gly Leu Met Cys 450 455 460 Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg Cys Glu Val Arg Thr Ser465 470 475 480 Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe Asn Arg Ala Thr Cys Tyr 485 490 495 Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn Cys Pro Tyr Gly Phe 500 505 510 Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro 515 520 525 Trp Val Ala Val Ser Leu Gly Val Gly Leu Ala Val Leu Leu Val Leu 530 535 540 Leu Gly Met Val Ala Val Ala Val Arg Gln Leu Arg Leu Arg Arg Pro545 550 555 560 Asp Asp Gly Ser Arg Glu Ala Met Asn Asn Leu Ser Asp Phe Gln Lys 565 570 575 Asp Asn Leu Ile Pro Ala Ala Gln Leu Lys Asn Thr Asn Gln Lys Lys 580 585 590 Glu Leu Glu Val Asp Cys Gly Leu Asp Lys Ser Asn Cys Gly Lys Gln 595 600 605 Gln Asn His Thr Leu Asp Tyr Asn Leu Ala Pro Gly Pro Leu Gly Arg 610 615 620 Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp Lys Ser Leu Gly Glu625 630 635 640 Lys Ala Pro Leu Arg Leu His Ser Glu Lys Pro Glu Cys Arg Ile Ser 645 650 655 Ala Ile Cys Ser Pro Arg Asp Ser Met Tyr Gln Ser Val Cys Leu Ile 660 665 670 Ser Glu Glu Arg Asn Glu Cys Val Ile Ala Thr Glu Val 675 680 685 3358DNAArtificial SequenceSynthetic 3gaggtgcaac tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttagt acctattgga tgaactgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaccaag atggaagtga gaaatactat 180gtggactctg tgaagggccg aatcaccatc tccagagaca acgccaagaa ctcactgtat 240ctgcaaatga acagcctgag agtcgaggac acggctgtat attactgtgc gagaaaatgg 300aacaactgga acccggagga gaactggggc cagggaaccc tggtcaccgt ctcctcag 3584119PRTArtificial SequenceSynthetic 4Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Ile Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Lys Trp Asn Asn Trp Asn Pro Glu Glu Asn Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 524DNAArtificial SequenceSynthetic 5ggattcacct ttagtaccta ttgg 2468PRTArtificial SequenceSynthetic 6Gly Phe Thr Phe Ser Thr Tyr Trp1 5 724DNAArtificial SequenceSynthetic 7ataaaccaag atggaagtga gaaa 2488PRTArtificial SequenceSynthetic 8Ile Asn Gln Asp Gly Ser Glu Lys1 5 936DNAArtificial SequenceSynthetic 9gcgagaaaat ggaacaactg gaacccggag gagaac 361012PRTArtificial SequenceSynthetic 10Ala Arg Lys Trp Asn Asn Trp Asn Pro Glu Glu Asn1 5 10 11337DNAArtificial SequenceSynthetic 11gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctg cataatagtg gatacaactt tttggattgg 120tacctgcaga agccagggca gtctccacaa ctcctgatct atttgcgttc taatcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaagatc 240agaagagtgg aggctgagga tgttgggatt tattactgca tgcaagctct acacactcct 300tacacttttg gccaggggac caaggtggag atcaaac 33712112PRTArtificial SequenceSynthetic 12Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Asn 20 25 30 Ser Gly Tyr Asn Phe Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Arg Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80 Arg Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95 Leu His Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 1333DNAArtificial SequenceSynthetic 13cagagcctcc tgcataatag tggatacaac ttt 331411PRTArtificial SequenceSynthetic 14Gln Ser Leu Leu His Asn Ser Gly Tyr Asn Phe1 5 10 159DNAArtificial SequenceSynthetic 15ttgcgttct 9163PRTArtificial SequenceSynthetic 16Leu Arg Ser1 1727DNAArtificial SequenceSynthetic 17atgcaagctc tacacactcc ttacact 27189PRTArtificial SequenceSynthetic 18Met Gln Ala Leu His Thr Pro Tyr Thr1 5 19376DNAArtificial SequenceSynthetic 19gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgtag cctctggatt cacctttagt agctattgga tgacctgggt ccgccaggct 120ccagggaagg ggctggagtg ggtggccaac ataaaacaag atggaagtga gaaatactat 180gtggactctg tgaagggccg attcaccgtc tccagagaca acgccaagaa ctcagtgtat 240ctgcaaatga gcagcctgag agccgaggac acggctgtgt attactgtgc gagagattgg 300aactatggcc ccgattacta ctactaccac ggtttggacg tctggggcca agggaccacg 360gtcaccgtct cctcag 37620125PRTArtificial SequenceSynthetic 20Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Trp Asn Tyr Gly Pro Asp Tyr Tyr Tyr Tyr His Gly Leu 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 2124DNAArtificial SequenceSynthetic 21ggattcacct ttagtagcta ttgg 24228PRTArtificial SequenceSynthetic 22Gly Phe Thr Phe Ser Ser Tyr Trp1 5 2324DNAArtificial SequenceSynthetic 23ataaaacaag atggaagtga gaaa 24248PRTArtificial SequenceSynthetic 24Ile Lys Gln Asp Gly Ser Glu Lys1 5 2554DNAArtificial SequenceSynthetic 25gcgagagatt ggaactatgg ccccgattac tactactacc acggtttgga cgtc 542618PRTArtificial SequenceSynthetic 26Ala Arg Asp Trp Asn Tyr Gly Pro Asp Tyr Tyr Tyr Tyr His Gly Leu1 5 10 15 Asp Val27322DNAArtificial SequenceSynthetic 27gacctccaga tgacccagtc tccgtcctcc ctgtctgtat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtttca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgctgcct 240gaagattttg caacttatta ctgtctacag cataatactt acccgtacac ttttggccag 300gggaccaagc tggagatcaa ac 32228107PRTArtificial SequenceSynthetic 28Asp Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Leu Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Thr Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 2918DNAArtificial SequenceSynthetic 29cagggcatta gaaatgat 18306PRTArtificial SequenceSynthetic 30Gln Gly Ile Arg Asn Asp1 5 319DNAArtificial SequenceSynthetic 31gctgcatcc 9323PRTArtificial SequenceSynthetic 32Ala Ala Ser1 3327DNAArtificial SequenceSynthetic 33ctacagcata atacttaccc gtacact 27349PRTArtificial SequenceSynthetic 34Leu Gln His Asn Thr Tyr Pro Tyr Thr1 5 35361DNAArtificial SequenceSynthetic 35caggggcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgaag catctggatt cagtttcaga agttatggca tgcactgggt ccgccaggct 120ccaggcaggg gactggagtg gatggcagtt atttggtacg atggcagtaa gacatactat 180acagagtccg tgacgggccg attcaccatc tccagagaca attccaagaa cacgctatat 240ctgcaaatga acagcctgag agccgaggac acggctgttt attactgtgc gagcggtttt 300tcagtgcctg ccacgatcct tgacaactgg ggccagggaa ccctggtctc cgtctcctca 360g 36136120PRTArtificial SequenceSynthetic 36Gln Gly Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Ser Phe Arg Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Met 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Lys Thr Tyr Tyr Thr Glu Ser Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Gly Phe Ser Val Pro Ala Thr Ile Leu Asp Asn Trp Gly Gln 100 105 110 Gly Thr Leu Val Ser Val Ser Ser 115 120 3724DNAArtificial SequenceSynthetic 37ggattcagtt tcagaagtta tggc 24388PRTArtificial SequenceSynthetic 38Gly Phe Ser Phe Arg Ser Tyr Gly1 5

3924DNAArtificial SequenceSynthetic 39atttggtacg atggcagtaa gaca 24408PRTArtificial SequenceSynthetic 40Ile Trp Tyr Asp Gly Ser Lys Thr1 5 4139DNAArtificial SequenceSynthetic 41gcgagcggtt tttcagtgcc tgccacgatc cttgacaac 394213PRTArtificial SequenceSynthetic 42Ala Ser Gly Phe Ser Val Pro Ala Thr Ile Leu Asp Asn1 5 10 43322DNAArtificial SequenceSynthetic 43gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtttca gcagaaacca 120gggaaagccc ctaaccgcct gatctatgga gcatccagtt tggaaggtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca caatcagcag cctgcagcca 240gaagattttg caacttatta ctgtctacag cataattctt acccgtggac gttcggccaa 300gggaccaagg tggaaatcaa ac 32244107PRTArtificial SequenceSynthetic 44Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Asn Arg Leu Ile 35 40 45 Tyr Gly Ala Ser Ser Leu Glu Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 4518DNAArtificial SequenceSynthetic 45cagggcatta gaaatgat 18466PRTArtificial SequenceSynthetic 46Gln Gly Ile Arg Asn Asp1 5 479DNAArtificial SequenceSynthetic 47ggagcatcc 9483PRTArtificial SequenceSynthetic 48Gly Ala Ser1 4927DNAArtificial SequenceSynthetic 49ctacagcata attcttaccc gtggacg 27509PRTArtificial SequenceSynthetic 50Leu Gln His Asn Ser Tyr Pro Trp Thr1 5 51367DNAArtificial SequenceSynthetic 51caggtgcagc tggtggagtc tgggggaggc gtagtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaaataa taaatactat 180atagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagaccgt 300ggatatagtg gctacgaggg atacttcgat ctctggggcc gtggcaccct ggtcactgtc 360tcctcag 36752122PRTArtificial SequenceSynthetic 52Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Asn Asn Lys Tyr Tyr Ile Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Glu Gly Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 5324DNAArtificial SequenceSynthetic 53ggattcacct tcagtagcta tggc 24548PRTArtificial SequenceSynthetic 54Gly Phe Thr Phe Ser Ser Tyr Gly1 5 5524DNAArtificial SequenceSynthetic 55atatggtatg atggaaataa taaa 24568PRTArtificial SequenceSynthetic 56Ile Trp Tyr Asp Gly Asn Asn Lys1 5 5745DNAArtificial SequenceSynthetic 57gcgagagacc gtggatatag tggctacgag ggatacttcg atctc 455815PRTArtificial SequenceSynthetic 58Ala Arg Asp Arg Gly Tyr Ser Gly Tyr Glu Gly Tyr Phe Asp Leu1 5 10 15 59337DNAArtificial SequenceSynthetic 59gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60ctcaactgta agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttatttct gtcagcaata ttatactact 300tggacgttcg gccaagggac caaggtggaa atcaaac 33760112PRTArtificial SequenceSynthetic 60Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15 Glu Arg Ala Thr Leu Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Phe Cys Gln Gln 85 90 95 Tyr Tyr Thr Thr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 6136DNAArtificial SequenceSynthetic 61cagagtgttt tatacagctc caacaataag aactac 366212PRTArtificial SequenceSynthetic 62Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1 5 10 639DNAArtificial SequenceSynthetic 63tgggcatct 9643PRTArtificial SequenceSynthetic 64Trp Ala Ser1 6524DNAArtificial SequenceSynthetic 65cagcaatatt atactacttg gacg 24668PRTArtificial SequenceSynthetic 66Gln Gln Tyr Tyr Thr Thr Trp Thr1 5 67385DNAArtificial SequenceSynthetic 67caggtgcagt tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cctctgcatc caccttcagt aggcatggca tgcactgggt ccgccaggct 120ccaggcaagg gactggagtg ggtggcagtt atatcatatg atggaaataa taaatactat 180gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga atagcctgag aactgacgac acggctgtgt attattgttc gaaagagtta 300gtaggtatta ctggaaacct ggtctactac tactactacg gaatggacgt ctggggccaa 360gggaccacgg tcaccgtctc ctcag 38568128PRTArtificial SequenceSynthetic 68Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Ser Thr Phe Ser Arg His 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Lys Glu Leu Val Gly Ile Thr Gly Asn Leu Val Tyr Tyr Tyr Tyr 100 105 110 Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 6924DNAArtificial SequenceSynthetic 69gcatccacct tcagtaggca tggc 24708PRTArtificial SequenceSynthetic 70Ala Ser Thr Phe Ser Arg His Gly1 5 7124DNAArtificial SequenceSynthetic 71atatcatatg atggaaataa taaa 24728PRTArtificial SequenceSynthetic 72Ile Ser Tyr Asp Gly Asn Asn Lys1 5 7363DNAArtificial SequenceSynthetic 73tcgaaagagt tagtaggtat tactggaaac ctggtctact actactacta cggaatggac 60gtc 637421PRTArtificial SequenceSynthetic 74Ser Lys Glu Leu Val Gly Ile Thr Gly Asn Leu Val Tyr Tyr Tyr Tyr1 5 10 15 Tyr Gly Met Asp Val 20 75325DNAArtificial SequenceSynthetic 75gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactattaac agcagctact taggctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctat ggtgcatcca acagggccac tggcatccca 180gacagtttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcaa cattataaca actcacctta cacttttggc 300caggggacca agctggagat caaac 32576108PRTArtificial SequenceSynthetic 76Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Asn Ser Ser 20 25 30 Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Ser Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asn Asn Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 7721DNAArtificial SequenceSynthetic 77cagactatta acagcagcta c 21787PRTArtificial SequenceSynthetic 78Gln Thr Ile Asn Ser Ser Tyr1 5 799DNAArtificial SequenceSynthetic 79ggtgcatcc 9803PRTArtificial SequenceSynthetic 80Gly Ala Ser1 8127DNAArtificial SequenceSynthetic 81caacattata acaactcacc ttacact 27829PRTArtificial SequenceSynthetic 82Gln His Tyr Asn Asn Ser Pro Tyr Thr1 5 83361DNAArtificial SequenceSynthetic 83caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccataagc agtggtggtt actactggag ctggatccgc 120cactacccag ggaagggcct ggagtggatt ggctacgtcc attacagtgg gaacacccac 180tacaatacgt ccctcaagag gcgacttacc atatcaatag acacgtctaa gagccaattc 240tccctggatc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g 36184120PRTArtificial SequenceSynthetic 84Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg His Tyr Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Asn Thr Ser 50 55 60 Leu Lys Arg Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Ser Gln Phe65 70 75 80 Ser Leu Asp Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 8530DNAArtificial SequenceSynthetic 85ggtggctcca taagcagtgg tggttactac 308610PRTArtificial SequenceSynthetic 86Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 8721DNAArtificial SequenceSynthetic 87gtccattaca gtgggaacac c 21887PRTArtificial SequenceSynthetic 88Val His Tyr Ser Gly Asn Thr1 5 8936DNAArtificial SequenceSynthetic 89gcgagagccc cccgtggata ccattacttt gcctac 369012PRTArtificial SequenceSynthetic 90Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1 5 10 91325DNAArtificial SequenceSynthetic 91gaaattgggt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattagc agcaggtact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatacca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat caaac 32592108PRTArtificial SequenceSynthetic 92Glu Ile Gly Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 9321DNAArtificial SequenceSynthetic 93cagagtatta gcagcaggta c 21947PRTArtificial SequenceSynthetic 94Gln Ser Ile Ser Ser Arg Tyr1 5 959DNAArtificial SequenceSynthetic 95ggtgcatcc 9963PRTArtificial SequenceSynthetic 96Gly Ala Ser1 9727DNAArtificial SequenceSynthetic 97cagcagtatg gtagctcacc gctcact 27989PRTArtificial SequenceSynthetic 98Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5 99361DNAArtificial SequenceSynthetic 99caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtagtggtt actactggag ttggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacgtcc attacagtgg gaacacccac 180tacagcccgt ccctcaagag tcgacttacc atatcagttg acacgtctaa gaaccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g 361100120PRTArtificial SequenceSynthetic 100Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 10130DNAArtificial SequenceSynthetic 101ggtggctcca tcagcagtag tggttactac 3010210PRTArtificial SequenceSynthetic 102Gly Gly Ser Ile Ser Ser Ser Gly Tyr Tyr1 5 10 10321DNAArtificial SequenceSynthetic 103gtccattaca gtgggaacac c 211047PRTArtificial SequenceSynthetic 104Val His Tyr Ser Gly Asn Thr1 5 10536DNAArtificial SequenceSynthetic 105gcgagagccc cccgtggata ccattacttt gcctac 3610612PRTArtificial SequenceSynthetic 106Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1 5 10 107325DNAArtificial SequenceSynthetic 107aaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctctcctgca gggccagtca gagtattagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggcca gacttcactc tcaccattag gagactggag 240cctgaagatt ttgcggtgta ttactgtcag cagtatggta gttcaccgct cactttcggc 300ggagggacca aggtggagat caaac 325108108PRTArtificial SequenceSynthetic 108Lys Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu

Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Pro Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 10921DNAArtificial SequenceSynthetic 109cagagtatta gcagcagcta c 211107PRTArtificial SequenceSynthetic 110Gln Ser Ile Ser Ser Ser Tyr1 5 1119DNAArtificial SequenceSynthetic 111ggtgcatcc 91123PRTArtificial SequenceSynthetic 112Gly Ala Ser1 11327DNAArtificial SequenceSynthetic 113cagcagtatg gtagttcacc gctcact 271149PRTArtificial SequenceSynthetic 114Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5 115358DNAArtificial SequenceSynthetic 115caggttcagt tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta caccttttcc acctatggta tcagctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgacaataa cgcggactat 180gcacagaact tccaggccag agtcaccatg accacagaca catccacgac cacagcctac 240atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gaggtatagc 300tggaactttc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358116119PRTArtificial SequenceSynthetic 116Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asp Asn Asn Ala Asp Tyr Ala Gln Asn Phe 50 55 60 Gln Ala Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Phe His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 11724DNAArtificial SequenceSynthetic 117ggttacacct tttccaccta tggt 241188PRTArtificial SequenceSynthetic 118Gly Tyr Thr Phe Ser Thr Tyr Gly1 5 11924DNAArtificial SequenceSynthetic 119atcagcgctt acgacaataa cgcg 241208PRTArtificial SequenceSynthetic 120Ile Ser Ala Tyr Asp Asn Asn Ala1 5 12136DNAArtificial SequenceSynthetic 121gcgaggtata gctggaactt tcactggttc gacccc 3612212PRTArtificial SequenceSynthetic 122Ala Arg Tyr Ser Trp Asn Phe His Trp Phe Asp Pro1 5 10 123325DNAArtificial SequenceSynthetic 123gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agtacctact tagcctggta ccagcagcaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta actcaccgtg gacgttcggc 300caagggacca aggtggaaat caaac 325124108PRTArtificial SequenceSynthetic 124Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Gln Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 12521DNAArtificial SequenceSynthetic 125cagagtgtta gcagtaccta c 211267PRTArtificial SequenceSynthetic 126Gln Ser Val Ser Ser Thr Tyr1 5 1279DNAArtificial SequenceSynthetic 127ggtgcatcc 91283PRTArtificial SequenceSynthetic 128Gly Ala Ser1 12927DNAArtificial SequenceSynthetic 129cagcagtatg gtaactcacc gtggacg 271309PRTArtificial SequenceSynthetic 130Gln Gln Tyr Gly Asn Ser Pro Trp Thr1 5 131358DNAArtificial SequenceSynthetic 131caggttcacc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaggg cttctggtta cacctttacc aactatggta tcacctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acagtggtaa cacagactat 180gcacagaagt tccaggccag aatcaccatg accacagaca catccacgac cacagcctac 240atggaactga ggagcctgac atctgacgac acggccgtgt attactgtgc gaggtatagc 300tggaactttc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358132119PRTArtificial SequenceSynthetic 132Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Ser Gly Asn Thr Asp Tyr Ala Gln Lys Phe 50 55 60 Gln Ala Arg Ile Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Phe His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 13324DNAArtificial SequenceSynthetic 133ggttacacct ttaccaacta tggt 241348PRTArtificial SequenceSynthetic 134Gly Tyr Thr Phe Thr Asn Tyr Gly1 5 13524DNAArtificial SequenceSynthetic 135atcagcgctt acagtggtaa caca 241368PRTArtificial SequenceSynthetic 136Ile Ser Ala Tyr Ser Gly Asn Thr1 5 13736DNAArtificial SequenceSynthetic 137gcgaggtata gctggaactt tcactggttc gacccc 3613812PRTArtificial SequenceSynthetic 138Ala Arg Tyr Ser Trp Asn Phe His Trp Phe Asp Pro1 5 10 139325DNAArtificial SequenceSynthetic 139gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga cagagtcacc 60ctctcctgca gggccagtca gagtgttagt agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagtctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg gctcaccgtg gacgttcggc 300caagggacca gggtggagat caaac 325140108PRTArtificial SequenceSynthetic 140Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Asp Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Cys Gly Gly Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys 100 105 14121DNAArtificial SequenceSynthetic 141cagagtgtta gtagcagcta c 211427PRTArtificial SequenceSynthetic 142Gln Ser Val Ser Ser Ser Tyr1 5 1439DNAArtificial SequenceSynthetic 143ggtgcatcc 91443PRTArtificial SequenceSynthetic 144Gly Ala Ser1 14527DNAArtificial SequenceSynthetic 145cagcagtgtg gtggctcacc gtggacg 271469PRTArtificial SequenceSynthetic 146Gln Gln Cys Gly Gly Ser Pro Trp Thr1 5 147358DNAArtificial SequenceSynthetic 147caggttcaac tggtgcagtc tgggcctgag gtgaagaagc ctggggcctc agtgaaggtc 60gcctgcaagg cttctggtta cacctttacc cactatggtt tcacctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acagtggtca tacagactat 180gcacggaagt tccaggccag agtcaccatg accacagaca cattcacgac cacagcctac 240atggaactga ggagcctgag atctgacgac acggccgttt attactgtgc gagttatagc 300tggaactttc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358148119PRTArtificial SequenceSynthetic 148Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ala Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr 20 25 30 Gly Phe Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Ser Gly His Thr Asp Tyr Ala Arg Lys Phe 50 55 60 Gln Ala Arg Val Thr Met Thr Thr Asp Thr Phe Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Tyr Ser Trp Asn Phe His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 14924DNAArtificial SequenceSynthetic 149ggttacacct ttacccacta tggt 241508PRTArtificial SequenceSynthetic 150Gly Tyr Thr Phe Thr His Tyr Gly1 5 15124DNAArtificial SequenceSynthetic 151atcagcgctt acagtggtca taca 241528PRTArtificial SequenceSynthetic 152Ile Ser Ala Tyr Ser Gly His Thr1 5 15336DNAArtificial SequenceSynthetic 153gcgagttata gctggaactt tcactggttc gacccc 3615412PRTArtificial SequenceSynthetic 154Ala Ser Tyr Ser Trp Asn Phe His Trp Phe Asp Pro1 5 10 155325DNAArtificial SequenceSynthetic 155caaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagt accacctact tagcctggta ccagcagaaa 120cctggccagg ctcccagtct cctcatctat ggtacatcca ccagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggact gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg gctcaccgtg gacgttcggc 300caagggacca aggtgaaaat caaac 325156108PRTArtificial SequenceSynthetic 156Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Thr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Cys Gly Gly Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Lys Ile Lys 100 105 15721DNAArtificial SequenceSynthetic 157cagagtgtta gtaccaccta c 211587PRTArtificial SequenceSynthetic 158Gln Ser Val Ser Thr Thr Tyr1 5 1599DNAArtificial SequenceSynthetic 159ggtacatcc 91603PRTArtificial SequenceSynthetic 160Gly Thr Ser1 16127DNAArtificial SequenceSynthetic 161cagcagtgtg gtggctcacc gtggacg 271629PRTArtificial SequenceSynthetic 162Gln Gln Cys Gly Gly Ser Pro Trp Thr1 5 163367DNAArtificial SequenceSynthetic 163caggtgcagt tggtgcagtc tggggctgag gtgaagaagc ctggggccgc tgtgaaggtc 60tcctgcaagg cttctggata cacgttcacc agttatgata tcaactgggt gcgacaggcc 120actggacaag ggcttgagtg gatgggatgg ataaacccta acagtggtaa cacaggctat 180gcacagaagt ttcagggcag agtcaccttg accaggaaca cctccataag cacagcctac 240atggaactga gcagcctgag atctgaggac acggccgttt attactgtgc gagagaggga 300tattgtggtg gtgattgcta tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360tcttcag 367164122PRTArtificial SequenceSynthetic 164Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ala Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Tyr Cys Gly Gly Asp Cys Tyr Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 16524DNAArtificial SequenceSynthetic 165ggatacacgt tcaccagtta tgat 241668PRTArtificial SequenceSynthetic 166Gly Tyr Thr Phe Thr Ser Tyr Asp1 5 16724DNAArtificial SequenceSynthetic 167ataaacccta acagtggtaa caca 241688PRTArtificial SequenceSynthetic 168Ile Asn Pro Asn Ser Gly Asn Thr1 5 16945DNAArtificial SequenceSynthetic 169gcgagagagg gatattgtgg tggtgattgc tatgcttttg atatc 4517015PRTArtificial SequenceSynthetic 170Ala Arg Glu Gly Tyr Cys Gly Gly Asp Cys Tyr Ala Phe Asp Ile1 5 10 15 171325DNAArtificial SequenceSynthetic 171gaaattgtgt tgacacaatc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat caaac 325172108PRTArtificial SequenceSynthetic 172Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 17321DNAArtificial SequenceSynthetic 173cagagtgtta gcagcagcta c 211747PRTArtificial SequenceSynthetic 174Gln Ser Val Ser Ser Ser Tyr1 5 1759DNAArtificial SequenceSynthetic 175ggtgcatcc 91763PRTArtificial SequenceSynthetic 176Gly Ala Ser1 17727DNAArtificial SequenceSynthetic 177cagcagtatg gtagctcacc gctcact 271789PRTArtificial SequenceSynthetic 178Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5

179361DNAArtificial SequenceSynthetic 179cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120cagcccccag ggaaggggct ggagtggatt gggagtatct attatagtgg gagcacctac 180tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240tccctgaagc tgagctctgt gaccgccgca gacacggctg tgtattactg tgcggcaaac 300tgggacgacg ccttcttctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360g 361180120PRTArtificial SequenceSynthetic 180Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Ala Asn Trp Asp Asp Ala Phe Phe Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 18130DNAArtificial SequenceSynthetic 181ggtggctcca tcagcagtag tagttactac 3018210PRTArtificial SequenceSynthetic 182Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr1 5 10 18321DNAArtificial SequenceSynthetic 183atctattata gtgggagcac c 211847PRTArtificial SequenceSynthetic 184Ile Tyr Tyr Ser Gly Ser Thr1 5 18536DNAArtificial SequenceSynthetic 185gcggcaaact gggacgacgc cttcttcttt gactac 3618612PRTArtificial SequenceSynthetic 186Ala Ala Asn Trp Asp Asp Ala Phe Phe Phe Asp Tyr1 5 10 187322DNAArtificial SequenceSynthetic 187gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaacag tataatagtt attcgtacac ttttggccag 300gggaccaagc tggagatcaa ac 322188107PRTArtificial SequenceSynthetic 188Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 18918DNAArtificial SequenceSynthetic 189cagagtatta gtagctgg 181906PRTArtificial SequenceSynthetic 190Gln Ser Ile Ser Ser Trp1 5 1919DNAArtificial SequenceSynthetic 191aaggcgtct 91923PRTArtificial SequenceSynthetic 192Lys Ala Ser1 19327DNAArtificial SequenceSynthetic 193caacagtata atagttattc gtacact 271949PRTArtificial SequenceSynthetic 194Gln Gln Tyr Asn Ser Tyr Ser Tyr Thr1 5 195352DNAArtificial SequenceSynthetic 195caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata ttcactgggt acgacaggcc 120cctggacaag gccttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcac cacagcctac 240atggagctga gcaggctgat atctgacgac acggccgtgt attactgtgc gagaggaccc 300tgggatttct ttgactactg gggccaggga accctggtca ccgtctcctc ag 352196117PRTArtificial SequenceSynthetic 196Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Ser Arg Leu Ile Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Trp Asp Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 19724DNAArtificial SequenceSynthetic 197ggatacacct tcaccggcta ctat 241988PRTArtificial SequenceSynthetic 198Gly Tyr Thr Phe Thr Gly Tyr Tyr1 5 19924DNAArtificial SequenceSynthetic 199atcaacccta acagtggtgg caca 242008PRTArtificial SequenceSynthetic 200Ile Asn Pro Asn Ser Gly Gly Thr1 5 20130DNAArtificial SequenceSynthetic 201gcgagaggac cctgggattt ctttgactac 3020210PRTArtificial SequenceSynthetic 202Ala Arg Gly Pro Trp Asp Phe Phe Asp Tyr1 5 10 203340DNAArtificial SequenceSynthetic 203gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300ccgtacactt ttggccaggg gaccaagctg gagatcaaac 340204113PRTArtificial SequenceSynthetic 204Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys20536DNAArtificial SequenceSynthetic 205cagagtgttt tatacagctc caacaataag aactac 3620612PRTArtificial SequenceSynthetic 206Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1 5 10 2079DNAArtificial SequenceSynthetic 207tgggcatct 92083PRTArtificial SequenceSynthetic 208Trp Ala Ser1 20927DNAArtificial SequenceSynthetic 209cagcaatatt atagtactcc gtacact 272109PRTArtificial SequenceSynthetic 210Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr1 5 211352DNAArtificial SequenceSynthetic 211caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggata caccttcacc ggctactata ttcactgggt acgacaggcc 120cctggacaag gccttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggaccc 300tgggatttct ttgactactg gggccaggga accctggtca ccgtctcctc ag 352212117PRTArtificial SequenceSynthetic 212Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Trp Asp Phe Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 21324DNAArtificial SequenceSynthetic 213ggatacacct tcaccggcta ctat 242148PRTArtificial SequenceSynthetic 214Gly Tyr Thr Phe Thr Gly Tyr Tyr1 5 21524DNAArtificial SequenceSynthetic 215atcaacccta acagtggtgg caca 242168PRTArtificial SequenceSynthetic 216Ile Asn Pro Asn Ser Gly Gly Thr1 5 21730DNAArtificial SequenceSynthetic 217gcgagaggac cctgggattt ctttgactac 3021810PRTArtificial SequenceSynthetic 218Ala Arg Gly Pro Trp Asp Phe Phe Asp Tyr1 5 10 219340DNAArtificial SequenceSynthetic 219gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtact 300ccgtacactt ttggccaggg gaccaagctg gagatcaaac 340220113PRTArtificial SequenceSynthetic 220Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys22136DNAArtificial SequenceSynthetic 221cagagtgttt tatacagctc caacaataag aactac 3622212PRTArtificial SequenceSynthetic 222Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr1 5 10 2239DNAArtificial SequenceSynthetic 223tgggcatct 92243PRTArtificial SequenceSynthetic 224Trp Ala Ser1 22527DNAArtificial SequenceSynthetic 225cagcaatatt atagtactcc gtacact 272269PRTArtificial SequenceSynthetic 226Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr1 5 227361DNAArtificial SequenceSynthetic 227caggtgcagt tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcggc agtggtggtt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacgtcc attacagtgg gaacacccac 180tacaacccgt ccctcaagag tcgactttcc atatcaatag acacgtctaa gatccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g 361228120PRTArtificial SequenceSynthetic 228Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Ser Ile Ser Ile Asp Thr Ser Lys Ile Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 22930DNAArtificial SequenceSynthetic 229ggtggctcca tcggcagtgg tggttactac 3023010PRTArtificial SequenceSynthetic 230Gly Gly Ser Ile Gly Ser Gly Gly Tyr Tyr1 5 10 23121DNAArtificial SequenceSynthetic 231gtccattaca gtgggaacac c 212327PRTArtificial SequenceSynthetic 232Val His Tyr Ser Gly Asn Thr1 5 23336DNAArtificial SequenceSynthetic 233gcgagagccc cccgtggata ccattacttt gcctac 3623412PRTArtificial SequenceSynthetic 234Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1 5 10 235325DNAArtificial SequenceSynthetic 235gaaattgtgt tgacacaatc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat caaac 325236108PRTArtificial SequenceSynthetic 236Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 23721DNAArtificial SequenceSynthetic 237cagagtgtta gcagcagcta c 212387PRTArtificial SequenceSynthetic 238Gln Ser Val Ser Ser Ser Tyr1 5 2399DNAArtificial SequenceSynthetic 239ggtgcatcc 92403PRTArtificial SequenceSynthetic 240Gly Ala Ser1 24127DNAArtificial SequenceSynthetic 241cagcagtatg gtagctcacc gctcact 272429PRTArtificial SequenceSynthetic 242Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5 243361DNAArtificial SequenceSynthetic 243caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120cagtacccag ggaagggcct ggagtggatt ggttacgtcc attacagtgg gagcacccac 180tacaacccgt ccctcaagag tcgacttacc atatcaatag acacgtctaa gagccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g 361244120PRTArtificial SequenceSynthetic 244Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Tyr Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Ser Thr His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Ser Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 24530DNAArtificial SequenceSynthetic 245ggtggctcca tcagcagtgg tggttactac 3024610PRTArtificial SequenceSynthetic 246Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 24721DNAArtificial SequenceSynthetic 247gtccattaca gtgggagcac c 212487PRTArtificial SequenceSynthetic 248Val His Tyr Ser Gly Ser Thr1 5 24936DNAArtificial SequenceSynthetic 249gcgagagccc cccgtggata ccattacttt gcctac 3625012PRTArtificial SequenceSynthetic 250Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr1 5 10 251325DNAArtificial SequenceSynthetic 251gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaggtact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatacca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat caaac 325252108PRTArtificial SequenceSynthetic 252Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 25321DNAArtificial SequenceSynthetic 253cagagtgtta gcagcaggta c 212547PRTArtificial SequenceSynthetic 254Gln Ser Val Ser Ser Arg Tyr1 5 2559DNAArtificial SequenceSynthetic 255ggtgcatcc 92563PRTArtificial SequenceSynthetic 256Gly Ala Ser1 25727DNAArtificial SequenceSynthetic 257cagcagtatg gtagctcacc gctcact 272589PRTArtificial SequenceSynthetic 258Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 5 259355DNAArtificial SequenceSynthetic 259caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt ccctcaagag tcgaattatc atatcagtag acacgtctaa gaaccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355260118PRTArtificial SequenceSynthetic 260Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Ile Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Ala Met Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 26130DNAArtificial SequenceSynthetic 261ggtggctcca tcagcagtgg tggttactac 3026210PRTArtificial SequenceSynthetic 262Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 26321DNAArtificial SequenceSynthetic 263atctattaca gtgggagcac c 212647PRTArtificial SequenceSynthetic 264Ile Tyr Tyr Ser Gly Ser Thr1 5 26530DNAArtificial SequenceSynthetic 265gcgagagaag gggctatggt ttttgactac 3026610PRTArtificial SequenceSynthetic 266Ala Arg Glu Gly Ala Met Val Phe Asp Tyr1 5 10 267322DNAArtificial SequenceSynthetic 267gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120gggaaagccc ctaaactcct gatttatgct gcatccgctt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac 322268107PRTArtificial SequenceSynthetic 268Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Trp Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 26918DNAArtificial SequenceSynthetic 269cagggcatta gcagttat 182706PRTArtificial SequenceSynthetic 270Gln Gly Ile Ser Ser Tyr1 5 2719DNAArtificial SequenceSynthetic 271gctgcatcc 92723PRTArtificial SequenceSynthetic 272Ala Ala Ser1 27327DNAArtificial SequenceSynthetic 273caacagctta atagttaccc gttcact 272749PRTArtificial SequenceSynthetic 274Gln Gln Leu Asn Ser Tyr Pro Phe Thr1 5 275355DNAArtificial SequenceSynthetic 275caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt ccctcaagag tcgaattatc atatcagtag acacgtctaa gaaccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355276118PRTArtificial SequenceSynthetic 276Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Ile Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Ala Met Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 27730DNAArtificial SequenceSynthetic 277ggtggctcca tcagcagtgg tggttactac 3027810PRTArtificial SequenceSynthetic 278Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 27921DNAArtificial SequenceSynthetic 279atctattaca gtgggagcac c 212807PRTArtificial SequenceSynthetic 280Ile Tyr Tyr Ser Gly Ser Thr1 5 28130DNAArtificial SequenceSynthetic 281gcgagagaag gggctatggt ttttgactac 3028210PRTArtificial SequenceSynthetic 282Ala Arg Glu Gly Ala Met Val Phe Asp Tyr1 5 10 283322DNAArtificial SequenceSynthetic 283gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120gggaaagccc ctaaactcct gatttatgct gcatccgctt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac 322284107PRTArtificial SequenceSynthetic 284Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Trp Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 28518DNAArtificial SequenceSynthetic 285cagggcatta gcagttat 182866PRTArtificial SequenceSynthetic 286Gln Gly Ile Ser Ser Tyr1 5 2879DNAArtificial SequenceSynthetic 287gctgcatcc 92883PRTArtificial SequenceSynthetic 288Ala Ala Ser1 28927DNAArtificial SequenceSynthetic 289caacagctta atagttaccc gttcact 272909PRTArtificial SequenceSynthetic 290Gln Gln Leu Asn Ser Tyr Pro Phe Thr1 5 291355DNAArtificial SequenceSynthetic 291caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggac ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt ccctcaagag tcgagttatc atatcagtag acacgtctaa gaaccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355292118PRTArtificial SequenceSynthetic 292Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Ile Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Ala Met Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 29330DNAArtificial SequenceSynthetic 293ggtggctcca tcagcagtgg tggttactac 3029410PRTArtificial SequenceSynthetic 294Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 29521DNAArtificial SequenceSynthetic 295atctattaca gtgggagcac c 212967PRTArtificial SequenceSynthetic 296Ile Tyr Tyr Ser Gly Ser Thr1 5 29730DNAArtificial SequenceSynthetic 297gcgagagaag gggctatggt ttttgactac 3029810PRTArtificial SequenceSynthetic 298Ala Arg Glu Gly Ala Met Val Phe Asp Tyr1 5 10 299322DNAArtificial SequenceSynthetic 299gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccgctt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac 322300107PRTArtificial SequenceSynthetic 300Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Trp Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 30118DNAArtificial SequenceSynthetic 301cagggcatta gcagttat 183026PRTArtificial SequenceSynthetic 302Gln Gly Ile Ser Ser Tyr1 5 3039DNAArtificial SequenceSynthetic 303gctgcatcc 93043PRTArtificial SequenceSynthetic 304Ala Ala Ser1 30527DNAArtificial SequenceSynthetic 305caacagctta atagttaccc gttcact 273069PRTArtificial SequenceSynthetic 306Gln Gln Leu Asn Ser Tyr Pro Phe Thr1 5 307355DNAArtificial SequenceSynthetic 307caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggac ctggatccgc 120cagtacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 180tacaacccgt ccctcaagag tcgagttatc atatcagtag acacgtctaa gaaccagttc 240tccctgaggc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagaa 300ggggctatgg tttttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355308118PRTArtificial SequenceSynthetic 308Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Tyr Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Ile Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Ala Met Val Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 30930DNAArtificial SequenceSynthetic 309ggtggctcca tcagcagtgg tggttactac 3031010PRTArtificial SequenceSynthetic 310Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 31121DNAArtificial SequenceSynthetic 311atctattaca gtgggagcac c 213127PRTArtificial SequenceSynthetic 312Ile Tyr Tyr Ser Gly Ser Thr1 5 31330DNAArtificial SequenceSynthetic 313gcgagagaag gggctatggt ttttgactac 3031410PRTArtificial SequenceSynthetic 314Ala Arg Glu Gly Ala Met Val Phe Asp Tyr1 5 10 315322DNAArtificial SequenceSynthetic 315gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgct gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120gggaaagccc ctaagctcct gatctatgct gcatccgctt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtcaacag cttaatagtt acccgttcac ttttggccag 300gggaccaagc tggagatcaa ac 322316107PRTArtificial SequenceSynthetic 316Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Trp Ala Ser Gln Gly

