ID MDR3_HUMAN Reviewed; 1286 AA. AC P21439; A0A2V7; A4D1D3; A4D1D4; A4D1D5; D6W5P3; D6W5P4; Q14813; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 20-FEB-2007, sequence version 2. DT 11-NOV-2015, entry version 163. DE RecName: Full=Phosphatidylcholine translocator ABCB4 {ECO:0000305}; DE AltName: Full=ATP-binding cassette sub-family B member 4 {ECO:0000312|HGNC:HGNC:45}; DE AltName: Full=Multidrug resistance protein 3 {ECO:0000303|PubMed:2892668}; DE EC=3.6.3.44; DE AltName: Full=P-glycoprotein 3 {ECO:0000250|UniProtKB:Q08201}; GN Name=ABCB4 {ECO:0000312|HGNC:HGNC:45}; GN Synonyms=MDR3 {ECO:0000303|PubMed:2892668}, PGY3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RX PubMed=2906314; DOI=10.1016/0378-1119(88)90057-1; RA van der Bliek A.M., Kooiman P.M., Schneider C., Borst P.; RT "Sequence of mdr3 cDNA encoding a human P-glycoprotein."; RL Gene 71:401-411(1988). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GBD1 ASP-528, AND VARIANTS RP VAL-238; VAL-263; GLN-590; ASN-651; GLY-652 AND GLN-788. RG NIEHS SNPs program; RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., RA Waterston R.H., Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., RA Mural R.J., Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-72 (ISOFORM 1). RC TISSUE=Liver; RX PubMed=7893760; DOI=10.1016/0167-4781(94)00214-N; RA Smit J.J., Mol C.A., van Deemter L., Wagenaar E., Schinkel A.H., RA Borst P.; RT "Characterization of the promoter region of the human MDR3 P- RT glycoprotein gene."; RL Biochim. Biophys. Acta 1261:44-56(1995). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 856-1286 (ISOFORM 1), AND ALTERNATIVE RP SPLICING. RX PubMed=2892668; RA van der Bliek A.M., Baas F., ten Houte de Lange T., Kooiman P.M., RA van der Velde-Koerts T., Borst P.; RT "The human mdr3 gene encodes a novel P-glycoprotein homologue and RT gives rise to alternatively spliced mRNAs in liver."; RL EMBO J. 6:3325-3331(1987). RN [8] RP GENE STRUCTURE. RX PubMed=2002063; RA Lincke C.R., Smit J.J.M., van der Velde-Koerts T., Borst P.; RT "Structure of the human MDR3 gene and physical mapping of the human RT MDR locus."; RL J. Biol. Chem. 266:5303-5310(1991). RN [9] RP FUNCTION. RX PubMed=7957936; DOI=10.1016/0014-5793(94)01135-4; RA Smith A.J., Timmermans-Hereijgers J.L., Roelofsen B., Wirtz K.W., RA van Blitterswijk W.J., Smit J.J., Schinkel A.H., Borst P.; RT "The human MDR3 P-glycoprotein promotes translocation of RT phosphatidylcholine through the plasma membrane of fibroblasts from RT transgenic mice."; RL FEBS Lett. 354:263-266(1994). RN [10] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=8898203; DOI=10.1016/S0092-8674(00)81370-7; RA van Helvoort A., Smith A.J., Sprong H., Fritzsche I., Schinkel A.H., RA Borst P., van Meer G.; RT "MDR1 P-glycoprotein is a lipid translocase of broad specificity, RT while MDR3 P-glycoprotein specifically translocates RT phosphatidylcholine."; RL Cell 87:507-517(1996). RN [11] RP FUNCTION. RX PubMed=9366571; DOI=10.1172/JCI119799; RA Crawford A.R., Smith A.J., Hatch V.C., Oude Elferink R.P., Borst P., RA Crawford J.M.; RT "Hepatic secretion of phospholipid vesicles in the mouse critically RT depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by RT electron microscopy."; RL J. Clin. Invest. 100:2562-2567(1997). RN [12] RP INVOLVEMENT IN PFIC3. RX PubMed=9419367; DOI=10.1073/pnas.95.1.282; RA de Vree J.M.L., Jacquemin E., Sturm E., Cresteil D., Bosma P.J., RA Aten J., Deleuze J.