18 The two TMDs contain specific sites for substrate binding and translocation, whereas the two NBDs, which display a high degree of sequence similarity with the equivalent domain of ABC transporters, couple the energy obtained from ATP hydrolysis to substrate transport.8 The ICDs are deemed to be involved in mediating the coupling between NBD conformational changes and the reorientation of TM helices concomitant with substrate extrusion.9 The ABCB1 gene, one of the most extensively studied ABC transporters, is responsible for the human multidrug resistance phenotype that is a rapidly growing obstacle to the treatment of numerous infectious diseases, including human immunodeficiency10 and malaria.11 The properties of this transporter are also exploited in cancer pharmacological therapy where ABCB1 translocates the chemotherapeutic drugs and other molecules with a broad but defined specificity.12 A gene duplication of ABCB1 and additional mutations selected as advantageous have created in mammals the T715I G723E L724AfsX744 A737V G954S G762X T775M G126E S320F A840D OUT IN Linker region F357L L701P A364V NBD-NH2 terminal NBD-COOH terminal A1193T NH2 COOH 1 2 54 6 7 8 129 11 10 EC2EC1 ICD2 A250P Y279X A286V ICD1 R159X T175A ICD3 EC3 EC4 EC6EC5 ICD4 ICD6 ICD5 E888X Y403H V475A A511T E558K R590Q T593A M630V 3 S379KfsX413 P726T Figure 1 (a) Localization of the 29 mutations identified in this study in the ABCB4 protein, schematically represented in its domains.

X

ABCB1 p.Ala250Pro 17726488:18:1203

status: NEW

Login to comment
110 Apart M630, located in the NBD, the remaining mutations involve either the helical loops (A250, A286, F357, A364) or TM segments (G126, P726, A840, G954; Figure 1b); the ...122_GLGAGVLVA_130... ...434_GLGAGVLVA_442... ...119_GLGGGVLVA_127... ...119_GLGGGVLLA_127... ...276_GLGAGVLVA_284... ...10_GLGGGVLIA_18.... ...120_GIGAGVLVA_128... ....73_GLMILRGIT_81.... ....73_GLMILRGIT_81.... ....73_GLMFVRGLS_81.... ...69_IFVIVRPPI_77.... Hs_ABCB4 Pt_ABCB4 Mm_ABCB4 Rn_ABCB4 Bt_ABCB4 Md_ABCB4 Hs_ABCB1 Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 246_LAAYAKAGA_254... 558_LAAYAKAGA_566... 243_LAAYAKAGA_251... 243_LAAYAKAGA_251... 400_LAAYAKAGA_408... 134_LAAYAKAGA_142... 244_LLAYAKAGA_252... 197_QNTMGQVTT_205... 197_QNTMGQVTT_205... 197_QTAMGHVTS_205... 193_SQALAEVQG_201... 282_HLENAKEIG_290... 594_HLENAKEIG_602... 279_HLENAKKIG_287... 279_HLENAKKIG_287... 436_HLENAKRIG_444... 170_HLENAKKIG_178... 280_NLEEAKRIG_288... 233_VSNRMRLQG_241... 233_VSNKMRLQG_241... 233_VSNSMRQQT_241... 229_KNTNFLTRA_237... 353_CIDAFANARGAAYVIF_368.... 665_CIDAFANARGAAYVIF_680.... 350_CIDAFANARGAAYVIF_365.... 350_CIDAFPNARGAAYVIF_365.... 507_CIDAFANARGAAYAIF_522.... 241_CIDSFANARGAAYAIF_256.... 351_SIEAFANARGAAYEIF_366.... 304_VNAQFQRGMAACQTLF_319.... 304_VNAQFQRGMAACQTLF_319.... 304_VTSEFQRGMAACQTLF_319.... 300_SFTTLTQSFASMDRVF_315.... G126E A250P A286V F357L A364V 399_VHFSYPSRA_407.... 711_VHFSYPSRA_719.... 396_VHFSYPSRA_404.... 396_VHFSYPSRA_404.... 553_VHFSYPARP_561.... 287_VHFSYPSRA_295.... 397_VHFSYPSRK_405.... 347_VTFTYPGR-_354.... 347_VTFTYPGR-_354.... 347_VTFTYQGK-_354.... 345_VSFQYNDN-_352.... 471_IIGVVSQEP_479.... 783_IIGVVSQEP_791.... 468_IIGVVSQEP_476.... 468_FIGVVSQEP_476.... 625_IIGVVSQEP_633.... 359_IIGVVSQEP_367.... 469_IIGVVSQEP_477.... 418_QVALVSQNV_426.... 418_QVALVSQNV_426.... 418_HFALVSQNV_426.... 416_QIGLVQQDN_424.... V475A Hs_ABCB4 Pt_ABCB4 Mm_ABCB4 Rn_ABCB4 Bt_ABCB4 Md_ABCB4 Hs_ABCB1 Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 ...507_KEANAYEFI_515... ...819_KEANAYEFI_827... ...504_KEANAYDFI_512... ...504_KEANAYDFI_512... ...661_KEANAYEFI_669... ...395_KDANAYEFI_403... ...505_KEANAYDFI_513... ...455_RMAYAMDFI_463... ...455_RMAYAMDFI_463... ...455_RQAHAMEFI_463... ..452_KMANAHDFI_460... A511T 554_LLLDEATSA_562... 866_LLLDEATSA_874... 551_LLLDEATSA_559... 551_LLLDEATSA_559... 708_LLLDEATSA_716... 442_LLLDEATSA_450... 552_LLLDEATSA_560... 502_LILDEATSA_510... 502_LILDEATSA_510... 502_LILDEATSA_510... 499_LILDEATSA_507... E558K 586_VIAHRLSTVRNA_597... 898_VIAHRLSTVRNA_909... 583_VIAHRLSTIRNA_594... 583_VIAHRLSTVRNA_594... 740_VIAHRLSTIRNA_751... 474_VIAHRLSTIRNA_485... 584_VIAHRLSTVRNA_595... 534_VIAHRLSTIEKA_545... 534_VIAHRLSTIEQA_545... 534_VIAHRLSTIEQA_545... 531_IVAHRLSTITHA_542... 626_KLVNMQTSG_634.. 938_KLVNMQTSG_946.. 623_RLVNMQTAG_631.. 623_RLVNMQTSG_631.. 780_RLVNTQISG_788.. 514_KLVNMQYIF_522... 624_KLVTMQTAG_632.. 574_QLHKMQFGQ_582.. 574_QLHKMQFGQ_582.. 574_QLHRIQFGE_582.. 570_HLYSIQN--_576.. 697_FLKVLKLNKTEWPYFVVGTVCAIANGGLQPAFSVIFSEIIAIF_739.

X

ABCB1 p.Ala250Pro 17726488:110:1344

status: NEW

Login to comment