Ile Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 31718DNAArtificial SequenceSynthetic 317cagggcatta gcagttat 183186PRTArtificial SequenceSynthetic 318Gln Gly Ile Ser Ser Tyr1 5 3199DNAArtificial SequenceSynthetic 319gctgcatcc 93203PRTArtificial SequenceSynthetic 320Ala Ala Ser1 32127DNAArtificial SequenceSynthetic 321caacagctta atagttaccc gttcact 273229PRTArtificial SequenceSynthetic 322Gln Gln Leu Asn Ser Tyr Pro Phe Thr1 5 323358DNAArtificial SequenceSynthetic 323caggttcacc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaggg cttctggtta cacctttacc aactatggta tcacctgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgcta acagtggtaa cacagactct 180gcacagaagt tccaggccag agtcaccatg accacagaca catccacgac cacagcctac 240atggaactga ggagcctgag atctgacgac acggccgtgt attattgtgc gacgtatagt 300tggaactttc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358324119PRTArtificial SequenceSynthetic 324Gln Val His Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Asn Ser Gly Asn Thr Asp Ser Ala Gln Lys Phe 50 55 60 Gln Ala Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Tyr Ser Trp Asn Phe His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 32524DNAArtificial SequenceSynthetic 325ggttacacct ttaccaacta tggt 243268PRTArtificial SequenceSynthetic 326Gly Tyr Thr Phe Thr Asn Tyr Gly1 5 32724DNAArtificial SequenceSynthetic 327atcagcgcta acagtggtaa caca 243288PRTArtificial SequenceSynthetic 328Ile Ser Ala Asn Ser Gly Asn Thr1 5 32936DNAArtificial SequenceSynthetic 329gcgacgtata gttggaactt tcactggttc gacccc 3633012PRTArtificial SequenceSynthetic 330Ala Thr Tyr Ser Trp Asn Phe His Trp Phe Asp Pro1 5 10 331325DNAArtificial SequenceSynthetic 331gaaattgtgt tgacgcagtc tccaggcact ctgtctttgt ctccagggga aagagtcacc 60ctctcctgca gggccagtca gagtgtcagt accaactact taacctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcattc tcaccatcag aagtctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtgtggtg gctcaccgtg gacgttcggc 300caagggacca gggtggaaat caaac 325332108PRTArtificial SequenceSynthetic 332Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Asn 20 25 30 Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Arg Ser Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Cys Gly Gly Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys 100 105 33321DNAArtificial SequenceSynthetic 333cagagtgtca gtaccaacta c 213347PRTArtificial SequenceSynthetic 334Gln Ser Val Ser Thr Asn Tyr1 5 3359DNAArtificial SequenceSynthetic 335ggtgcatcc 93363PRTArtificial SequenceSynthetic 336Gly Ala Ser1 33727DNAArtificial SequenceSynthetic 337cagcagtgtg gtggctcacc gtggacg 273389PRTArtificial SequenceSynthetic 338Gln Gln Cys Gly Gly Ser Pro Trp Thr1 5 339355DNAArtificial SequenceSynthetic 339caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc tctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg gactggagtg ggtggcagtt atatggtatg atggaagtaa taaatattat 180ggagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtat attactgtgc gagagatgga 300gtagacggtg cttttgatat ttggggccaa gggacaacgg tcaccgtctc ttcag 355340118PRTArtificial SequenceSynthetic 340Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Val Asp Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 34124DNAArtificial SequenceSynthetic 341ggattcacct tcagtagcta tggc 243428PRTArtificial SequenceSynthetic 342Gly Phe Thr Phe Ser Ser Tyr Gly1 5 34324DNAArtificial SequenceSynthetic 343atatggtatg atggaagtaa taaa 243448PRTArtificial SequenceSynthetic 344Ile Trp Tyr Asp Gly Ser Asn Lys1 5 34533DNAArtificial SequenceSynthetic 345gcgagagatg gagtagacgg tgcttttgat att 3334611PRTArtificial SequenceSynthetic 346Ala Arg Asp Gly Val Asp Gly Ala Phe Asp Ile1 5 10 347322DNAArtificial SequenceSynthetic 347gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca ggacattaga aatgatttag gctggtatca gcagaaacca 120gggaaagccc ctaaactcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tggcacagat ttcactctca ccatcagcag actgcagcct 240gaagattttg caacttatta ctgtcaacaa gattacaatt acctgtatac ttttggccag 300gggaccaacc tggagatcaa ac 322348107PRTArtificial SequenceSynthetic 348Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Asn Tyr Leu Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Asn Leu Glu Ile Lys 100 105 34918DNAArtificial SequenceSynthetic 349caggacatta gaaatgat 183506PRTArtificial SequenceSynthetic 350Gln Asp Ile Arg Asn Asp1 5 3519DNAArtificial SequenceSynthetic 351gctgcatcc 93523PRTArtificial SequenceSynthetic 352Ala Ala Ser1 35327DNAArtificial SequenceSynthetic 353caacaagatt acaattacct gtatact 273549PRTArtificial SequenceSynthetic 354Gln Gln Asp Tyr Asn Tyr Leu Tyr Thr1 5 355364DNAArtificial SequenceSynthetic 355gaggtgcagt tggtggagtc ggggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgaag cctctggatt cacctttgat aactattata tgacctgggt ccgccagact 120ccagggaagg ggctggagtg ggtggccaac ataaaggaag atggaaatga tagatactat 180gtggactctg tgaagggccg cttcaccatc tccagagaca acgccaagca gtcactgttt 240ctacaaatga acagtctgag agccgaggac acggctgttt attactgtgc gagagaattt 300tggagtggcc ctcactacgg tttggacgtc tggggccaag ggaccacggt caccgtctcc 360tcag 364356121PRTArtificial SequenceSynthetic 356Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Asp Asn Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Glu Asp Gly Asn Asp Arg Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Gln Ser Leu Phe65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Phe Trp Ser Gly Pro His Tyr Gly Leu Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 35724DNAArtificial SequenceSynthetic 357ggattcacct ttgataacta ttat 243588PRTArtificial SequenceSynthetic 358Gly Phe Thr Phe Asp Asn Tyr Tyr1 5 35924DNAArtificial SequenceSynthetic 359ataaaggaag atggaaatga taga 243608PRTArtificial SequenceSynthetic 360Ile Lys Glu Asp Gly Asn Asp Arg1 5 36142DNAArtificial SequenceSynthetic 361gcgagagaat tttggagtgg ccctcactac ggtttggacg tc 4236214PRTArtificial SequenceSynthetic 362Ala Arg Glu Phe Trp Ser Gly Pro His Tyr Gly Leu Asp Val1 5 10 363322DNAArtificial SequenceSynthetic 363gccctccaga tgacccagtc tccatcctcc ctgtctgcac ctgtaggcga cagagtcacc 60atcacttgcc gggcaagtca ggacgttaga aataatttag gctggtatca gcagaaacca 120gggaatgccc ctaaattcct gatctatgct gcatccagtt tacaaagtgg aatcccatca 180aggttcagcg gcagtggatc tggctcagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacaa gattacaatt accctccgac gttcggccag 300gggaccaagg tggaaatcaa gc 322364107PRTArtificial SequenceSynthetic 364Ala Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Pro Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Arg Asn Asn 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Lys Phe Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 36518DNAArtificial SequenceSynthetic 365caggacgtta gaaataat 183666PRTArtificial SequenceSynthetic 366Gln Asp Val Arg Asn Asn1 5 3679DNAArtificial SequenceSynthetic 367gctgcatcc 93683PRTArtificial SequenceSynthetic 368Ala Ala Ser1 36927DNAArtificial SequenceSynthetic 369ctacaagatt acaattaccc tccgacg 273709PRTArtificial SequenceSynthetic 370Leu Gln Asp Tyr Asn Tyr Pro Pro Thr1 5 371370DNAArtificial SequenceSynthetic 371caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt ttatggtatg atggaagtaa taaaaactat 180gtagactccg tgaagggccg attcaccatc tcaagagaca attccaagaa cacgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac 300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cttggtcacc 360gtctcctcag 370372123PRTArtificial SequenceSynthetic 372Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Leu Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 37324DNAArtificial SequenceSynthetic 373ggattcacct tcagtagtta tggc 243748PRTArtificial SequenceSynthetic 374Gly Phe Thr Phe Ser Ser Tyr Gly1 5 37524DNAArtificial SequenceSynthetic 375ttatggtatg atggaagtaa taaa 243768PRTArtificial SequenceSynthetic 376Leu Trp Tyr Asp Gly Ser Asn Lys1 5 37748DNAArtificial SequenceSynthetic 377gcgagagatc acgattttag gagtggttat gaggggtggt tcgacccc 4837816PRTArtificial SequenceSynthetic 378Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro1 5 10 15 379322DNAArtificial SequenceSynthetic 379gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttcgc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcagcac cgtagcaact ggcctcccac tttcggcgga 300gggaccgagg tggaggtcag ac 322380107PRTArtificial SequenceSynthetic 380Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Glu Val Glu Val Arg 100 105 38118DNAArtificial SequenceSynthetic 381cagagtgttc gcagctac 183826PRTArtificial SequenceSynthetic 382Gln Ser Val Arg Ser Tyr1 5 3839DNAArtificial SequenceSynthetic 383gatgcatcc 93843PRTArtificial SequenceSynthetic 384Asp Ala Ser1 38527DNAArtificial SequenceSynthetic 385cagcaccgta gcaactggcc tcccact 273869PRTArtificial SequenceSynthetic 386Gln His Arg Ser Asn Trp Pro Pro Thr1 5 38716DNAArtificial SequenceSynthetic 387taccggctcc cgatgg

1638819DNAArtificial SequenceSynthetic 388ggcggctaag gtgtttgga 1938922DNAArtificial SequenceSynthetic 389ttgggaatga ggaaagcaaa ct 2239018DNAArtificial SequenceSynthetic 390ctgaagtacc ggaggaga 1839120DNAArtificial SequenceSynthetic 391atcacgctgg tggtcctctt 2039216DNAArtificial SequenceSynthetic 392gctgcggcga gtgctt 1639323DNAArtificial SequenceSynthetic 393tggcaaatgc tggacccaac aca 2339419DNAArtificial SequenceSynthetic 394gggtcctggc atcttgtcc 1939522DNAArtificial SequenceSynthetic 395gcagatgaaa aactgggaac ca 22396372DNAArtificial SequenceSynthetic 396caggtgcagc tggtgcagtc aggtccagga ctggtgaagc cctcgcagaa cctctcactc 60acctgtgcca tctccggaga cagtgtctct agtgatagtg ctgcttggaa ctggatcagg 120cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180aatgattatg cagtatctgt gaaaagtcga ataaccttca acccagatac atccaagaac 240cacatctccc tgcagctgaa ctctgtgact cccgaggaca cggctatcta ttactgtgca 300agagaggggg ataattggaa ttacggctgg ctcgacccct ggggccaggg aaccacggtc 360accgtctcct ca 372397124PRTArtificial SequenceSynthetic 397Gln Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Asn Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asp 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 Val Ser Val Lys Ser Arg Ile Thr Phe Asn Pro Asp Thr Ser Lys Asn65 70 75 80 His Ile Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Ile 85 90 95 Tyr Tyr Cys Ala Arg Glu Gly Asp Asn Trp Asn Tyr Gly Trp Leu Asp 100 105 110 Pro Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 39830DNAArtificial SequenceSynthetic 398ggagacagtg tctctagtga tagtgctgct 3039910PRTArtificial SequenceSynthetic 399Gly Asp Ser Val Ser Ser Asp Ser Ala Ala1 5 10 40027DNAArtificial SequenceSynthetic 400acatactaca ggtccaagtg gtataat 274019PRTArtificial SequenceSynthetic 401Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn1 5 40242DNAArtificial SequenceSynthetic 402gcaagagagg gggataattg gaattacggc tggctcgacc cc 4240314PRTArtificial SequenceSynthetic 403Ala Arg Glu Gly Asp Asn Trp Asn Tyr Gly Trp Leu Asp Pro1 5 10 404336DNAArtificial SequenceSynthetic 404gacatccagt tgacccagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60atctcctgca ggtctagtca gagcctcctt cttagtaatg gatacaacta tttggattgg 120tacctgcaga agccagggca gtctccacaa ctcctgatct atttggtttc tagtcgggcc 180tccggggtcc ctgacaggtt cagtggcagt ggatccggca cagattttac actgaaaatc 240agcagagtgg aggctgagga ttttggaatt tattattgta tgcaagctct acaaactccg 300tacacttttg gccgggggac caaggtggaa atcaaa 336405112PRTArtificial SequenceSynthetic 405Asp Ile Gln Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Leu Ser 20 25 30 Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Val Ser Ser Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80 Ser Arg Val Glu Ala Glu Asp Phe Gly Ile Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Tyr Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys 100 105 110 40633DNAArtificial SequenceSynthetic 406cagagcctcc ttcttagtaa tggatacaac tat 3340711PRTArtificial SequenceSynthetic 407Gln Ser Leu Leu Leu Ser Asn Gly Tyr Asn Tyr1 5 10 4089DNAArtificial SequenceSynthetic 408ttggtttct 94093PRTArtificial SequenceSynthetic 409Leu Val Ser1 41027DNAArtificial SequenceSynthetic 410atgcaagctc tacaaactcc gtacact 274119PRTArtificial SequenceSynthetic 411Met Gln Ala Leu Gln Thr Pro Tyr Thr1 5 412360DNAArtificial SequenceSynthetic 412caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtaatt actactggag ctgggtccgc 120caacacccag ggaagggcct ggagtggttt ggttacatca aaaacagtgg gggcacctac 180tacaacccgt ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccacttc 240tccctgaggc tgagctctat gacggccgcg gacacggccg tgtattactg tgcgagagct 300ggttcgggga gtcactactt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360413120PRTArtificial SequenceSynthetic 413Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Asn Tyr Tyr Trp Ser Trp Val Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Phe Gly Tyr Ile Lys Asn Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn His Phe65 70 75 80 Ser Leu Arg Leu Ser Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 41430DNAArtificial SequenceSynthetic 414ggtggctccg tcagcagtgg taattactac 3041510PRTArtificial SequenceSynthetic 415Gly Gly Ser Val Ser Ser Gly Asn Tyr Tyr1 5 10 41621DNAArtificial SequenceSynthetic 416atcaaaaaca gtgggggcac c 214177PRTArtificial SequenceSynthetic 417Ile Lys Asn Ser Gly Gly Thr1 5 41836DNAArtificial SequenceSynthetic 418gcgagagctg gttcggggag tcactacttt gactac 3641912PRTArtificial SequenceSynthetic 419Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr1 5 10 420324DNAArtificial SequenceSynthetic 420gacatccagt tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcaactact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt gtgcagtgta ttactgtcag cagtacggtt actcaccgat caccttcggc 300caagggacca agctggagat caaa 324421108PRTArtificial SequenceSynthetic 421Asp Ile Gln Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 42221DNAArtificial SequenceSynthetic 422cagagtgtta gcagcaacta c 214237PRTArtificial SequenceSynthetic 423Gln Ser Val Ser Ser Asn Tyr1 5 4249DNAArtificial SequenceSynthetic 424ggtgcatcc 94253PRTArtificial SequenceSynthetic 425Gly Ala Ser1 42627DNAArtificial SequenceSynthetic 426cagcagtacg gttactcacc gatcacc 274279PRTArtificial SequenceSynthetic 427Gln Gln Tyr Gly Tyr Ser Pro Ile Thr1 5 428369DNAArtificial SequenceSynthetic 428gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtgtcattt ttatggtatg atggaactaa taaaaactat 180gtagagtccg tgaagggccg attcaccatc tcaagagaca attccaagaa tatgctgtat 240ctggaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac 300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc 360gtctcctca 369429123PRTArtificial SequenceSynthetic 429Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Phe Leu Trp Tyr Asp Gly Thr Asn Lys Asn Tyr Val Glu Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr65 70 75 80 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 43024DNAArtificial SequenceSynthetic 430ggattcacct tcagtagtta tggc 244318PRTArtificial SequenceSynthetic 431Gly Phe Thr Phe Ser Ser Tyr Gly1 5 43224DNAArtificial SequenceSynthetic 432ttatggtatg atggaactaa taaa 244338PRTArtificial SequenceSynthetic 433Leu Trp Tyr Asp Gly Thr Asn Lys1 5 43448DNAArtificial SequenceSynthetic 434gcgagagatc acgattttag gagtggttat gaggggtggt tcgacccc 4843516PRTArtificial SequenceSynthetic 435Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro1 5 10 15 436321DNAArtificial SequenceSynthetic 436gaaatagtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a 321437107PRTArtificial SequenceSynthetic 437Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 43818DNAArtificial SequenceSynthetic 438cagagtgtta gcagctac 184396PRTArtificial SequenceSynthetic 439Gln Ser Val Ser Ser Tyr1 5 4409DNAArtificial SequenceSynthetic 440gatgcatcc 94413PRTArtificial SequenceSynthetic 441Asp Ala Ser1 44227DNAArtificial SequenceSynthetic 442caacaccgta gcaactggcc tcccact 274439PRTArtificial SequenceSynthetic 443Gln His Arg Ser Asn Trp Pro Pro Thr1 5 444366DNAArtificial SequenceSynthetic 444caggtacagc tgcagcagtc gggtccagga ctgctgaaac cttcacagac cctgtccctc 60acctgctctg tctctggtgg ctccatcagc agtggtaatt actactggac ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatca agaacagtgg aagcgcctac 180tacaatccgt ccctcaagag tcgacttacc atgtcaatag acacgtctca gaaccacttc 240tccttgattt tgacttctgt gactgccgcg gacacggcct tatattactg tgcgagagat 300gaaaatatag cagttcgtca tgcttttgat atctggggcc aagggacatc ggtcaccgtc 360tcctca 366445122PRTArtificial SequenceSynthetic 445Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Leu Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Asn Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Asn Ser Gly Ser Ala Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Met Ser Ile Asp Thr Ser Gln Asn His Phe65 70 75 80 Ser Leu Ile Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Leu Tyr Tyr 85 90 95 Cys Ala Arg Asp Glu Asn Ile Ala Val Arg His Ala Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 44630DNAArtificial SequenceSynthetic 446ggtggctcca tcagcagtgg taattactac 3044710PRTArtificial SequenceSynthetic 447Gly Gly Ser Ile Ser Ser Gly Asn Tyr Tyr1 5 10 44821DNAArtificial SequenceSynthetic 448atcaagaaca gtggaagcgc c 214497PRTArtificial SequenceSynthetic 449Ile Lys Asn Ser Gly Ser Ala1 5 45042DNAArtificial SequenceSynthetic 450gcgagagatg aaaatatagc agttcgtcat gcttttgata tc 4245114PRTArtificial SequenceSynthetic 451Ala Arg Asp Glu Asn Ile Ala Val Arg His Ala Phe Asp Ile1 5 10 452324DNAArtificial SequenceSynthetic 452gaaatagtgt tgacacagtc tccaggcgcc ctgtctttgt ctccaggaga aagagccacc 60ctctcctgta gggccagtcg gactgttagc agcagctact tagcctggta ccaacagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca gccgggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcac cagactggag 240cctgaagatt ttgcaatata ttactgtcag cagtctggtt actcacctct cactttcggc 300ggagggacca aggtggaaat caaa 324453108PRTArtificial SequenceSynthetic 453Glu Ile Val Leu Thr Gln Ser Pro Gly Ala Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Thr Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Ser Gly Tyr Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 45421DNAArtificial SequenceSynthetic 454cggactgtta gcagcagcta c 214557PRTArtificial SequenceSynthetic 455Arg Thr Val Ser Ser Ser Tyr1 5 4569DNAArtificial SequenceSynthetic 456ggtacatcc 94573PRTArtificial SequenceSynthetic 457Gly Thr Ser1 45827DNAArtificial SequenceSynthetic 458cagcagtctg gttactcacc tctcact 274599PRTArtificial SequenceSynthetic 459Gln Gln Ser Gly Tyr Ser Pro Leu Thr1 5 460357DNAArtificial SequenceSynthetic 460caggtgcagc tgcaggagtc gggcccagga ctggtgaagc