-F., Desrochers M., Burdelski M., Bernard O., RA Oude Elferink R.P.J., Hadchouel M.; RT "Mutations in the MDR3 gene cause progressive familial intrahepatic RT cholestasis."; RL Proc. Natl. Acad. Sci. U.S.A. 95:282-287(1998). RN [13] RP SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=15258199; DOI=10.1194/jlr.M400132-JLR200; RA Shoda J., Inada Y., Tsuji A., Kusama H., Ueda T., Ikegami T., RA Suzuki H., Sugiyama Y., Cohen D.E., Tanaka N.; RT "Bezafibrate stimulates canalicular localization of NBD-labeled PC in RT HepG2 cells by PPARalpha-mediated redistribution of ABCB4."; RL J. Lipid Res. 45:1813-1825(2004). RN [14] RP FUNCTION, ENZYME REGULATION, GLYCOSYLATION, AND MUTAGENESIS OF LYS-435 RP AND LYS-1075. RX PubMed=17523162; DOI=10.1002/hep.21591; RA Morita S.Y., Kobayashi A., Takanezawa Y., Kioka N., Handa T., Arai H., RA Matsuo M., Ueda K.; RT "Bile salt-dependent efflux of cellular phospholipids mediated by ATP RT binding cassette protein B4."; RL Hepatology 46:188-199(2007). RN [15] RP INTERACTION WITH GNB2L1, AND SUBCELLULAR LOCATION. RX PubMed=19674157; DOI=10.1111/j.1872-034X.2009.00544.x; RA Ikebuchi Y., Takada T., Ito K., Yoshikado T., Anzai N., Kanai Y., RA Suzuki H.; RT "Receptor for activated C-kinase 1 regulates the cellular localization RT and function of ABCB4."; RL Hepatol. Res. 39:1091-1107(2009). RN [16] RP FUNCTION, GLYCOSYLATION, AND SUBCELLULAR LOCATION. RX PubMed=21820390; DOI=10.1053/j.gastro.2011.07.042; RA Groen A., Romero M.R., Kunne C., Hoosdally S.J., Dixon P.H., RA Wooding C., Williamson C., Seppen J., Van den Oever K., Mok K.S., RA Paulusma C.C., Linton K.J., Oude Elferink R.P.; RT "Complementary functions of the flippase ATP8B1 and the floppase ABCB4 RT in maintaining canalicular membrane integrity."; RL Gastroenterology 141:1927-1937(2011). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, AND ENZYME REGULATION. RX PubMed=23468132; DOI=10.1194/jlr.M032425; RA Morita S.Y., Tsuda T., Horikami M., Teraoka R., Kitagawa S., RA Terada T.; RT "Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized RT in nonraft membranes."; RL J. Lipid Res. 54:1221-1230(2013). RN [18] RP SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=24122873; DOI=10.1002/hep.26894; RA Ghonem N.S., Ananthanarayanan M., Soroka C.J., Boyer J.L.; RT "Peroxisome proliferator-activated receptor alpha activates human RT multidrug resistance transporter 3/ATP-binding cassette protein RT subfamily B4 transcription and increases rat biliary RT phosphatidylcholine secretion."; RL Hepatology 59:1030-1042(2014). RN [19] RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS PFIC3 RP VAL-286 AND PHE-320, AND MUTAGENESIS OF ALA-953. RX PubMed=24806754; DOI=10.1002/hep.26970; RA Andress E.J., Nicolaou M., Romero M.R., Naik S., Dixon P.H., RA Williamson C., Linton K.J.; RT "Molecular mechanistic explanation for the spectrum of cholestatic RT disease caused by the S320F variant of ABCB4."; RL Hepatology 59:1921-1931(2014). RN [20] RP VARIANT ICP3 ASP-546, AND CHARACTERIZATION OF VARIANT ICP3 ASP-546. RX PubMed=10767346; DOI=10.1093/hmg/9.8.1209; RA Dixon P.H., Weerasekera N., Linton K.J., Donaldson O., Chambers J., RA Egginton E., Weaver J., Nelson-Piercy C., de Swiet M., Warnes G., RA Elias E., Higgins C.F., Johnston D.G., McCarthy M.I., Williamson C.; RT "Heterozygous MDR3 missense mutation associated with intrahepatic RT cholestasis of pregnancy: evidence for a defect in protein RT trafficking."; RL Hum. Mol. Genet. 9:1209-1217(2000). RN [21] RP VARIANTS PFIC3 ARG-138; ILE-346; GLY-395; ALA-424; MET-425; PHE-541; RP ARG-556; GLY-564; SER-711 AND SER-983, AND VARIANT GLY-652. RX PubMed=11313315; DOI=10.1053/gast.2001.23984; RA Jacquemin E., De Vree J.M.L., Cresteil D., Sokal E.M., Sturm E., RA Dumont M., Scheffer G.L., Paul M., Burdelski M., Bosma P.J., RA Bernard O., Hadchouel M., Elferink R.P.; RT "The wide spectrum of multidrug resistance 3 deficiency: from neonatal RT cholestasis to cirrhosis of adulthood."; RL Gastroenterology 120:1448-1458(2001). RN [22] RP VARIANTS GBD1 PHE-320 AND SER-1168, AND VARIANT ALA-175. RX PubMed=11313316; DOI=10.1053/gast.2001.23947; RA Rosmorduc O., Hermelin B., Poupon R.; RT "MDR3 gene defect in adults with symptomatic intrahepatic and RT gallbladder cholesterol cholelithiasis."; RL Gastroenterology 120:1459-1467(2001). RN [23] RP VARIANT PFIC3 ASP-535. RX PubMed=12671900; DOI=10.1053/gast.2003.50144; RA Lucena J.-F., Herrero J.I., Quiroga J., Sangro B., RA Garcia-Foncillas J., Zabalegui N., Sola J., Herraiz M., Medina J.F., RA Prieto J.; RT "A multidrug resistance 3 gene mutation causing cholelithiasis, RT cholestasis of pregnancy, and adulthood biliary cirrhosis."; RL Gastroenterology 124:1037-1042(2003). RN [24] RP VARIANTS GBD1 ILE-165; THR-301; PHE-320; ASP-528; GLN-591 AND RP SER-1168, AND VARIANTS ALA-175; GLN-590; GLY-652; SER-742; GLN-788 AND RP THR-934. RX PubMed=12891548; DOI=10.1016/S0016-5085(03)00898-9; RA Rosmorduc O., Hermelin B., Boelle P.Y., Parc R., Taboury J., RA Poupon R.; RT "ABCB4 gene mutation-associated cholelithiasis in adults."; RL Gastroenterology 125:452-459(2003). RN [25] RP VARIANT ICP3 LYS-150, AND VARIANT GLY-652. RX PubMed=12746424; DOI=10.1136/jmg.40.5.e70; RA Muellenbach R., Linton K.J., Wiltshire S., Weerasekera N., RA Chambers J., Elias E., Higgins C.F., Johnston D.G., McCarthy M.I., RA Williamson C.; RT "ABCB4 gene sequence variation in women with intrahepatic cholestasis RT of pregnancy."; RL J. Med. Genet. 40:E70-E70(2003). RN [26] RP VARIANTS ALA-175; GLY-652 AND MET-775, AND VARIANTS ICP3 PHE-320; RP ASP-528 AND GLU-762. RX PubMed=15077010; DOI=10.1097/00008571-200402000-00003; RA Pauli-Magnus C., Lang T., Meier Y., Zodan-Marin T., Jung D., RA Breymann C., Zimmermann R., Kenngott S., Beuers U., Reichel C., RA Kerb R., Penger A., Meier P.J., Kullak-Ublick G.A.; RT "Sequence analysis of bile salt export pump (ABCB11) and multidrug RT resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with RT intrahepatic cholestasis of pregnancy."; RL Pharmacogenetics 14:91-102(2004). RN [27] RP VARIANTS GLU-87; SER-95; ALA-175; VAL-367; GLY-450; GLN-590 AND RP GLY-652. RX PubMed=16763017; DOI=10.1124/dmd.105.008854; RA Lang T., Haberl M., Jung D., Drescher A., Schlagenhaufer R., Keil A., RA Mornhinweg E., Stieger B., Kullak-Ublick G.A., Kerb R.; RT "Genetic variability, haplotype structures, and ethnic diversity of RT hepatic transporters MDR3 (ABCB4) and bile salt export pump RT (ABCB11)."; RL Drug Metab. Dispos. 