cttcacagac cctgtccctc 60acctgcactg tctctgatga ctccatcaac aatgttgaat cctactggac ctggatccgc 120caacacccag ggaagggcct ggagtggatt ggatacatca aatacactgg gggcatccac 180tataacccgt ccctcaagag tcgactcgcc atatcagtgg acacgtcaaa gaaccagttc 240tccctgaaaa tgaactctgt gactgccgcg gacacggcca aatattactg tgcgagagca 300cgtggaagtc atacttttga tgtctggggc caggggacaa cggtcaccgt ctcctca 357461119PRTArtificial SequenceSynthetic 461Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Asn Asn Val 20 25 30 Glu Ser Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Gly Ile His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Ala Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Met Asn Ser Val Thr Ala Ala Asp Thr Ala Lys Tyr Tyr 85 90 95 Cys Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 46230DNAArtificial SequenceSynthetic 462gatgactcca tcaacaatgt tgaatcctac 3046310PRTArtificial SequenceSynthetic 463Asp Asp Ser Ile Asn Asn Val Glu Ser Tyr1 5 10 46421DNAArtificial SequenceSynthetic 464atcaaataca ctgggggcat c 214657PRTArtificial SequenceSynthetic 465Ile Lys Tyr Thr Gly Gly Ile1 5 46633DNAArtificial SequenceSynthetic 466gcgagagcac gtggaagtca tacttttgat gtc 3346711PRTArtificial SequenceSynthetic 467Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val1 5 10 468324DNAArtificial SequenceSynthetic 468gccatccggt tgacccagtc tccaggcacc ctgtcttggt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agtaactact tagcctggta ccagcagaaa 120cctggccagg ctccccgact cctcatttat ggtgcatcca gcagggtcgc tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcactgta ttattgtcag caatatagta ggtcaccgat caccttcggc 300caagggacca agctggagat caaa 324469108PRTArtificial SequenceSynthetic 469Ala Ile Arg Leu Thr Gln Ser Pro Gly Thr Leu Ser Trp Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Val Ala Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 47021DNAArtificial SequenceSynthetic 470cagagtgtta gcagtaacta c 214717PRTArtificial SequenceSynthetic 471Gln Ser Val Ser Ser Asn Tyr1 5 4729DNAArtificial SequenceSynthetic 472ggtgcatcc 94733PRTArtificial SequenceSynthetic 473Gly Ala Ser1 47427DNAArtificial SequenceSynthetic 474cagcaatata gtaggtcacc gatcacc 274759PRTArtificial SequenceSynthetic 475Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 476357DNAArtificial SequenceSynthetic 476caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc 120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac 180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc 240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct 300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca 357477119PRTArtificial SequenceSynthetic 477Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Ser Val 20 25 30 Thr Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val Phe Tyr 85 90 95 Cys Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 47830DNAArtificial SequenceSynthetic 478ggtggctcca tcaacagtgt tacttactac 3047910PRTArtificial SequenceSynthetic 479Gly Gly Ser Ile Asn Ser Val Thr Tyr Tyr1 5 10 48021DNAArtificial SequenceSynthetic 480atcaaattca gtgggagcac c 214817PRTArtificial SequenceSynthetic 481Ile Lys Phe Ser Gly Ser Thr1 5 48233DNAArtificial SequenceSynthetic 482gcgagagctt ctggaagtca tacttttgat atc 3348311PRTArtificial SequenceSynthetic 483Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1 5 10 484321DNAArtificial SequenceSynthetic 484gccatccgga tgacccagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgct gggccagtca gagtattagc ggctattttg cctggtatca acagaaacct 120ggccaggctc ccaggctcct catctatgat acatcctaca gggccactga cgtcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcaacaa cctagagcct 240gaagattttg cagtttatta ctgtcagcag cgtagcgact ggccgctcag cttcggcgga 300gggaccaaac tggagatcaa a 321485107PRTArtificial SequenceSynthetic 485Ala Ile Arg Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Ser Ile Ser Gly Tyr 20 25 30 Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Thr Ser Tyr Arg Ala Thr Asp Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Pro Leu 85 90 95 Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 48618DNAArtificial SequenceSynthetic 486cagagtatta gcggctat 184876PRTArtificial SequenceSynthetic 487Gln Ser Ile Ser Gly Tyr1 5 4889DNAArtificial SequenceSynthetic 488gatacatcc 94893PRTArtificial SequenceSynthetic 489Asp Thr Ser1 49027DNAArtificial SequenceSynthetic 490cagcagcgta gcgactggcc gctcagc 274919PRTArtificial SequenceSynthetic 491Gln Gln Arg Ser Asp Trp Pro Leu Ser1 5 492357DNAArtificial SequenceSynthetic 492caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc 120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac 180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc 240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct 300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca 357493119PRTArtificial SequenceSynthetic 493Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Ser Val 20 25 30 Thr Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val Phe Tyr 85 90 95 Cys Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 49430DNAArtificial SequenceSynthetic 494ggtggctcca tcaacagtgt tacttactac 3049510PRTArtificial SequenceSynthetic 495Gly Gly Ser Ile Asn Ser Val Thr Tyr Tyr1 5 10 49621DNAArtificial SequenceSynthetic 496atcaaattca gtgggagcac c 214977PRTArtificial SequenceSynthetic 497Ile Lys Phe Ser Gly Ser Thr1 5 49833DNAArtificial SequenceSynthetic 498gcgagagctt ctggaagtca tacttttgat atc 3349911PRTArtificial SequenceSynthetic 499Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1 5 10 500324DNAArtificial SequenceSynthetic 500gatattgtga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc aacagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctct ggtgcgtcca gcagggtcac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttggaatgta ttactgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacca aggtggaaat caaa 324501108PRTArtificial SequenceSynthetic 501Asp Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Gly Met Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 50221DNAArtificial SequenceSynthetic 502cagagtgtta gcaacagcta c 215037PRTArtificial SequenceSynthetic 503Gln Ser Val Ser Asn Ser Tyr1 5 5049DNAArtificial SequenceSynthetic 504ggtgcgtcc 95053PRTArtificial SequenceSynthetic 505Gly Ala Ser1 50627DNAArtificial SequenceSynthetic 506cagcagtata gtaggtcacc gatcacc 275079PRTArtificial SequenceSynthetic 507Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 508357DNAArtificial SequenceSynthetic 508gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta ctcctttacc agctttggtt tcagctgggt gcgacaggcc 120cctggacaag gacttgagtg gctgggatgg atcagcgctt acagtggtga cacagactat 180gcacagaagt tccagggcag agtcaccctg accactgaca catccacgac cactgcctac 240atggagctga ggagcctgag atctgacgac acggccgtct attactgtgc gcgatataac 300tggaacctcc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctca 357509119PRTArtificial SequenceSynthetic 509Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Phe 20 25 30 Gly Phe Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45 Gly Trp Ile Ser Ala Tyr Ser Gly Asp Thr Asp Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Asn Trp Asn Leu His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 51024DNAArtificial SequenceSynthetic 510ggttactcct ttaccagctt tggt 245118PRTArtificial SequenceSynthetic 511Gly Tyr Ser Phe Thr Ser Phe Gly1 5 51224DNAArtificial SequenceSynthetic 512atcagcgctt acagtggtga caca 245138PRTArtificial SequenceSynthetic 513Ile Ser Ala Tyr Ser Gly Asp Thr1 5 51436DNAArtificial SequenceSynthetic 514gcgcgatata actggaacct ccactggttc gacccc 3651512PRTArtificial SequenceSynthetic 515Ala Arg Tyr Asn Trp Asn Leu His Trp Phe Asp Pro1 5 10 516324DNAArtificial SequenceSynthetic 516gacatccgga tgacccagtc tccaggcatc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gaatattaaa agcaactact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtacatcca acagggccac tgccatttca 180gacaggttca gtggcagtgg gtctgggaca gacttccttt tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta actcaccgtg gacgttcggc 300caagggacca aagtggatat caaa 324517108PRTArtificial SequenceSynthetic 517Asp Ile Arg Met Thr Gln Ser Pro Gly Ile Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Lys Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Thr Ser Asn Arg Ala Thr Ala Ile Ser Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Leu Phe Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 51821DNAArtificial SequenceSynthetic 518cagaatatta aaagcaacta c 215197PRTArtificial SequenceSynthetic 519Gln Asn Ile Lys Ser Asn Tyr1 5 5209DNAArtificial SequenceSynthetic 520ggtacatcc 95213PRTArtificial SequenceSynthetic 521Gly Thr Ser1 52227DNAArtificial SequenceSynthetic 522cagcagtatg gtaactcacc gtggacg 275239PRTArtificial SequenceSynthetic 523Gln Gln Tyr Gly Asn Ser Pro Trp Thr1 5 524357DNAArtificial SequenceSynthetic 524caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctgatgg ctccatcaac agtgttgaat cctactggac ctggatccgc 120cagcacccag ggaagggcct ggagtggatt ggatacatca aatacactgg gggcatccac 180tataacccgt ccctcaagag tcgacttgcc atatcagtgg acacgtcaaa gaaccagttc 240tccctgaaaa tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagca 300cgtggaagtc atacttttga tgtctggggc caggggacaa tggtcaccgt ctcttca 357525119PRTArtificial SequenceSynthetic 525Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile Asn Ser Val 20 25 30 Glu Ser Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Gly Ile His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Ala Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 52630DNAArtificial SequenceSynthetic 526gatggctcca tcaacagtgt tgaatcctac