34:1582-1599(2006). RN [28] RP VARIANTS PFIC3 GLU-126; PRO-250; VAL-286; PHE-320; LEU-357; VAL-364; RP HIS-403; ALA-475; THR-511; LYS-558; ALA-593; VAL-630; PRO-701; RP ILE-715; GLU-723; THR-726; VAL-737; ASP-840; SER-954 AND THR-1193, AND RP VARIANTS ALA-175; GLN-590 AND MET-775. RX PubMed=17726488; DOI=10.1038/sj.ejhg.5201908; RA Degiorgio D., Colombo C., Seia M., Porcaro L., Costantino L., RA Zazzeron L., Bordo D., Coviello D.A.; RT "Molecular characterization and structural implications of 25 new RT ABCB4 mutations in progressive familial intrahepatic cholestasis type RT 3 (PFIC3)."; RL Eur. J. Hum. Genet. 15:1230-1238(2007). RN [29] RP VARIANTS ALA-175; GLN-590; GLY-652; LEU-764 AND GLN-1082. RX PubMed=17264802; DOI=10.1097/01.fpc.0000230418.28091.76; RA Lang C., Meier Y., Stieger B., Beuers U., Lang T., Kerb R., RA Kullak-Ublick G.A., Meier P.J., Pauli-Magnus C.; RT "Mutations and polymorphisms in the bile salt export pump and the RT multidrug resistance protein 3 associated with drug-induced liver RT injury."; RL Pharmacogenet. Genomics 17:47-60(2007). RN [30] RP VARIANTS GLN-590 AND GLY-652. RX PubMed=19261551; DOI=10.1016/j.dld.2008.12.101; RA Tavian D., Degiorgio D., Roncaglia N., Vergani P., Cameroni I., RA Colombo R., Coviello D.A.; RT "A new splicing site mutation of the ABCB4 gene in intrahepatic RT cholestasis of pregnancy with raised serum gamma-GT."; RL Dig. Liver Dis. 41:671-675(2009). RN [31] RP VARIANTS PFIC3 ARG-70; VAL-73; PHE-320 AND HIS-403, AND VARIANT RP GLY-652. RX PubMed=21119540; DOI=10.1097/MPG.0b013e3181f50363; RA Colombo C., Vajro P., Degiorgio D., Coviello D.A., Costantino L., RA Tornillo L., Motta V., Consonni D., Maggiore G., Balli F., Berardi S., RA Calacoci M., Castellano E., Marazzi M.G., Gaslini G., D'Antiga L., RA Ferretti E., Giannini A., Indolfi G., Iorio R., Martelossi S., RA Moretti C., Nebbia G., Oliveri F., Poggiani C., Raggi M., Riva S., RA Sciveres M., Torre G., Zancan L.; RT "Clinical features and genotype-phenotype correlations in children RT with progressive familial intrahepatic cholestasis type 3 related to RT ABCB4 mutations."; RL J. Pediatr. Gastroenterol. Nutr. 52:73-83(2011). RN [32] RP VARIANTS GBD1 MET-34; GLY-47; VAL-286 AND ASP-528, AND VARIANTS RP GLN-47; ALA-175; PHE-320; GLN-406; MET-775 AND THR-964. RX PubMed=22331132; DOI=10.1007/s00428-012-1202-6; RA Wendum D., Barbu V., Rosmorduc O., Arrive L., Flejou J.F., Poupon R.; RT "Aspects of liver pathology in adult patients with MDR3/ABCB4 gene RT mutations."; RL Virchows Arch. 460:291-298(2012). RN [33] RP VARIANTS GBD1 GLY-47; HIS-71; VAL-73; CYS-78; PHE-99; SER-124; RP SER-154; ILE-165; VAL-286; THR-301; PHE-320; GLY-406; SER-510; RP THR-511; LYS-513; ASP-528; PHE-541; HIS-545; HIS-549; THR-589; RP GLN-591; MET-593; LYS-647; LEU-726; LEU-729; VAL-975 AND TRP-1084, AND RP VARIANTS ALA-175; GLN-590; GLN-788 AND THR-934. RX PubMed=23533021; DOI=10.1002/hep.26424; RA Poupon R., Rosmorduc O., Boelle P.Y., Chretien Y., Corpechot C., RA Chazouilleres O., Housset C., Barbu V.; RT "Genotype-phenotype relationships in the low-phospholipid-associated RT cholelithiasis syndrome: a study of 156 consecutive patients."; RL Hepatology 58:1105-1110(2013). RN [34] RP VARIANT PFIC3 ARG-481, CHARACTERIZATION OF VARIANTS PFIC3 HIS-403 AND RP ARG-481, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24045840; DOI=10.1038/ejhg.2013.214; RA Degiorgio D., Corsetto P.A., Rizzo A.M., Colombo C., Seia M., RA Costantino L., Montorfano G., Tomaiuolo R., Bordo D., Sansanelli S., RA Li M., Tavian D., Rastaldi M.P., Coviello D.A.; RT "Two ABCB4 point mutations of strategic NBD-motifs do not prevent RT protein targeting to the plasma membrane but promote MDR3 RT dysfunction."; RL Eur. J. Hum. Genet. 