3052710PRTArtificial SequenceSynthetic 527Asp Gly Ser Ile Asn Ser Val Glu Ser Tyr1 5 10 52821DNAArtificial SequenceSynthetic 528atcaaataca ctgggggcat c 215297PRTArtificial SequenceSynthetic 529Ile Lys Tyr Thr Gly Gly Ile1 5 53033DNAArtificial SequenceSynthetic 530gcgagagcac gtggaagtca tacttttgat gtc 3353111PRTArtificial SequenceSynthetic 531Ala Arg Ala Arg Gly Ser His Thr Phe Asp Val1 5 10 532324DNAArtificial SequenceSynthetic 532gaaattgtgc tgactcagtc tccaggcacc ctgtcttggt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtattagc agtaactact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatttat ggtgcatcca gcagggtcac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcactgta ttattgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacca aagtggatat caaa 324533108PRTArtificial SequenceSynthetic 533Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Trp Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 53421DNAArtificial SequenceSynthetic 534cagagtatta gcagtaacta c 215357PRTArtificial SequenceSynthetic 535Gln Ser Ile Ser Ser Asn Tyr1 5 5369DNAArtificial SequenceSynthetic 536ggtgcatcc 95373PRTArtificial SequenceSynthetic 537Gly Ala Ser1 53827DNAArtificial SequenceSynthetic 538cagcagtata gtaggtcacc gatcacc 275399PRTArtificial SequenceSynthetic 539Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 540360DNAArtificial SequenceSynthetic 540caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccgtcagc agtggtaatt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggttt gggtacatca aaaacagtgg gggcacctac 180tacaacccgt ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccacttc 240tccctgaggc tgagctctat gacggccgcg gacacggccg tgtattactg tgcgagagct 300ggttcgggga gtcactactt tgactactgg ggccagggaa ccctggtcac cgtctcctca 360541120PRTArtificial SequenceSynthetic 541Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Asn Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Phe Gly Tyr Ile Lys Asn Ser Gly Gly Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn His Phe65 70 75 80 Ser Leu Arg Leu Ser Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 54230DNAArtificial SequenceSynthetic 542ggtggctccg tcagcagtgg taattactac 3054310PRTArtificial SequenceSynthetic 543Gly Gly Ser Val Ser Ser Gly Asn Tyr Tyr1 5 10 54421DNAArtificial SequenceSynthetic 544atcaaaaaca gtgggggcac c 215457PRTArtificial SequenceSynthetic 545Ile Lys Asn Ser Gly Gly Thr1 5 54636DNAArtificial SequenceSynthetic 546gcgagagctg gttcggggag tcactacttt gactac 3654712PRTArtificial SequenceSynthetic 547Ala Arg Ala Gly Ser Gly Ser His Tyr Phe Asp Tyr1 5 10 548324DNAArtificial SequenceSynthetic 548gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggctca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt gtgcagtgta ttactgtcag cagtatggtt actcaccgat caccttcggc 300caagggacca aggtggaaat caaa 324549108PRTArtificial SequenceSynthetic 549Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 55021DNAArtificial SequenceSynthetic 550cagagtgtta gcagcagcta c 215517PRTArtificial SequenceSynthetic 551Gln Ser Val Ser Ser Ser Tyr1 5 5529DNAArtificial SequenceSynthetic 552ggtgcatcc 95533PRTArtificial SequenceSynthetic 553Gly Ala Ser1 55427DNAArtificial SequenceSynthetic 554cagcagtatg gttactcacc gatcacc 275559PRTArtificial SequenceSynthetic 555Gln Gln Tyr Gly Tyr Ser Pro Ile Thr1 5 556369DNAArtificial SequenceSynthetic 556gaagtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtacag cgtctggatt caccttcagt agctatgcca tgtactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaaaactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaagtga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac 300gattttttga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc 360gtctcctca 369557123PRTArtificial SequenceSynthetic 557Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Leu Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 55824DNAArtificial SequenceSynthetic 558ggattcacct tcagtagcta tgcc 245598PRTArtificial SequenceSynthetic 559Gly Phe Thr Phe Ser Ser Tyr Ala1 5 56024DNAArtificial SequenceSynthetic 560atatggtatg atggaagtaa taaa 245618PRTArtificial SequenceSynthetic 561Ile Trp Tyr Asp Gly Ser Asn Lys1 5 56248DNAArtificial SequenceSynthetic 562gcgagagatc acgatttttt gagtggttat gaggggtggt tcgacccc 4856316PRTArtificial SequenceSynthetic 563Ala Arg Asp His Asp Phe Leu Ser Gly Tyr Glu Gly Trp Phe Asp Pro1 5 10 15 564321DNAArtificial SequenceSynthetic 564gaaattgtgc tgactcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagt agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagtag cctagagcct 240gaagattttg cagtttatta ctgtcagcaa cgtagcaact ggcctcccac tttcggcgga 300gggaccaaag tggatatcaa a 321565107PRTArtificial SequenceSynthetic 565Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 105 56618DNAArtificial SequenceSynthetic 566cagagtgtta gtagctac 185676PRTArtificial SequenceSynthetic 567Gln Ser Val Ser Ser Tyr1 5 5689DNAArtificial SequenceSynthetic 568gatgcatcc 95693PRTArtificial SequenceSynthetic 569Asp Ala Ser1 57027DNAArtificial SequenceSynthetic 570cagcaacgta gcaactggcc tcccact 275719PRTArtificial SequenceSynthetic 571Gln Gln Arg Ser Asn Trp Pro Pro Thr1 5 572375DNAArtificial SequenceSynthetic 572gaggtgcagc tggtgcagtc tggagctgaa gtgaagaacc ctggggcctc agttagggtc 60tcctgcaagg cttctggtta cacctttacc acctatggta tcacctgggt gcgacagggc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt tcaatggtga cacaaacttt 180gcacagaacc tccagaacag agtcaccctg accacagaca catccactag cacagcctat 240atggaactga ggagcctgag atctgacgac acggccgttt attactgtgc gagaggggga 300ggagctcgtc cggggaactt cttcttctac ggtatggacg tctggggcca ggggaccacg 360gtcaccgtct cctca 375573125PRTArtificial SequenceSynthetic 573Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Asn Pro Gly Ala1 5 10 15 Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Ile Thr Trp Val Arg Gln Gly Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Phe Asn Gly Asp Thr Asn Phe Ala Gln Asn Leu 50 55 60 Gln Asn Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Gly Ala Arg Pro Gly Asn Phe Phe Phe Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 57424DNAArtificial SequenceSynthetic 574ggttacacct ttaccaccta tggt 245758PRTArtificial SequenceSynthetic 575Gly Tyr Thr Phe Thr Thr Tyr Gly1 5 57624DNAArtificial SequenceSynthetic 576atcagcgctt tcaatggtga caca 245778PRTArtificial SequenceSynthetic 577Ile Ser Ala Phe Asn Gly Asp Thr1 5 57854DNAArtificial SequenceSynthetic 578gcgagagggg gaggagctcg tccggggaac ttcttcttct acggtatgga cgtc 5457918PRTArtificial SequenceSynthetic 579Ala Arg Gly Gly Gly Ala Arg Pro Gly Asn Phe Phe Phe Tyr Gly Met1 5 10 15 Asp Val580321DNAArtificial SequenceSynthetic 580gatgttgtga tgactcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgta gggccagtca gagttttgcc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat acctcctaca gggccactgg cgtcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca acatcagcaa cctggagcct 240gaagattttg cagtttatta ctgtcagcaa cgtggcaact ggccgctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321581107PRTArtificial SequenceSynthetic 581Asp Val Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ala Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Thr Ser Tyr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile Ser Asn Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Gly Asn Trp Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 58218DNAArtificial SequenceSynthetic 582cagagttttg ccagctac 185836PRTArtificial SequenceSynthetic 583Gln Ser Phe Ala Ser Tyr1 5 5849DNAArtificial SequenceSynthetic 584gatacctcc 95853PRTArtificial SequenceSynthetic 585Asp Thr Ser1 58627DNAArtificial SequenceSynthetic 586cagcaacgtg gcaactggcc gctcact 275879PRTArtificial SequenceSynthetic 587Gln Gln Arg Gly Asn Trp Pro Leu Thr1 5 588357DNAArtificial SequenceSynthetic 588caggtgcagc tggtgcagtc tggaactgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttagc tacaatggtg tcacttgggt acgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgatggtaa cacagactat 180gcacagaagt tccaagacag aatcaccatg accacagaca catccacgag tacagcctac 240atggaactga ggagccttag atctgacgac acggccgtct attactgtgc gaggtatagt 300tggaacaacc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctca 357589119PRTArtificial SequenceSynthetic 589Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Asn 20 25 30 Gly Val Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Ile Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Asn His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 59024DNAArtificial SequenceSynthetic 590ggttacacct ttagctacaa tggt 245918PRTArtificial SequenceSynthetic 591Gly Tyr Thr Phe Ser Tyr Asn Gly1 5 59224DNAArtificial SequenceSynthetic 592atcagcgctt acgatggtaa caca 245938PRTArtificial SequenceSynthetic 593Ile Ser Ala Tyr Asp Gly Asn Thr1 5 59436DNAArtificial SequenceSynthetic 594gcgaggtata gttggaacaa ccactggttc gacccc 3659512PRTArtificial SequenceSynthetic 595Ala Arg Tyr Ser Trp Asn Asn His Trp Phe Asp Pro1 5 10 596324DNAArtificial SequenceSynthetic 596gatattgtga tgactcagtc tccaggcacc ctgtctttgt ctccaggaga cggggccacc 60ctctcctgca gggccagtca gagtgtttcc ggcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatttat ggtgcatcca acagggccac tggcatccca 180gacaggttca ctggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta tttctgtcag cagagtgctt tctcaccgtg gacgttcggc 300caagggacca agctggagat caaa 324597108PRTArtificial SequenceSynthetic 597Asp Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Asp Gly Ala Thr Leu Ser

Cys Arg Ala Ser Gln Ser Val Ser Gly Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Thr 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Ala Phe Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 59821DNAArtificial SequenceSynthetic 598cagagtgttt ccggcagcta c 215997PRTArtificial SequenceSynthetic 599Gln Ser Val Ser Gly Ser Tyr1 5 6009DNAArtificial SequenceSynthetic 600ggtgcatcc 96013PRTArtificial SequenceSynthetic 601Gly Ala Ser1 60227DNAArtificial SequenceSynthetic 602cagcagagtg ctttctcacc gtggacg 276039PRTArtificial SequenceSynthetic 603Gln Gln Ser Ala Phe Ser Pro Trp Thr1 5 604351DNAArtificial SequenceSynthetic 604gaagtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60tcctgtgcag cctctggatt caccttcagt atgtacgaca tgcactgggt ccgccaaact 120ataggaaaag gtctggagtg ggtctcagca attggtactg ctggtgacac atactatcca 180ggctccgtga agggccgatt caccatctcc agagaaaatg ccaagaactc cttgtttctt 240caaatgaaca gcctgagagc cggggacacg gctgtttatt actgtgtaag atccgggact 300acagagtggt tcgacccctg gggccaggga accccggtca ctgtctcctc a 351605117PRTArtificial SequenceSynthetic 605Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Asp Met His Trp Val Arg Gln Thr Ile Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Phe Leu65 70 75 80 Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Val 85 90 95 Arg Ser Gly Thr Thr Glu Trp Phe Asp Pro Trp Gly Gln Gly Thr Pro 100 105 110 Val Thr Val Ser Ser 115 60624DNAArtificial SequenceSynthetic 606ggattcacct tcagtatgta cgac 246078PRTArtificial SequenceSynthetic 607Gly Phe Thr Phe Ser Met Tyr Asp1 5 60821DNAArtificial SequenceSynthetic 608attggtactg ctggtgacac a 216097PRTArtificial SequenceSynthetic 609Ile Gly Thr Ala Gly Asp Thr1 5 61033DNAArtificial SequenceSynthetic 610gtaagatccg ggactacaga gtggttcgac ccc 3361111PRTArtificial SequenceSynthetic 611Val Arg Ser Gly Thr Thr Glu Trp Phe Asp Pro1 5 10 612321DNAArtificial SequenceSynthetic 612gacatccggt tgacccagtc tccatcttcc gtgtctgcat ctgtgggaga cagagtcacc 60atcacttgtc ggacgagtca gggtattagt agctggttag cctggtatca gcagaaacca 120ggaaaagccc ctaacctcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240gaagattttg caacttacta ttgtctacag gctaacagtt tcccgtacac ttttggccag 300gggaccaagg tggagatcaa a 321613107PRTArtificial SequenceSynthetic 613Asp Ile Arg Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ala Asn Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 61418DNAArtificial SequenceSynthetic 614cagggtatta gtagctgg 186156PRTArtificial SequenceSynthetic 615Gln Gly Ile Ser Ser Trp1 5 6169DNAArtificial SequenceSynthetic 616gctgcatcc 96173PRTArtificial SequenceSynthetic 617Ala Ala Ser1 61827DNAArtificial SequenceSynthetic 618ctacaggcta acagtttccc gtacact 276199PRTArtificial SequenceSynthetic 619Leu Gln Ala Asn Ser Phe Pro Tyr Thr1 5 620369DNAArtificial SequenceSynthetic 620caggtccagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt ttatggtatg atggaagtaa taaaaactat 180gtagactccg tgaagggccg attcaccatc tcaagagaca attccaagaa cacgctttat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attattgtgc gagagatcat 300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc 360gtctcctca 369621123PRTArtificial SequenceSynthetic 621Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Leu Trp Tyr Asp Gly Ser Asn Lys Asn Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 62224DNAArtificial SequenceSynthetic 622ggattcacct tcagtagtta tggc 246238PRTArtificial SequenceSynthetic 623Gly Phe Thr Phe Ser Ser Tyr Gly1 5 62424DNAArtificial SequenceSynthetic 624ttatggtatg atggaagtaa taaa 246258PRTArtificial SequenceSynthetic 625Leu Trp Tyr Asp Gly Ser Asn Lys1 5 62648DNAArtificial SequenceSynthetic 626gcgagagatc atgattttag gagtggttat gaggggtggt tcgacccc 4862716PRTArtificial SequenceSynthetic 627Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro1 5 10 15 628321DNAArtificial SequenceSynthetic 628gaaattgtgc tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttcgc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a 321629107PRTArtificial SequenceSynthetic 629Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 63018DNAArtificial SequenceSynthetic 630cagagtgttc gcagctac 186316PRTArtificial SequenceSynthetic 631Gln Ser Val Arg Ser Tyr1 5 6329DNAArtificial SequenceSynthetic 632gatgcatcc 96333PRTArtificial SequenceSynthetic 633Asp Ala Ser1 63427DNAArtificial SequenceSynthetic 634caacaccgta gcaactggcc tcccact 276359PRTArtificial SequenceSynthetic 635Gln His Arg Ser Asn Trp Pro Pro Thr1 5 636354DNAArtificial SequenceSynthetic 636caggtcacct tgaaggagtc gggcccagga ctggtgaagt cttcggagac cctgtccctc 60acttgcactg tctctactgg ctccatcagc agtagtagtt actactgggc ctggatccgc 120cagcccccag ggaagggact ggagtggatt gggagtatct attatagtgg gagtaaattc 180tacagcccgt ccctcaagag tcgagtcacc atatacgttg acacgtccaa gaatcagttc 240tccctgcaac tgagctcggt gaccgccgca gacacggctg tatattactg tgcgagacag 300gtcggtgcaa tctttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354637118PRTArtificial SequenceSynthetic 637Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Leu Val Lys Ser Ser Glu1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Thr Gly Ser Ile Ser Ser Ser 20 25 30 Ser Tyr Tyr Trp Ala Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Lys Phe Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Tyr Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Gln Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gln Val Gly Ala Ile Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 63830DNAArtificial SequenceSynthetic 638actggctcca tcagcagtag tagttactac 3063910PRTArtificial SequenceSynthetic 639Thr Gly Ser Ile Ser Ser Ser Ser Tyr Tyr1 5 10 64021DNAArtificial SequenceSynthetic 640atctattata gtgggagtaa a 216417PRTArtificial SequenceSynthetic 641Ile Tyr Tyr Ser Gly Ser Lys1 5 64230DNAArtificial SequenceSynthetic 642gcgagacagg tcggtgcaat ctttgactac 3064310PRTArtificial SequenceSynthetic 643Ala Arg Gln Val Gly Ala Ile Phe Asp Tyr1 5 10 644321DNAArtificial SequenceSynthetic 644gccatccggt tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atctcttgcc gggccagtca gagtattagt agttggttgg cctggtatca gcacaaacca 120gggaaagccc ctaaactcct gctctataag gcgtctagtt tagaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240gatgattttg caacttatta ctgccaacag tataatagtt attctcggac gttcggccaa 300gggaccaagg tggagatcaa a 321645107PRTArtificial SequenceSynthetic 645Ala Ile Arg Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Lys Leu Leu Leu 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 64618DNAArtificial SequenceSynthetic 646cagagtatta gtagttgg 186476PRTArtificial SequenceSynthetic 647Gln Ser Ile Ser Ser Trp1 5 6489DNAArtificial SequenceSynthetic 648aaggcgtct 96493PRTArtificial SequenceSynthetic 649Lys Ala Ser1 65027DNAArtificial SequenceSynthetic 650caacagtata atagttattc tcggacg 276519PRTArtificial SequenceSynthetic 651Gln Gln Tyr Asn Ser Tyr Ser Arg Thr1 5 652372DNAArtificial SequenceSynthetic 652gaggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cctctggtta cacctttaac atctatggta tcagctgggt acgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatggtaa cacaaactat 180gcacagaaac tccagggcag agtcaccatg accacagaaa catccacgac cacagcctac 240atggagttga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagattct 300gattggggaa ctccctacca ctactacggt atggacgtct ggggccaagg gaccacggtc 360accgtctcct ca 372653124PRTArtificial SequenceSynthetic 653Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Ile Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Glu Thr Ser Thr Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Asp Trp Gly Thr Pro Tyr His Tyr Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 65424DNAArtificial SequenceSynthetic 654ggttacacct ttaacatcta tggt 246558PRTArtificial SequenceSynthetic 655Gly Tyr Thr Phe Asn Ile Tyr Gly1 5 65624DNAArtificial SequenceSynthetic 656atcagcgctt acaatggtaa caca 246578PRTArtificial SequenceSynthetic 657Ile Ser Ala Tyr Asn Gly Asn Thr1 5 65851DNAArtificial SequenceSynthetic 658gcgagagatt ctgattgggg aactccctac cactactacg gtatggacgt c 5165917PRTArtificial SequenceSynthetic 659Ala Arg Asp Ser Asp Trp Gly Thr Pro Tyr His Tyr Tyr Gly Met Asp1 5 10 15 Val660339DNAArtificial SequenceSynthetic 660gatattgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60atcaactgca agtccagcca gaatatttta tacacctcca acaataagaa ctacttagct 120tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atttacccgg 180aaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttataatact 300cctcggacgt tcggccaagg gaccaaagtg gatatcaaa 339661113PRTArtificial SequenceSynthetic 661Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Asn Ile Leu Tyr Thr 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Phe Thr Arg Lys Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Asn Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Asp Ile 100 105 110 Lys66236DNAArtificial SequenceSynthetic 662cagaatattt tatacacctc caacaataag aactac 3666312PRTArtificial SequenceSynthetic 663Gln Asn Ile Leu Tyr Thr Ser Asn Asn Lys Asn Tyr1 5 10 6649DNAArtificial SequenceSynthetic 664tgggcattt 96653PRTArtificial SequenceSynthetic 665Trp Ala Phe1 66627DNAArtificial SequenceSynthetic 666cagcaatatt ataatactcc tcggacg 276679PRTArtificial SequenceSynthetic 667Gln Gln Tyr Tyr Asn Thr Pro Arg Thr1 5