22:633-639(2014). RN [35] RP VARIANTS GBD1 MET-34 AND GLY-47, CHARACTERIZATION OF VARIANTS GBD1 RP MET-34 AND GLY-47, FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT RP THR-34, GLYCOSYLATION, MUTAGENESIS OF THR-34; THR-44 AND SER-49, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=24723470; DOI=10.1002/hep.27170; RA Gautherot J., Delautier D., Maubert M.A., Ait-Slimane T., Bolbach G., RA Delaunay J.L., Durand-Schneider A.M., Firrincieli D., Barbu V., RA Chignard N., Housset C., Maurice M., Falguieres T.; RT "Phosphorylation of ABCB4 impacts its function: insights from disease- RT causing mutations."; RL Hepatology 60:610-621(2014). RN [36] RP VARIANTS PFIC3 ARG-68; MET-201; HIS-459; LEU-479; PRO-978 AND RP LYS-1125, CHARACTERIZATION OF VARIANTS PFIC3 ARG-68; MET-201; HIS-459; RP LEU-479; PRO-978 AND LYS-1125, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24594635; DOI=10.1136/gutjnl-2014-306896; RA Gordo-Gilart R., Andueza S., Hierro L., Martinez-Fernandez P., RA D'Agostino D., Jara P., Alvarez L.; RT "Functional analysis of ABCB4 mutations relates clinical outcomes of RT progressive familial intrahepatic cholestasis type 3 to the degree of RT MDR3 floppase activity."; RL Gut 64:147-155(2015). CC -!- FUNCTION: Energy-dependent phospholipid efflux translocator that CC acts as a positive regulator of biliary lipid secretion. Functions CC as a floppase that translocates specifically phosphatidylcholine CC (PC) from the inner to the outer leaflet of the canalicular CC membrane bilayer into the canaliculi of hepatocytes. Translocation CC of PC makes the biliary phospholipids available for extraction CC into the canaliculi lumen by bile salt mixed micelles and CC therefore protects the biliary tree from the detergent activity of CC bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, CC PubMed:17523162, PubMed:23468132, PubMed:24806754, CC PubMed:24723470, PubMed:24594635, PubMed:21820390). Plays a role CC in the recruitment of phosphatidylcholine (PC), CC phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to CC nonraft membranes and to fu rther enrichment of SM and cholesterol CC in raft membranes in hepatocytes (PubMed:23468132). Required for CC proper phospholipid bile formation (By similarity). Indirectly CC involved in cholesterol efflux activity from hepatocytes into the CC canalicular lumen in the presence of bile salts in an ATP- CC dependent manner (PubMed:24045840). May promote biliary CC phospholipid secretion as canaliculi-containing vesicles from the CC canalicular plasma membrane (PubMed:9366571). In cooperation with CC ATP8B1, functions to protect hepatocytes from the deleterious CC detergent activity of bile salts (PubMed:21820390). Does not CC confer multidrug resistance (By similarity). CC {ECO:0000250|UniProtKB:P21440, ECO:0000269|PubMed:17523162, CC ECO:0000269|PubMed:21820390, ECO:0000269|PubMed:23468132, CC ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, CC ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:24806754, CC ECO:0000269|PubMed:7957936, ECO:0000269|PubMed:8898203, CC ECO:0000269|PubMed:9366571}. CC -!- CATALYTIC ACTIVITY: ATP + H(2)O + xenobiotic(In) = ADP + phosphate CC + xenobiotic(Out). CC -!- ENZYME REGULATION: Translocation activity is inhibited by the CC ATPase inhibitor vanadate and the calcium channel blocker CC verapamil (PubMed:17523162, PubMed:23468132). Translocation CC activity is enhanced by the addition of the bile salt taurocholate CC (PubMed:17523162, PubMed:23468132). {ECO:0000269|PubMed:17523162, CC ECO:0000269|PubMed:23468132}. CC -!- SUBUNIT: May interact with GNB2L1 (PubMed:19674157). Interacts CC with HAX1 (By similarity). {ECO:0000250|UniProtKB:Q08201, CC ECO:0000269|PubMed:19674157}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23468132, CC ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24806754}; Multi- CC pass membrane protein {ECO:0000255|PROSITE-ProRule:PRU00441}. CC Apical cell membrane {ECO:0000269|PubMed:15258199, CC ECO:0000269|PubMed:19674157, ECO:0000269|PubMed:21820390, CC ECO:0000269|PubMed:24122873, ECO:0000269|PubMed:24594635, CC ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:8898203}; Multi- CC pass membrane protein {ECO:0000255|PROSITE-ProRule:PRU00441}. CC Membrane raft {ECO:0000269|PubMed:23468132}. Cytoplasm CC {ECO:0000269|PubMed:24045840}. Cytoplasmic vesicle, clathrin- CC coated vesicle {ECO:0000250|UniProtKB:Q08201}. Note=Localized at CC the apical canalicular membrane of the epithelial cells lining the CC lumen of the bile canaliculi and biliary ductules (By similarity). CC Transported from the Golgi to the apical bile canalicular membrane CC in a GNB2L1-dependent manner (PubMed:19674157). Redistributed into CC pseudocanaliculi formed between cells in a bezafibrate- or PPARA- CC dependent manner (PubMed:15258199). Localized preferentially in CC lipid nonraft domains of canalicular plasma membranes CC (PubMed:23468132). {ECO:0000250|UniProtKB:P21440, CC ECO:0000269|PubMed:15258199, ECO:0000269|PubMed:19674157, CC ECO:0000269|PubMed:23468132}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P21439-1; Sequence=Displayed; CC Name=2; CC IsoId=P21439-2; Sequence=VSP_023263; CC Name=3; CC IsoId=P21439-3; Sequence=VSP_046258, VSP_023263; CC Note=No experimental confirmation available. Gene prediction CC based on EST data.; CC -!- INDUCTION: Up-regulated by PPARA (PubMed:24122873). Up-regulated CC by compounds that cause peroxisome proliferation, such as CC fenofibrate (at protein level). Up-regulated by bezafibrate CC (PubMed:15258199). Up-regulated by compounds that cause peroxisome CC proliferation, such as fenofibrate, bezafibrate and gemfibrozil CC (PubMed:24122873). {ECO:0000269|PubMed:15258199, CC ECO:0000269|PubMed:24122873}. CC -!- PTM: Phosphorylated (PubMed:24723470). Phosphorylation on Thr-34 CC is required for PC efflux activity. Phosphorylation occurs on CC serine and threonine residues in a protein kinase A- or C- CC dependent manner (PubMed:24723470). May be phosphorylated on Thr- CC 44 and Ser-49 (PubMed:24723470). {ECO:0000269|PubMed:24723470}. CC -!- PTM: Glycosylated (PubMed:17523162, PubMed:24723470, CC PubMed:21820390). {ECO:0000269|PubMed:17523162, CC ECO:0000269|PubMed:21820390, ECO:0000269|PubMed:24723470}. CC -!- DISEASE: Cholestasis, progressive familial intrahepatic, 3 (PFIC3) CC [MIM:602347]: A disorder characterized by early onset of CC cholestasis that progresses to hepatic fibrosis, cirrhosis, and CC end-stage liver disease before adulthood. CC {ECO:0000269|PubMed:11313315, ECO:0000269|PubMed:12671900, CC ECO:0000269|PubMed:17726488, ECO:0000269|PubMed:21119540, CC ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, CC ECO:0000269|PubMed:24806754, ECO:0000269|PubMed:9419367}. Note=The CC disease is caused by mutations affecting the gene represented in CC this entry. CC -!