668357DNAArtificial SequenceSynthetic 668cagatcacct tgaaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctgatgg ctccatcaac agtggtggtt cctactggag ctggatccgc 120cagcacccgg ggaagggcct ggagtggatt gggtacatca aatacagtgg gggcgtccac 180tataacccgt ccctcaagag tcgaatcacc atatcagtgg acacgtctaa gaaccatttc 240tccctgaaaa tgacctctgt gactgccgcg gacacggccg tgtatttctg tgcgagagca 300cctggaagtc acacttttga tatctggggc caggggacaa tggtcaccgt ctcttca 357669119PRTArtificial SequenceSynthetic 669Gln Ile Thr Leu Lys Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Ile Asn Ser Gly 20 25 30 Gly Ser Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Ser Gly Gly Val His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn His Phe65 70 75 80 Ser Leu Lys Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe 85 90 95 Cys Ala Arg Ala Pro Gly Ser His Thr Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 67030DNAArtificial SequenceSynthetic 670gatggctcca tcaacagtgg tggttcctac 3067110PRTArtificial SequenceSynthetic 671Asp Gly Ser Ile Asn Ser Gly Gly Ser Tyr1 5 10 67221DNAArtificial SequenceSynthetic 672atcaaataca gtgggggcgt c 216737PRTArtificial SequenceSynthetic 673Ile Lys Tyr Ser Gly Gly Val1 5 67433DNAArtificial SequenceSynthetic 674gcgagagcac ctggaagtca cacttttgat atc 3367511PRTArtificial SequenceSynthetic 675Ala Arg Ala Pro Gly Ser His Thr Phe Asp Ile1 5 10 676324DNAArtificial SequenceSynthetic 676gatattgtga tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc aacaactact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctat ggtacatcca atagggtcag tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgaactata ttattgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacac gactggagat taaa 324677108PRTArtificial SequenceSynthetic 677Asp Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Arg Val Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Glu Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 67821DNAArtificial SequenceSynthetic 678cagagtgtta gcaacaacta c 216797PRTArtificial SequenceSynthetic 679Gln Ser Val Ser Asn Asn Tyr1 5 6809DNAArtificial SequenceSynthetic 680ggtacatcc 96813PRTArtificial SequenceSynthetic 681Gly Thr Ser1 68227DNAArtificial SequenceSynthetic 682cagcagtata gtaggtcacc gatcacc 276839PRTArtificial SequenceSynthetic 683Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 684360DNAArtificial SequenceSynthetic 684gaggtgcagc tggtgcagtc tgggggaggc ttggtacaac ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttaac aactttgcca tgacctgggt ccgccaggct 120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatggc 300gccttctata gtggctacga acactactgg ggccagggaa caatggtcac cgtctcctca 360685120PRTArtificial SequenceSynthetic 685Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val Ser Ser 115 120 68624DNAArtificial SequenceSynthetic 686ggattcacct ttaacaactt tgcc 246878PRTArtificial SequenceSynthetic 687Gly Phe Thr Phe Asn Asn Phe Ala1 5 68824DNAArtificial SequenceSynthetic 688attagtggta gtggcgttga caca 246898PRTArtificial SequenceSynthetic 689Ile Ser Gly Ser Gly Val Asp Thr1 5 69039DNAArtificial SequenceSynthetic 690gcgaaagatg gcgccttcta tagtggctac gaacactac 3969113PRTArtificial SequenceSynthetic 691Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1 5 10 692324DNAArtificial SequenceSynthetic 692gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggcctc tggcatccca 180gacaggctca ttggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc 300caagggacca aagtggatat caaa 324693108PRTArtificial SequenceSynthetic 693Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Arg Ala Ser Gly Ile Pro Asp Arg Leu Ile 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Arg Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 69421DNAArtificial SequenceSynthetic 694cagagtgtta gcagcagcta c 216957PRTArtificial SequenceSynthetic 695Gln Ser Val Ser Ser Ser Tyr1 5 6969DNAArtificial SequenceSynthetic 696ggtacatcc 96973PRTArtificial SequenceSynthetic 697Gly Thr Ser1 69827DNAArtificial SequenceSynthetic 698cagcagtatg gtagctcacc tcggacg 276999PRTArtificial SequenceSynthetic 699Gln Gln Tyr Gly Ser Ser Pro Arg Thr1 5 700363DNAArtificial SequenceSynthetic 700gaggtgcagc tggtgcagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taaatactat 180gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa catgctgtat 240ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc ggcttacgat 300attttgattg gttattcccc ggttgactac tggggccagg gaaccctggt caccgtctcc 360tca 363 701121PRTArtificial SequenceSynthetic 701Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Tyr Asp Ile Leu Ile Gly Tyr Ser Pro Val Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 70224DNAArtificial SequenceSynthetic 702ggattcacct tcagtagcta tggc 247038PRTArtificial SequenceSynthetic 703Gly Phe Thr Phe Ser Ser Tyr Gly1 5 70424DNAArtificial SequenceSynthetic 704atatggtatg atggaagtaa taaa 247058PRTArtificial SequenceSynthetic 705Ile Trp Tyr Asp Gly Ser Asn Lys1 5 70642DNAArtificial SequenceSynthetic 706gcggcttacg atattttgat tggttattcc ccggttgact ac 4270714PRTArtificial SequenceSynthetic 707Ala Ala Tyr Asp Ile Leu Ile Gly Tyr Ser Pro Val Asp Tyr1 5 10 708318DNAArtificial SequenceSynthetic 708gatattgtga tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gactgttagt agcaacttag cctggttcca gcagaaacct 120ggccaggctc ccagactcct catctatgat gcatccacca gggccactgg tatcccagcc 180aggttcagtg gcagtgggtc tgggacagaa ttcactctca ccatcagcag cctgcagtct 240gaagattttg cagtttatta ctgtcagcag tataataact ggtacacttt tggccagggg 300accaagctgg agatcaaa 318709106PRTArtificial SequenceSynthetic 709Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Asn 20 25 30 Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Tyr Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 71018DNAArtificial SequenceSynthetic 710cagactgtta gtagcaac 187116PRTArtificial SequenceSynthetic 711Gln Thr Val Ser Ser Asn1 5 7129DNAArtificial SequenceSynthetic 712gatgcatcc 97133PRTArtificial SequenceSynthetic 713Asp Ala Ser1 71424DNAArtificial SequenceSynthetic 714cagcagtata ataactggta cact 247158PRTArtificial SequenceSynthetic 715Gln Gln Tyr Asn Asn Trp Tyr Thr1 5 716357DNAArtificial SequenceSynthetic 716gaggtgcagc tggtgcagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccattacc agtggtggtt actactggac ctggatccgc 120cagcacccag ggaagggcct ggaatggatt ggatacatca aatttagtgg gaacacctac 180tacaacccgt ccctcaggag tcgagtcacc atatcacttg acacgtctaa gaatcagttc 240tccctgaata tgacctctgt gactgccgcg gacacggccg tgtattattg tgcgagagca 300cctggaagtc ataactttga catctggggc caagggacaa tggtcaccgt ctcttca 357717119PRTArtificial SequenceSynthetic 717Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Gly 20 25 30 Gly Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Asn Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Ser His Asn Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 71830DNAArtificial SequenceSynthetic 718ggtggctcca ttaccagtgg tggttactac 3071910PRTArtificial SequenceSynthetic 719Gly Gly Ser Ile Thr Ser Gly Gly Tyr Tyr1 5 10 72021DNAArtificial SequenceSynthetic 720atcaaattta gtgggaacac c 217217PRTArtificial SequenceSynthetic 721Ile Lys Phe Ser Gly Asn Thr1 5 72233DNAArtificial SequenceSynthetic 722gcgagagcac ctggaagtca taactttgac atc 3372311PRTArtificial SequenceSynthetic 723Ala Arg Ala Pro Gly Ser His Asn Phe Asp Ile1 5 10 724324DNAArtificial SequenceSynthetic 724gccatccggt tgacccagtc tccagacacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtgt gagtattagt aataactatt tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag aagactggag 240tctgcagatt ttgcaccgta ttactgtcag caatatagta ggtcaccgat caccttcggc 300caagggacac gactggagat taaa 324725108PRTArtificial SequenceSynthetic 725Ala Ile Arg Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Ser Ile Ser Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65 70 75 80 Ser Ala Asp Phe Ala Pro Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 72621DNAArtificial SequenceSynthetic 726gtgagtatta gtaataacta t 217277PRTArtificial SequenceSynthetic 727Val Ser Ile Ser Asn Asn Tyr1 5 7289DNAArtificial SequenceSynthetic 728ggtgcatcc 97293PRTArtificial SequenceSynthetic 729Gly Ala Ser1 73027DNAArtificial SequenceSynthetic 730cagcaatata gtaggtcacc gatcacc 277319PRTArtificial SequenceSynthetic 731Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 732357DNAArtificial SequenceSynthetic 732caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcaac agtgttactt actactggac ctggatccgc 120cagcacccag ggaggggcct agagtggatt gggtacatca aattcagtgg gagcacctac 180tacaacccgt ccctcaaggg tcgagtcacc atatcagtgg acacgtctaa gaaccaattc 240tcccttaaaa ttaactctgt gactgccgcg gacacggccg tgttttactg tgcgagagct 300tctggaagtc atacttttga tatctggggc caagggacaa tggtcaccgt ctcctca 357733119PRTArtificial SequenceSynthetic 733Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Ser Val 20 25 30 Thr Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Gly Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Ile Asn Ser Val Thr Ala Ala Asp Thr Ala Val Phe Tyr 85 90 95 Cys Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115

73430DNAArtificial SequenceSynthetic 734ggtggctcca tcaacagtgt tacttactac 3073510PRTArtificial SequenceSynthetic 735Gly Gly Ser Ile Asn Ser Val Thr Tyr Tyr1 5 10 73621DNAArtificial SequenceSynthetic 736atcaaattca gtgggagcac c 217377PRTArtificial SequenceSynthetic 737Ile Lys Phe Ser Gly Ser Thr1 5 73833DNAArtificial SequenceSynthetic 738gcgagagctt ctggaagtca tacttttgat atc 3373911PRTArtificial SequenceSynthetic 739Ala Arg Ala Ser Gly Ser His Thr Phe Asp Ile1 5 10 740324DNAArtificial SequenceSynthetic 740gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc aacagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctct ggtgcgtcca gcagggtcac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttggaatgta ttactgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacca agctggagat caaa 324741108PRTArtificial SequenceSynthetic 741Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Ser Ser Arg Val Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Gly Met Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 74221DNAArtificial SequenceSynthetic 742cagagtgtta gcaacagcta c 217437PRTArtificial SequenceSynthetic 743Gln Ser Val Ser Asn Ser Tyr1 5 7449DNAArtificial SequenceSynthetic 744ggtgcgtcc 97453PRTArtificial SequenceSynthetic 745Gly Ala Ser1 74627DNAArtificial SequenceSynthetic 746cagcagtata gtaggtcacc gatcacc 277479PRTArtificial SequenceSynthetic 747Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 748357DNAArtificial SequenceSynthetic 748gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggagt caccttggat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaagt attagttgga atagtggtag tataggctat 180gcggactctg tgaagggccg cttcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatggg 300tggaacccgt actactttga ctattggggc cagggaataa cggtcaccgt ctcctca 357749119PRTArtificial SequenceSynthetic 749Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Leu Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Trp Asn Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Ile Thr Val Thr Val Ser Ser 115 75024DNAArtificial SequenceSynthetic 750ggagtcacct tggatgatta tgcc 247518PRTArtificial SequenceSynthetic 751Gly Val Thr Leu Asp Asp Tyr Ala1 5 75224DNAArtificial SequenceSynthetic 752attagttgga atagtggtag tata 247538PRTArtificial SequenceSynthetic 753Ile Ser Trp Asn Ser Gly Ser Ile1 5 75436DNAArtificial SequenceSynthetic 754gcaaaagatg ggtggaaccc gtactacttt gactat 3675512PRTArtificial SequenceSynthetic 755Ala Lys Asp Gly Trp Asn Pro Tyr Tyr Phe Asp Tyr1 5 10 756321DNAArtificial SequenceSynthetic 756gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga agtgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacttatta ctgtctacag cataatagtt accctctcac tttcggcgga 300gggaccaagg tggaaatcaa a 321757107PRTArtificial SequenceSynthetic 757Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 75818DNAArtificial SequenceSynthetic 758cagggcatta gaagtgat 187596PRTArtificial SequenceSynthetic 759Gln Gly Ile Arg Ser Asp1 5 7609DNAArtificial SequenceSynthetic 760gctgcatcc 97613PRTArtificial SequenceSynthetic 761Ala Ala Ser1 76227DNAArtificial SequenceSynthetic 762ctacagcata atagttaccc tctcact 277639PRTArtificial SequenceSynthetic 763Leu Gln His Asn Ser Tyr Pro Leu Thr1 5 764357DNAArtificial SequenceSynthetic 764cagatcacct tgaaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcgccg tctctggtga ctccttcagc agtggtaatt actactggag ctggatccgc 120caacacccag ggaagggcct ggagtggatt gggtacatca agtacactgg gagcacctac 180tacaacccgt ccctcaagag tcgagttatt atattagtag acacgtctaa gacccagttc 240tccctgaagc tgagctctgt gaatgccgcg gacacggccg tgtattactg tgcgagagca 300cctggaactc atgcttttga tgtttggggc caagggacaa tggtcaccgt ctcctca 357765119PRTArtificial SequenceSynthetic 765Gln Ile Thr Leu Lys Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Phe Ser Ser Gly 20 25 30 Asn Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Ile Ile Leu Val Asp Thr Ser Lys Thr Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Asn Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Thr His Ala Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 76630DNAArtificial SequenceSynthetic 766ggtgactcct tcagcagtgg taattactac 3076710PRTArtificial SequenceSynthetic 767Gly Asp Ser Phe Ser Ser Gly Asn Tyr Tyr1 5 10 76821DNAArtificial SequenceSynthetic 768atcaagtaca ctgggagcac c 217697PRTArtificial SequenceSynthetic 769Ile Lys Tyr Thr Gly Ser Thr1 5 77033DNAArtificial SequenceSynthetic 770gcgagagcac ctggaactca tgcttttgat gtt 3377111PRTArtificial SequenceSynthetic 771Ala Arg Ala Pro Gly Thr His Ala Phe Asp Val1 5 10 772324DNAArtificial SequenceSynthetic 772gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ttccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agtagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgtgaca gactccactc tcaccatcag cagcctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacca agctggagat caaa 324773108PRTArtificial SequenceSynthetic 773Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Phe Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Val Thr Asp Ser Thr Leu Thr Ile Ser Ser Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 77421DNAArtificial SequenceSynthetic 774cagagtgtta gcagtagcta c 217757PRTArtificial SequenceSynthetic 775Gln Ser Val Ser Ser Ser Tyr1 5 7769DNAArtificial SequenceSynthetic 776ggtgcatcc 97773PRTArtificial SequenceSynthetic 777Gly Ala Ser1 77827DNAArtificial SequenceSynthetic 778cagcagtata gtaggtcacc gatcacc 277799PRTArtificial SequenceSynthetic 779Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 780360DNAArtificial SequenceSynthetic 780gaagtgcagc tggtgcagtc tgggggagcc ttggtacaac ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttaac aactttgcca tgacctgggt ccgccaggct 120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgttc gaaagatggc 300gccttctata gtggctacga acactactgg ggccagggaa ccacggtcac cgtctcctca 360781120PRTArtificial SequenceSynthetic 781Glu Val Gln Leu Val Gln Ser Gly Gly Ala Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser 115 120 78224DNAArtificial SequenceSynthetic 782ggattcacct ttaacaactt tgcc 247838PRTArtificial SequenceSynthetic 783Gly Phe Thr Phe Asn Asn Phe Ala1 5 78424DNAArtificial SequenceSynthetic 784attagtggta gtggcgttga caca 247858PRTArtificial SequenceSynthetic 785Ile Ser Gly Ser Gly Val Asp Thr1 5 78639DNAArtificial SequenceSynthetic 786tcgaaagatg gcgccttcta tagtggctac gaacactac 3978713PRTArtificial SequenceSynthetic 787Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1 5 10 788324DNAArtificial SequenceSynthetic 788gaaacgacac tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc 300caagggacca aggtggagat caaa 324789108PRTArtificial SequenceSynthetic 789Glu Thr Thr Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 79021DNAArtificial SequenceSynthetic 790cagagtgtta gcagcagcta c 217917PRTArtificial SequenceSynthetic 791Gln Ser Val Ser Ser Ser Tyr1 5 7929DNAArtificial SequenceSynthetic 792ggtacatcc 97933PRTArtificial SequenceSynthetic 793Gly Thr Ser1 79427DNAArtificial SequenceSynthetic 794cagcagtatg gtagctcacc tcggacg 277959PRTArtificial SequenceSynthetic 795Gln Gln Tyr Gly Ser Ser Pro Arg Thr1 5 796357DNAArtificial SequenceSynthetic 796gaagtgcagc tggtgcagtc tggacctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc tactatggta tcagttggat acgacagacc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgatggtaa cacagactat 180gcacagaagt tccaagacag aatcaccatg accacagaca catcctcgac cacagcctac 240atggaactga ggagcctgag atctgacgac acggccgtct attactgtgc gaggtatagt 300tggaacaagc actggttcga cccctggggc cagggaacca tggtcaccgt ctcttca 357797119PRTArtificial SequenceSynthetic 797Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Tyr 20 25 30 Gly Ile Ser Trp Ile Arg Gln Thr Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Ile Thr Met Thr Thr Asp Thr Ser Ser Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Lys His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 79824DNAArtificial SequenceSynthetic 798ggttacacct ttacctacta tggt 247998PRTArtificial SequenceSynthetic 799Gly Tyr Thr Phe Thr Tyr Tyr Gly1 5 80024DNAArtificial SequenceSynthetic 800atcagcgctt acgatggtaa caca 248018PRTArtificial SequenceSynthetic 801Ile Ser Ala Tyr Asp Gly Asn Thr1 5 80236DNAArtificial SequenceSynthetic 802gcgaggtata gttggaacaa gcactggttc gacccc 3680312PRTArtificial SequenceSynthetic 803Ala Arg Tyr Ser Trp Asn Lys His Trp Phe Asp Pro1 5 10 804324DNAArtificial SequenceSynthetic 804gaaattgtga tgacacagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60ctctcctgca gggccagtca gagtgttacc ggcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctat ggtgcatcca acagggccac tggcatccca 180gacaggttca ctggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta tttctgtcaa cagtctgctt tctcaccgtg gacgttcggc 300caggggacca aggtggaaat caaa 324805108PRTArtificial SequenceSynthetic 805Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Gly Ser 20 25 30 Tyr Leu Ala Trp Tyr