- DISEASE: Cholestasis of pregnancy, intrahepatic 3 (ICP3) CC [MIM:614972]: A liver disorder of pregnancy. It presents during CC the second or, more commonly, the third trimester of pregnancy CC with intense pruritus which becomes more severe with advancing CC gestation and cholestasis. It causes fetal distress, spontaneous CC premature delivery and intrauterine death. Patients have CC spontaneous and progressive disappearance of cholestasis after CC delivery. Cholestasis results from abnormal biliary transport from CC the liver into the small intestine. {ECO:0000269|PubMed:10767346, CC ECO:0000269|PubMed:12746424, ECO:0000269|PubMed:15077010}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- DISEASE: Gallbladder disease 1 (GBD1) [MIM:600803]: One of the CC major digestive diseases. Gallstones composed of cholesterol CC (cholelithiasis) are the common manifestations in western CC countries. Most people with gallstones, however, remain CC asymptomatic through their lifetimes. CC {ECO:0000269|PubMed:11313316, ECO:0000269|PubMed:12891548, CC ECO:0000269|PubMed:22331132, ECO:0000269|PubMed:23533021, CC ECO:0000269|PubMed:24723470, ECO:0000269|Ref.2}. Note=The disease CC is caused by mutations affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCB CC family. Multidrug resistance exporter (TC 3.A.1.201) subfamily. CC {ECO:0000305}. CC -!- SIMILARITY: Contains 2 ABC transmembrane type-1 domains. CC {ECO:0000255|PROSITE-ProRule:PRU00441}. CC -!- SIMILARITY: Contains 2 ABC transporter domains. CC {ECO:0000255|PROSITE-ProRule:PRU00434}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA84542.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/abcb4/"; CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC CC proteins; CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=P21439"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M23234; AAA36207.1; -; mRNA. DR EMBL; EF034088; ABJ53424.1; -; Genomic_DNA. DR EMBL; AC005045; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC005068; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC006154; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH236949; EAL24174.1; -; Genomic_DNA. DR EMBL; CH236949; EAL24175.1; -; Genomic_DNA. DR EMBL; CH236949; EAL24176.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76946.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76947.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76948.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76950.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76951.1; -; Genomic_DNA. DR EMBL; CH471091; EAW76952.1; -; Genomic_DNA. DR EMBL; Z35284; CAA84542.1; ALT_SEQ; mRNA. DR EMBL; X06181; CAA29547.1; -; mRNA. DR CCDS; CCDS5605.1; -. [P21439-2] DR CCDS; CCDS5606.1; -. [P21439-1] DR CCDS; CCDS5607.1; -. [P21439-3] DR PIR; JS0051; DVHU3. DR RefSeq; NP_000434.1; NM_000443.3. [P21439-2] DR RefSeq; NP_061337.1; NM_018849.2. [P21439-1] DR RefSeq; NP_061338.1; NM_018850.2. [P21439-3] DR RefSeq; XP_011514610.1; XM_011516308.1. [P21439-1] DR RefSeq; XP_011514611.1; XM_011516309.1. [P21439-2] DR RefSeq; XP_011514615.1; XM_011516313.1. [P21439-3] DR UniGene; Hs.654403; -. DR ProteinModelPortal; P21439; -. DR SMR; P21439; 40-632. DR BioGrid; 111263; 2. DR