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Thr 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Ala Phe Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 80621DNAArtificial SequenceSynthetic 806cagagtgtta ccggcagcta c 218077PRTArtificial SequenceSynthetic 807Gln Ser Val Thr Gly Ser Tyr1 5 8089DNAArtificial SequenceSynthetic 808ggtgcatcc 98093PRTArtificial SequenceSynthetic 809Gly Ala Ser1 81027DNAArtificial SequenceSynthetic 810caacagtctg ctttctcacc gtggacg 278119PRTArtificial SequenceSynthetic 811Gln Gln Ser Ala Phe Ser Pro Trp Thr1 5 812357DNAArtificial SequenceSynthetic 812gaggtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60tcctgtgcag cctctggagt caccttggat gattatgcca tgcactgggt ccggcaagct 120ccagggaagg gcctggagtg ggtctcaagt attagttgga atagtggtag tataggctat 180gcggactctg tgaagggccg cttcaccatc tccagagaca acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatggg 300tggaacccgt actactttga ctattggggc cagggaatac cggtcaccgt ctcctca 357813119PRTArtificial SequenceSynthetic 813Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Leu Asp Asp Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Trp Asn Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Ile Pro Val Thr Val Ser Ser 115 81424DNAArtificial SequenceSynthetic 814ggagtcacct tggatgatta tgcc 248158PRTArtificial SequenceSynthetic 815Gly Val Thr Leu Asp Asp Tyr Ala1 5 81624DNAArtificial SequenceSynthetic 816attagttgga atagtggtag tata 248178PRTArtificial SequenceSynthetic 817Ile Ser Trp Asn Ser Gly Ser Ile1 5 81836DNAArtificial SequenceSynthetic 818gcaaaagatg ggtggaaccc gtactacttt gactat 3681912PRTArtificial SequenceSynthetic 819Ala Lys Asp Gly Trp Asn Pro Tyr Tyr Phe Asp Tyr1 5 10 820321DNAArtificial SequenceSynthetic 820gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgcc gggcaagtca gggcattaga agtgatttag gctggtatca gcagaaacca 120gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240gaagattttg caacctatta ctgtctacag cataatagtt accctctcac tttcggcgga 300gggaccaagc tggagatcaa a 321821107PRTArtificial SequenceSynthetic 821Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 82218DNAArtificial SequenceSynthetic 822cagggcatta gaagtgat 188236PRTArtificial SequenceSynthetic 823Gln Gly Ile Arg Ser Asp1 5 8249DNAArtificial SequenceSynthetic 824gctgcatcc 98253PRTArtificial SequenceSynthetic 825Ala Ala Ser1 82627DNAArtificial SequenceSynthetic 826ctacagcata atagttaccc tctcact 278279PRTArtificial SequenceSynthetic 827Leu Gln His Asn Ser Tyr Pro Leu Thr1 5 828357DNAArtificial SequenceSynthetic 828caggtacagc tgcagcagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcgctg tctctggtga ctccttcagc agtggtaatt actactggag ctggatccgc 120caacacccag ggaagggcct ggagtggatt gggtacatca agtacactgg gagcacctac 180tacaacccgt ccctcaagag tcgagttacc atattagtag acacgtctaa gacccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagca 300cctggaactc atgtttttga tgtctggggc caagggacaa tggtcaccgt ctcttca 357829119PRTArtificial SequenceSynthetic 829Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Phe Ser Ser Gly 20 25 30 Asn Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Leu Val Asp Thr Ser Lys Thr Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Thr His Val Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 83030DNAArtificial SequenceSynthetic 830ggtgactcct tcagcagtgg taattactac 3083110PRTArtificial SequenceSynthetic 831Gly Asp Ser Phe Ser Ser Gly Asn Tyr Tyr1 5 10 83221DNAArtificial SequenceSynthetic 832atcaagtaca ctgggagcac c 218336PRTArtificial SequenceSynthetic 833Lys Tyr Thr Gly Ser Thr1 5 83433DNAArtificial SequenceSynthetic 834gcgagagcac ctggaactca tgtttttgat gtc 3383511PRTArtificial SequenceSynthetic 835Ala Arg Ala Pro Gly Thr His Val Phe Asp Val1 5 10 836324DNAArtificial SequenceSynthetic 836gacatccagt tgacccagtc tccaggcacc ctgtctttgc ttccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agtagctatt tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgtgaca gacttcactc tcaccatcag cagcctggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacca aggtggagat caaa 324837108PRTArtificial SequenceSynthetic 837Asp Ile Gln Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Leu Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Val Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 83821DNAArtificial SequenceSynthetic 838cagagtgtta gcagtagcta t 218397PRTArtificial SequenceSynthetic 839Gln Ser Val Ser Ser Ser Tyr1 5 8409DNAArtificial SequenceSynthetic 840ggtgcatcc 98413PRTArtificial SequenceSynthetic 841Gly Ala Ser1 84227DNAArtificial SequenceSynthetic 842cagcagtata gtaggtcacc gatcacc 278439PRTArtificial SequenceSynthetic 843Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 844363DNAArtificial SequenceSynthetic 844caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac 180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc 240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat 300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccacggt caccgtctcc 360tca 363845121PRTArtificial SequenceSynthetic 845Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 84630DNAArtificial SequenceSynthetic 846ggtggctcca tcagcagtgg tggttactac 3084710PRTArtificial SequenceSynthetic 847Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr1 5 10 84821DNAArtificial SequenceSynthetic 848atccattata gtgggaacac c 218497PRTArtificial SequenceSynthetic 849Ile His Tyr Ser Gly Asn Thr1 5 85039DNAArtificial SequenceSynthetic 850gcgaggaata tggttcgggg agttcactgg ttcgacccc 3985113PRTArtificial SequenceSynthetic 851Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro1 5 10 852324DNAArtificial SequenceSynthetic 852gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctcttctgtt gggccagtcg gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctct ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtata tttctgtcaa cagtatagta gttcaccgct cactttcggc 300ggagggacca agctggagat caaa 324853108PRTArtificial SequenceSynthetic 853Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 85421DNAArtificial SequenceSynthetic 854cggagtgtta gcagcagcta c 218557PRTArtificial SequenceSynthetic 855Arg Ser Val Ser Ser Ser Tyr1 5 8569DNAArtificial SequenceSynthetic 856ggtgcatcc 98573PRTArtificial SequenceSynthetic 857Gly Ala Ser1 85827DNAArtificial SequenceSynthetic 858caacagtata gtagttcacc gctcact 278599PRTArtificial SequenceSynthetic 859Gln Gln Tyr Ser Ser Ser Pro Leu Thr1 5 860357DNAArtificial SequenceSynthetic 860caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctagtga ctccatcagc agtggtaata actactggac ctggatccgc 120cagcacccag ggaggggcct ggagtggatt gggtacatca aatacactgg gagcgcccac 180tacaacccgt ccctcaagag tcgagtcacc atgtcagtag acacgtctaa gaatcagttc 240tccctgaaaa tgacctctgt gactgacgcg gacacggccg tgtattattg tgcgagggca 300cctggaagcc attcttttga tatatggggc cgagggacaa tggtcaccgt ctcctca 357861119PRTArtificial SequenceSynthetic 861Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Ser Asp Ser Ile Ser Ser Gly 20 25 30 Asn Asn Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Tyr Thr Gly Ser Ala His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Met Thr Ser Val Thr Asp Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Ser His Ser Phe Asp Ile Trp Gly Arg Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 86230DNAArtificial SequenceSynthetic 862agtgactcca tcagcagtgg taataactac 3086310PRTArtificial SequenceSynthetic 863Ser Asp Ser Ile Ser Ser Gly Asn Asn Tyr1 5 10 86421DNAArtificial SequenceSynthetic 864atcaaataca ctgggagcgc c 218657PRTArtificial SequenceSynthetic 865Ile Lys Tyr Thr Gly Ser Ala1 5 86633DNAArtificial SequenceSynthetic 866gcgagggcac ctggaagcca ttcttttgat ata 3386711PRTArtificial SequenceSynthetic 867Ala Arg Ala Pro Gly Ser His Ser Phe Asp Ile1 5 10 868324DNAArtificial SequenceSynthetic 868gatgttgtga tgacccagtc tccaggcacc ctgtttttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaacatcag cagactggag 240cctgaagatt ttgcactgta ttactgtcag cagtatagta ggtcaccgat caccttcggc 300caagggacac gactggagat taaa 324869108PRTArtificial SequenceSynthetic 869Asp Val Val Met Thr Gln Ser Pro Gly Thr Leu Phe Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 87021DNAArtificial SequenceSynthetic 870cagagtgtta gcagcagcta c 218717PRTArtificial SequenceSynthetic 871Gln Ser Val Ser Ser Ser Tyr1 5 8729DNAArtificial SequenceSynthetic 872ggtgcatcc 98733PRTArtificial SequenceSynthetic 873Gly Ala Ser1 87427DNAArtificial SequenceSynthetic 874cagcagtata gtaggtcacc gatcacc 278759PRTArtificial SequenceSynthetic 875Gln Gln Tyr Ser Arg Ser Pro Ile Thr1 5 876360DNAArtificial SequenceSynthetic 876caggtgcagc tggtgcagtc tgggggaggc ttggtacaac ctggggggtc cctaagactc 60tcctgtgcag cctctggatt cacctctaac aactttgcca

tgacctgggt ccgccaggct 120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag agtcgaggac acggccgtat attactgtgc taaagatggc 300gccttctata gtggctacga acactactgg ggccagggaa ccctggtcac cgtctcctca 360877120PRTArtificial SequenceSynthetic 877Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ser Asn Asn Phe 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 87824DNAArtificial SequenceSynthetic 878ggattcacct ctaacaactt tgcc 248798PRTArtificial SequenceSynthetic 879Gly Phe Thr Ser Asn Asn Phe Ala1 5 88024DNAArtificial SequenceSynthetic 880attagtggta gtggcgttga caca 248818PRTArtificial SequenceSynthetic 881Ile Ser Gly Ser Gly Val Asp Thr1 5 88239DNAArtificial SequenceSynthetic 882gctaaagatg gcgccttcta tagtggctac gaacactac 3988313PRTArtificial SequenceSynthetic 883Ala Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr1 5 10 884324DNAArtificial SequenceSynthetic 884gatgttgtga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggcctc tggcatccca 180gacaagttca ttggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc 300caagggacca aagtggatat caaa 324885108PRTArtificial SequenceSynthetic 885Asp Val Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Arg Ala Ser Gly Ile Pro Asp Lys Phe Ile 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Arg Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 100 105 88621DNAArtificial SequenceSynthetic 886cagagtgtta gcagcagcta c 218877PRTArtificial SequenceSynthetic 887Gln Ser Val Ser Ser Ser Tyr1 5 8889DNAArtificial SequenceSynthetic 888ggtacatcc 98893PRTArtificial SequenceSynthetic 889Gly Thr Ser1 89027DNAArtificial SequenceSynthetic 890cagcagtatg gtagctcacc tcggacg 278919PRTArtificial SequenceSynthetic 891Gln Gln Tyr Gly Ser Ser Pro Arg Thr1 5 892360DNAArtificial SequenceSynthetic 892caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg 60acctgcaccg tgtccggcgg ctccatcggc tccggcggct actactggtc ctggatccgg 120cagcaccccg gcaagggcct ggagtggatc ggctacgtgc actactccgg caacacctac 180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc 240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccgggcc 300ccccggggct accactactt cgcctactgg ggccagggca ccctggtgac cgtgtcctcc 360893120PRTArtificial SequenceSynthetic 893Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 894324DNAArtificial SequenceSynthetic 894gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca gtccgtgtcc tcctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta ctactgccag cagtacggct cctcccccct gaccttcggc 300ggcggcacca aggtggagat caag 324895108PRTArtificial SequenceSynthetic 895Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 896369DNAArtificial SequenceSynthetic 896caggtgcagc tggtggagtc cggcggcggc gtggtgcagc ccggccggtc cctgcggctg 60tcctgcgccg cctccggctt caccttctcc tcctacggca tgcactgggt gcggcaggcc 120cccggcaagg gcctggagtg ggtggccgtg ctgtggtacg acggcaccaa caagtactac 180gccgactccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 240ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc ccgggaccac 300gacttccggt ccggctacga gggctggttc gacccctggg gccagggcac cctggtgacc 360gtgtcctcc 369897123PRTArtificial SequenceSynthetic 897Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Leu Trp Tyr Asp Gly Thr Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 898321DNAArtificial SequenceSynthetic 898gagatcgtgc tgacccagtc ccccgccacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca gtccgtgtcc tcctacctgg cctggtacca gcagaagccc 120ggccaggccc cccggctgct gatctacgac gcctccaacc gggccaccgg catccccgcc 180cggttctccg gctccggctc cggcaccgac ttcaccctga ccatctcctc cctggagccc 240gaggacttcg ccgtgtacta ctgccagcac cggtccaact ggccccccac cttcggcggc 300ggcaccaagg tggagatcaa g 321899107PRTArtificial SequenceSynthetic 899Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 900369DNAArtificial SequenceSynthetic 900caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60tcctgtgcag cgtctggatt caccttcagt agttatggca tgcactgggt ccgccaggct 120ccaggcaagg ggctggagtg ggtgtcattt ttatggtatg atggaactaa taaaaactat 180gtagagtccg tgaagggccg attcaccatc tcaagagaca attccaagaa tatgctgtat 240ctggaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatcac 300gattttagga gtggttatga ggggtggttc gacccctggg gccagggaac cctggtcacc 360gtctcctca 369901123PRTArtificial SequenceSynthetic 901Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Phe Leu Trp Tyr Asp Gly Thr Asn Lys Asn Tyr Val Glu Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr65 70 75 80 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Asp Phe Arg Ser Gly Tyr Glu Gly Trp Phe Asp Pro 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 902321DNAArtificial SequenceSynthetic 902gaaatagtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240gaagattttg cagtttatta ctgtcaacac cgtagcaact ggcctcccac tttcggcgga 300gggaccaagg tggaaatcaa a 321903107PRTArtificial SequenceSynthetic 903Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 904363DNAArtificial SequenceSynthetic 904caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac 180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc 240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat 300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccacggt caccgtctcc 360tca 363905121PRTArtificial SequenceSynthetic 905Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 906324DNAArtificial SequenceSynthetic 906gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctcttctgtt gggccagtcg gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctct ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtata tttctgtcaa cagtatagta gttcaccgct cactttcggc 300ggagggacca agctggagat caaa 324907108PRTArtificial SequenceSynthetic 907Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 908363DNAArtificial SequenceSynthetic 908caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg 60acctgcaccg tgtccggcgg ctccatctcc tccggcggct actactggtc ctggatccgg 120cagcaccccg gcaagggcct ggagtggatc ggctacatcc actactccgg caacacctac 180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc 240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccggaac 300atggtgcggg gcgtgcactg gttcgacccc tggggccagg gcaccctggt gaccgtgtcc 360tcc 363909121PRTArtificial SequenceSynthetic 909Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 910324DNAArtificial SequenceSynthetic 910gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctcccg gtccgtgtcc tcctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta ctactgccag cagtactcct cctcccccct gaccttcggc 300ggcggcacca aggtggagat caag 324911108PRTArtificial SequenceSynthetic 911Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Arg Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 912363DNAArtificial SequenceSynthetic 912caggtgcagc tgcaggagtc gggcctagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacatcc attatagtgg gaacacccac 180tacaatccga ccctcaagag tcgaattacc atatcagtag acacgtctaa gaaccagttc 240tcccttgagg tgaactctgt gactgccgcg gacacggccg tatactactg tgcgaggaat 300atggttcggg gagttcactg gttcgacccc tggggccagg gaaccctggt caccgtctcc 360tca 363913121PRTArtificial SequenceSynthetic 913Gln Val Gln Leu Gln Glu Ser Gly Leu Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile His Tyr Ser Gly Asn Thr His Tyr Asn Pro Thr 50 55 60 Leu Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Glu Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Met Val Arg Gly Val His Trp Phe Asp Pro Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 914324DNAArtificial SequenceSynthetic 914gaaatagtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga gagagccacc 60ctcttctgtt gggccagtcg gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctct ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtata tttctgtcaa cagtatagta gttcaccgct cactttcggc 300ggagggacca aggtggaaat caaa 324915108PRTArtificial SequenceSynthetic 915Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Phe Cys Trp Ala Ser Arg Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Ser Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 916357DNAArtificial SequenceSynthetic 916caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctcccagac cctgtccctg 60acctgcaccg tgtccggcgg ctccatcacc tccggcggct actactggtc ctggatccgg 120cagcaccccg gcaagggcct ggagtggatc ggctacatca agttctccgg caacacctac 180tacaacccct ccctgaagtc ccgggtgacc atctccgtgg acacctccaa gaaccagttc 240tccctgaagc tgtcctccgt gaccgccgcc gacaccgccg tgtactactg cgcccgggcc 300cccggctccc acaacttcga catctggggc cagggcacca tggtgaccgt gtcctcc 357917119PRTArtificial SequenceSynthetic 917Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Ser His Asn Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 918324DNAArtificial SequenceSynthetic 918gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccgt gtccatctcc aacaactacc tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc tgaccatccg gcggctggag 240cccgaggact tcgcccccta ctactgccag cagtactccc ggtcccccat caccttcggc 300cagggcaccc ggctggagat caag 324919108PRTArtificial SequenceSynthetic 919Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Ser Ile Ser Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Pro Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 920360DNAArtificial SequenceSynthetic 920gaggtgcagc tggtggagtc cggcggcggc ctggtgcagc ccggcggctc cctgcggctg 60tcctgcgccg cctccggctt caccttcaac aacttcgcca tgtcctgggt gcggcaggcc 120cccggcaagg gcctggagtg ggtgtccgcc atctccggct ccggcgtgga cacctactac 180gccgactccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 240ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgctc caaggacggc 300gccttctact ccggctacga gcactactgg ggccagggca ccctggtgac cgtgtcctcc 360921120PRTArtificial SequenceSynthetic 921Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Val Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 922324DNAArtificial SequenceSynthetic 922gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca gtccgtgtcc tcctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcacctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta ctactgccag cagtacggct cctccccccg gaccttcggc 300cagggcacca aggtggagat caag 324923108PRTArtificial SequenceSynthetic 923Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 924357DNAArtificial SequenceSynthetic 924caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60tcctgcaagg cctccggcta caccttcacc tactacggca tctcctgggt gcggcaggcc 120cccggccagg gcctggagtg gatgggctgg atctccgcct acgacggcaa caccaactac 180gcccagaagc tgcagggccg ggtgaccatg accaccgaca cctccacctc caccgcctac 240atggagctgc ggtccctgcg gtccgacgac accgccgtgt actactgcgc ccggtactcc 300tggaacaagc actggttcga cccctggggc cagggcaccc tggtgaccgt gtcctcc 357925119PRTArtificial SequenceSynthetic 925Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Lys His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 926324DNAArtificial SequenceSynthetic 926gagatcgtgc tgacccagtc ccccggcacc ctgtccctgt cccccggcga gcgggccacc 60ctgtcctgcc gggcctccca gtccgtgacc ggctcctacc tggcctggta ccagcagaag 120cccggccagg ccccccggct gctgatctac ggcgcctcct cccgggccac cggcatcccc 180gaccggttct ccggctccgg ctccggcacc gacttcaccc tgaccatctc ccggctggag 240cccgaggact tcgccgtgta ctactgccag cagtccgcct tctccccctg gaccttcggc 300cagggcacca aggtggagat caag 324927108PRTArtificial SequenceSynthetic 927Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Gly Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ala Phe Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 9288PRTArtificial SequenceSynthetic 928Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 9298PRTArtificial SequenceSynthetic 929Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 93016PRTArtificial SequenceSynthetic 930Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15 9317PRTArtificial SequenceSynthetic 931Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 9323PRTArtificial SequenceSynthetic 932Xaa Xaa Xaa1 9339PRTArtificial SequenceSynthetic 933Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 934357DNAArtificial SequenceSynthetic 934caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccattacc agtggtggtt actactggac ctggatccgc 120cagcacccag ggaagggcct ggaatggatt ggatacatca aatttagtgg gaacacctac 180tacaacccgt ccctcaggag tcgagtcacc atatcacttg acacgtctaa gaatcagttc 240tccctgaata tgacctctgt gactgccgcg gacacggccg tgtattattg tgcgagagca 300cctggaagtc ataactttga catctggggc caagggacaa tggtcaccgt ctcttca 357935119PRTArtificial SequenceSynthetic 935Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Gly 20 25 30 Gly Tyr Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Lys Phe Ser Gly Asn Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe65 70 75 80 Ser Leu Asn Met Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Gly Ser His Asn Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 936324DNAArtificial SequenceSynthetic 936gaaatcgtgt tgacccagtc tccagacacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtgt gagtattagt aataactatt tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag aagactggag 240tctgcagatt ttgcaccgta ttactgtcag caatatagta ggtcaccgat caccttcggc 300caagggacac gactggagat taaa 324937108PRTArtificial SequenceSynthetic 937Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Val Ser Ile Ser Asn Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu65 70 75 80 Ser Ala Asp Phe Ala Pro Tyr Tyr Cys Gln Gln Tyr Ser Arg Ser Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 938360DNAArtificial SequenceSynthetic 938gaagtgcagc tggtggagtc tgggggagcc ttggtacaac ctggggggtc cctgagactc 60tcctgtgcag cctctggatt cacctttaac aactttgcca tgacctgggt ccgccaggct 120ccagggaagg gcctggagtg ggtctcaact attagtggta gtggcgttga cacatactgc 180gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacactgtat 240ctgcaaatga acagcctgag agccgaggac acggccgtat attactgttc gaaagatggc 300gccttctata gtggctacga acactactgg ggccagggaa ccctggtcac cgtctcctca 360939120PRTArtificial SequenceSynthetic 939Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Gly1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Phe 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Val Asp Thr Tyr Cys Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Lys Asp Gly Ala Phe Tyr Ser Gly Tyr Glu His Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 940324DNAArtificial SequenceSynthetic 940gaaattgtgc tcacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatctat ggtacatcca acagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctcg gacgttcggc 300caagggacca aggtggagat caaa 324941108PRTArtificial SequenceSynthetic 941Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Thr Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 942357DNAArtificial SequenceSynthetic 942caggtgcagc

tggtgcagtc tggacctgag gtgaagaagc ctggggcctc agtgaaggtc 60tcctgcaagg cttctggtta cacctttacc tactatggta tcagttggat acgacagacc 120cctggacaag ggcttgagtg gatgggatgg atcagcgctt acgatggtaa cacagactat 180gcacagaagt tccaagacag aatcaccatg accacagaca catcctcgac cacagcctac 240atggaactga ggagcctgag atctgacgac acggccgtct attactgtgc gaggtatagt 300tggaacaagc actggttcga cccctggggc cagggaaccc tggtcaccgt ctcttca 357943119PRTArtificial SequenceSynthetic 943Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Tyr 20 25 30 Gly Ile Ser Trp Ile Arg Gln Thr Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asp Gly Asn Thr Asp Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Ile Thr Met Thr Thr Asp Thr Ser Ser Thr Thr Ala Tyr65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Tyr Ser Trp Asn Lys His Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 944324DNAArtificial SequenceSynthetic 944gaaattgtgt tgacacagtc tccaggcacc ctgtctttgt ctccagggga cagagccacc 60ctctcctgca gggccagtca gagtgttacc ggcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccagact cctcatctat ggtgcatcca acagggccac tggcatccca 180gacaggttca ctggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta tttctgtcaa cagtctgctt tctcaccgtg gacgttcggc 300caggggacca aggtggaaat caaa 324945108PRTArtificial SequenceSynthetic 945Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Gly Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Asp Arg Phe Thr 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ser Ala Phe Ser Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 946361DNAArtificial SequenceSynthetic 946caggtgcagt tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60acctgcactg tctctggtgg ctccatcggc agtggtggtt actactggag ctggatccgc 120cagcacccag ggaagggcct ggagtggatt gggtacgtcc attacagtgg gaacacccac 180tacaacccgt ccctcaagag tcgactttcc atatcaatag acacgtctaa gatccagttc 240tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagagcc 300ccccgtggat accattactt tgcctactgg ggccagggaa ccctggtcac cgtctcctca 360g 361947120PRTArtificial SequenceSynthetic 947Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Gly Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Val His Tyr Ser Gly Asn Thr His Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Ser Ile Ser Ile Asp Thr Ser Lys Ile Gln Phe65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Ala Pro Arg Gly Tyr His Tyr Phe Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 948325DNAArtificial SequenceSynthetic 948gaaattgtgt tgacacaatc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120cctggccagg ctcccaggct cctcatcttt ggtgcatcca gcagggccac tggcatccca 180gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccgct cactttcggc 300ggagggacca aggtggagat caaac 325949108PRTArtificial SequenceSynthetic 949Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Phe Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 950330PRTArtificial SequenceSynthetic 950Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 951327PRTArtificial SequenceSynthetic 951Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 952327PRTArtificial SequenceSynthetic 952Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr65 70 75 80 Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 100 105 110 Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 115 120 125 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 130 135 140 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp145 150 155 160 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 165 170 175 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 180 185 190 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 195 200 205 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 210 215 220 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys225 230 235 240 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 245 250 255 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 260 265 270 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 275 280 285 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 290 295 300 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser305 310 315 320 Leu Ser Leu Ser Leu Gly Lys 325 953544PRTHomo sapiens 953Met Gly Ser Arg Cys Ala Leu Ala Leu Ala Val Leu Ser Ala Leu Leu1 5 10 15 Cys Gln Val Trp Ser Ser Gly Val Phe Glu Leu Lys Leu Gln Glu Phe 20 25 30 Val Asn Lys Lys Gly Leu Leu Gly Asn Arg Asn Cys Cys Arg Gly Gly 35 40 45 Ala Gly Pro Pro Pro Cys Ala Cys Arg Thr Phe Phe Arg Val Cys Leu 50 55 60 Lys His Tyr Gln Ala Ser Val Ser Pro Glu Pro Pro Cys Thr Tyr Gly65 70 75 80 Ser Ala Val Thr Pro Val Leu Gly Val Asp Ser Phe Ser Leu Pro Asp 85 90 95 Gly Gly Gly Ala Asp Ser Ala Phe Ser Asn Pro Ile Arg Phe Pro Phe 100 105 110 Gly Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu Ala Leu His 115 120 125 Thr Asp Ser Pro Asp Asp Leu Ala Thr Glu Asn Pro Glu Arg Leu Ile 130 135 140 Ser Arg Leu Ala Thr Gln Arg His Leu Thr Val Gly Glu Glu Trp Ser145 150 155 160 Gln Asp Leu His Ser Ser Gly Arg Thr Asp Leu Lys Tyr Ser Tyr Arg 165 170 175 Phe Val Cys Asp Glu His Tyr Tyr Gly Glu Gly Cys Ser Val Phe Cys 180 185 190 Arg Pro Arg Asp Asp Ala Phe Gly His Phe Thr Cys Gly Glu Arg Gly 195 200 205 Glu Lys Val Cys Asn Pro Gly Trp Lys Gly Pro Tyr Cys Thr Glu Pro 210 215 220 Ile Cys Leu Pro Gly Cys Asp Glu Gln His Gly Phe Cys Asp Lys Pro225 230 235 240 Gly Glu Cys Lys Cys Arg Val Gly Trp Gln Gly Arg Tyr Cys Asp Glu 245 250 255 Cys Ile Arg Tyr Pro Gly Cys Leu His Gly Thr Cys Gln Gln Pro Trp 260 265 270 Gln Cys Asn Cys Gln Glu Gly Trp Gly Gly Leu Phe Cys Asn Gln Asp 275 280 285 Leu Asn Tyr Cys Thr His His Lys Pro Cys Lys Asn Gly Ala Thr Cys 290 295 300 Thr Asn Thr Gly Gln Gly Ser Tyr Thr Cys Ser Cys Arg Pro Gly Tyr305 310 315 320 Thr Gly Ala Thr Cys Glu Leu Gly Ile Asp Glu Cys Asp Pro Ser Pro 325 330 335 Cys Lys Asn Gly Gly Ser Cys Thr Asp Leu Glu Asn Ser Tyr Ser Cys 340 345 350 Thr Cys Pro Pro Gly Phe Tyr Gly Lys Ile Cys Glu Leu Ser Ala Met 355 360 365 Thr Cys Ala Asp Gly Pro Cys Phe Asn Gly Gly Arg Cys Ser Asp Ser 370 375 380 Pro Asp Gly Gly Tyr Ser Cys Arg Cys Pro Val Gly Tyr Ser Gly Phe385 390 395 400 Asn Cys Glu Lys Lys Ile Asp Tyr Cys Ser Ser Ser Pro Cys Ser Asn 405 410 415 Gly Ala Lys Cys Val Asp Leu Gly Asp Ala Tyr Leu Cys Arg Cys Gln 420 425 430 Ala Gly Phe Ser Gly Arg His Cys Asp Asp Asn Val Asp Asp Cys Ala 435 440 445 Ser Ser Pro Cys Ala Asn Gly Gly Thr Cys Arg Asp Gly Val Asn Asp 450 455 460 Phe Ser Cys Thr Cys Pro Pro Gly Tyr Thr Gly Arg Asn Cys Ser Ala465 470 475 480 Pro Val Ser Arg Cys Glu His Ala Pro Cys His Asn Gly Ala Thr Cys 485 490 495 His Glu Arg Gly His Arg Tyr Val Cys Glu Cys Ala Arg Gly Tyr Gly 500 505 510 Gly Pro Asn Cys Gln Phe Leu Leu Pro Glu Leu Pro Pro Gly Pro Ala 515 520 525 Val Val Asp Leu Thr Glu Lys Leu Glu Gly Gln Gly Gly Pro Phe Pro 530 535 540 954490PRTHomo sapiens 954Met Val Ser Pro Arg Met Ser Gly Leu Leu Ser Gln Thr Val Ile Leu1 5 10 15 Ala Leu Ile Phe Leu Pro Gln Thr Arg Pro Ala Gly Val Phe Glu Leu 20 25 30 Gln Ile His Ser Phe Gly Pro Gly Pro

Gly Pro Gly Ala Pro Arg Ser 35 40 45 Pro Cys Ser Ala Arg Leu Pro Cys Arg Leu Phe Phe Arg Val Cys Leu 50 55 60 Lys Pro Gly Leu Ser Glu Glu Ala Ala Glu Ser Pro Cys Ala Leu Gly65 70 75 80 Ala Ala Leu Ser Ala Arg Gly Pro Val Tyr Thr Glu Gln Pro Gly Ala 85 90 95 Pro Ala Pro Asp Leu Pro Leu Pro Asp Gly Leu Leu Gln Val Pro Phe 100 105 110 Arg Asp Ala Trp Pro Gly Thr Phe Ser Phe Ile Ile Glu Thr Trp Arg 115 120 125 Glu Glu Leu Gly Asp Gln Ile Gly Gly Pro Ala Trp Ser Leu Leu Ala 130 135 140 Arg Val Ala Gly Arg Arg Arg Leu Ala Ala Gly Gly Pro Trp Ala Arg145 150 155 160 Asp Ile Gln Arg Ala Gly Ala Trp Glu Leu Arg Phe Ser Tyr Arg Ala 165 170 175 Arg Cys Glu Pro Pro Ala Val Gly Thr Ala Cys Thr Arg Leu Cys Arg 180 185 190 Pro Arg Ser Ala Pro Ser Arg Cys Gly Pro Gly Leu Arg Pro Cys Ala 195 200 205 Pro Leu Glu Asp Glu Cys Glu Ala Pro Pro Val Cys Arg Ala Gly Cys 210 215 220 Ser Pro Glu His Gly Phe Cys Glu Gln Pro Gly Glu Cys Arg Cys Leu225 230 235 240 Glu Gly Trp Thr Gly Pro Leu Cys Thr Val Pro Val Ser Thr Ser Ser 245 250 255 Cys Leu Ser Pro Arg Gly Pro Ser Ser Ala Thr Thr Gly Cys Leu Val 260 265 270 Pro Gly Pro Gly Pro Cys Asp Gly Asn Pro Cys Ala Asn Gly Gly Ser 275 280 285 Cys Ser Glu Thr Pro Arg Ser Phe Glu Cys Thr Cys Pro Arg Gly Phe 290 295 300 Tyr Gly Leu Arg Cys Glu Val Ser Gly Val Thr Cys Ala Asp Gly Pro305 310 315 320 Cys Phe Asn Gly Gly Leu Cys Val Gly Gly Ala Asp Pro Asp Ser Ala 325 330 335 Tyr Ile Cys His Cys Pro Pro Gly Phe Gln Gly Ser Asn Cys Glu Lys 340 345 350 Arg Val Asp Arg Cys Ser Leu Gln Pro Cys Arg Asn Gly Gly Leu Cys 355 360 365 Leu Asp Leu Gly His Ala Leu Arg Cys Arg Cys Arg Ala Gly Phe Ala 370 375 380 Gly Pro Arg Cys Glu His Asp Leu Asp Asp Cys Ala Gly Arg Ala Cys385 390 395 400 Ala Asn Gly Gly Thr Cys Val Glu Gly Gly Gly Ala His Arg Cys Ser 405 410 415 Cys Ala Leu Gly Phe Gly Gly Arg Asp Cys Arg Glu Arg Ala Asp Pro 420 425 430 Cys Ala Ala Arg Pro Cys Ala His Gly Gly Arg Cys Tyr Ala His Phe 435 440 445 Ser Gly Leu Val Cys Ala Cys Ala Pro Gly Tyr Met Gly Ala Arg Cys 450 455 460 Glu Phe Pro Val His Pro Asp Gly Ala Ser Ala Leu Pro Ala Ala Pro465 470 475 480 Pro Gly Leu Arg Pro Gly Asp Pro Gln Arg 485 490 955527PRTMus musculus 955Met Thr Pro Ala Ser Arg Ser Ala Cys Arg Trp Ala Leu Leu Leu Leu1 5 10 15 Ala Val Leu Trp Pro Gln Gln Arg Ala Ala Gly Ser Gly Ile Phe Gln 20 25 30 Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly Met Leu Ala Asn Gly 35 40 45 Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Ile Cys Leu Lys 50 55 60 His Phe Gln Ala Thr Phe Ser Glu Gly Pro Cys Thr Phe Gly Asn Val65 70 75 80 Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Val Val Arg Asp Lys Asn 85 90 95 Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp 100 105 110 Pro Gly Thr Phe Ser Leu Asn Ile Gln Ala Trp His Thr Pro Gly Asp 115 120 125 Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser Leu Ile Ser Gln Ile 130 135 140 Ile Ile Gln Gly Ser Leu Ala Val Gly Lys Ile Trp Arg Thr Asp Glu145 150 155 160 Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser Tyr Arg Val Ile Cys 165 170 175 Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser Arg Leu Cys Lys Lys Arg 180 185 190 Asp Asp His Phe Gly His Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser 195 200 205 Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp Gln Pro Ile Cys Leu 210 215 220 Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Asp Glu Cys225 230 235 240 Ile Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys Ile Pro 245 250 255 His Asn Gly Cys Arg His Gly Thr Cys Ser Ile Pro Trp Gln Cys Ala 260 265 270 Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr 275 280 285 Cys Thr His His Ser Pro Cys Lys Asn Gly Ser Thr Cys Ser Asn Ser 290 295 300 Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu305 310 315 320 His Cys Glu Leu Gly Leu Ser Lys Cys Ala Ser Asn Pro Cys Arg Asn 325 330 335 Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr His Cys Leu Cys Pro 340 345 350 Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser Thr Leu Thr Cys Ala 355 360 365 Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly 370 375 380 Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys385 390 395 400 Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Ala Asn Gly Gly 405 410 415 Gln Cys Gln Asn Arg Gly Pro Ser Arg Thr Cys Arg Cys Arg Pro Gly 420 425 430 Phe Thr Gly Thr His Cys Glu Leu His Ile Ser Asp Cys Ala Arg Ser 435 440 445 Pro Cys Ala His Gly Gly Thr Cys His Asp Leu Glu Asn Gly Pro Val 450 455 460 Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg Cys Glu Val Arg Ile465 470 475 480 Thr His Asp Ala Cys Ala Ser Gly Pro Cys Phe Asn Gly Ala Thr Cys 485 490 495 Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly 500 505 510 Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser 515 520 525 956498PRTMacaca fascicularis 956Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe Val Asn Glu Arg Gly1 5 10 15 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Ser Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu Ala Trp 85 90 95 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 Leu Ile Ser Lys Ile Ala Ile Gln Gly Ser Leu Ala Val Gly Gln Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val Ile Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro Ile Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys Ile Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr225 230 235 240 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Ala Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Ala Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Arg His Val Ser 405 410 415 Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Ser Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe 450 455 460 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Met Gly 485 490 495 Leu Pro957498PRTMacaca mulatta 957Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe Val Asn Glu Arg Gly1 5 10 15 Val Leu Ala Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Ala Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Ser Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala 50 55 60 Val Arg Asp Asp Ser Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Ile Ile Glu Ala Trp 85 90 95 His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro Pro Asp Ala 100 105 110 Leu Ile Ser Lys Ile Ala Ile Gln Gly Ser Leu Ala Val Gly Gln Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val Ile Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro Ile Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Ala Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys Ile Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr225 230 235 240 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 Thr Leu Ser Cys Ala Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Ala Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Ala Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Arg His Val Ser 405 410 415 Asp Cys Ala Arg Asn Pro Cys Ala His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Ser Gly Leu Met Cys Thr Cys Pro Ala Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser Ile Asp Ala Cys Ala Ser Ser Pro Cys Phe 450 455 460 Asn Arg Ala Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro

Claims

1.-16. (canceled)

17. A method for inhibiting the activity of delta-like ligand 4 (Dll4) in a cell, comprising contacting the cell with an antibody or fragment thereof that specifically binds human delta-like ligand 4 (Dll4), wherein the antibody or fragment thereof comprises a heavy chain variable region (HCVR) comprising heavy chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:431, 433 and 435, respectively, or a light chain variable region (LCVR) comprising light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:439, 441 and 443, respectively, thereby inhibiting the activity of delta-like ligand 4 (Dll4) in the cell.

18. The method of claim 17, wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901.

19. The method of claim 17, wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903.

20. The method of claim 17, wherein the antibody or fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:431, 433 and 435, respectively, and light chain CDR1, CDR2 and CDR3 sequences of SEQ ID NOS:439, 441 and 443, respectively.

21. The method of claim 17, wherein the antibody or fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:429 or 901.

22. The method of claim 17, wherein the antibody or fragment thereof comprises a LCVR comprising the amino acid sequence of SEQ ID NO:437 or 903.

23. The method of claim 17, wherein the Dll4 activity is binding of Dll4 to a Notch receptor.

24. The method of claim 23, wherein the Notch receptor is the Notch 1 receptor.

25. The method of claim 17, wherein the Dll4 activity is Notch 1 cleavage.

26. The method of claim 17, wherein the Dll4 activity is hHes1 and EphB2 gene expression.

27. The method of claim 17, wherein the cell is contacted in vitro.

28. The method of claim 17, wherein the cell is contacted in vivo.

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