IntAct; P21439; 3. DR STRING; 9606.ENSP00000265723; -. DR ChEMBL; CHEMBL1743129; -. DR DrugBank; DB01394; Colchicine. DR DrugBank; DB06414; Etravirine. DR DrugBank; DB06207; Silodosin. DR TCDB; 3.A.1.201.3; the atp-binding cassette (abc) superfamily. DR PhosphoSite; P21439; -. DR BioMuta; ABCB4; -. DR DMDM; 126302568; -. DR PaxDb; P21439; -. DR PRIDE; P21439; -. DR Ensembl; ENST00000265723; ENSP00000265723; ENSG00000005471. [P21439-1] DR Ensembl; ENST00000358400; ENSP00000351172; ENSG00000005471. [P21439-3] DR Ensembl; ENST00000359206; ENSP00000352135; ENSG00000005471. [P21439-2] DR Ensembl; ENST00000453593; ENSP00000392983; ENSG00000005471. [P21439-3] DR GeneID; 5244; -. DR KEGG; hsa:5244; -. DR UCSC; uc003uiv.1; human. [P21439-1] DR UCSC; uc003uiw.1; human. [P21439-2] DR UCSC; uc003uix.1; human. DR CTD; 5244; -. DR GeneCards; ABCB4; -. DR HGNC; HGNC:45; ABCB4. DR HPA; CAB004498; -. DR HPA; HPA049395; -. DR HPA; HPA053288; -. DR MIM; 171060; gene. DR MIM; 600803; phenotype. DR MIM; 602347; phenotype. DR MIM; 614972; phenotype. DR neXtProt; NX_P21439; -. DR Orphanet; 69665; Intrahepatic cholestasis of pregnancy. DR Orphanet; 69663; Low phospholipid associated cholelithiasis. DR Orphanet; 79305; Progressive familial intrahepatic cholestasis type 3. DR PharmGKB; PA268; -. DR eggNOG; KOG0055; Eukaryota. DR eggNOG; COG1132; LUCA. DR GeneTree; ENSGT00530000062896; -. DR HOVERGEN; HBG080809; -. DR InParanoid; P21439; -. DR KO; K05659; -. DR OMA; SRKYQNG; -. DR OrthoDB; EOG7Z3F4H; -. DR PhylomeDB; P21439; -. DR TreeFam; TF105193; -. DR Reactome; R-HSA-1989781; PPARA activates gene expression. DR Reactome; R-HSA-5678771; Defective ABCB4 causes progressive familial intrahepatic cholestasis 3, intrahepatic cholestasis of pregnancy 3 and gallbladder disease 1. DR GeneWiki; ABCB4; -. DR GenomeRNAi; 5244; -. DR NextBio; 20258; -. DR PRO; PR:P21439; -. DR Proteomes; UP000005640; Chromosome 7. DR Bgee; P21439; -. DR CleanEx; HS_ABCB4; -. DR ExpressionAtlas; P21439; baseline and differential. DR Genevisible; P21439; HS. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc. DR GO; GO:0046581; C:intercellular canaliculus; IEA:Ensembl. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042626; F:ATPase activity, coupled to transmembrane movement of substances; IDA:UniProtKB. DR GO; GO:0008525; F:phosphatidylcholine transporter activity; IDA:UniProtKB. DR GO; GO:0090554; F:phosphatidylcholine-translocating ATPase activity; IDA:UniProtKB. DR GO; GO:0008559; F:xenobiotic-transporting ATPase activity; IEA:UniProtKB-EC. DR GO; GO:0032782; P:bile acid secretion; ISS:UniProtKB. DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome. DR GO; GO:1903413; P:cellular response to bile acid; IDA:UniProtKB. DR GO; GO:0055088; P:lipid homeostasis; IDA:UniProtKB. DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc. DR GO; GO:0045332; P:phospholipid translocation; IMP:UniProtKB. DR GO; GO:0032376; P:positive regulation of cholesterol transport; IDA:UniProtKB. DR GO; GO:0061092; P:positive regulation of phospholipid translocation; IDA:UniProtKB. DR GO; GO:2001140; P:positive regulation of phospholipid transport; IDA:UniProtKB. DR GO; GO:0042493; P:response to drug; TAS:ProtInc. DR GO; GO:1901557; P:response to fenofibrate; ISS:UniProtKB. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central. DR GO; GO:0006810; P:transport; TAS:ProtInc. DR Gene3D; 3.40.50.300; -; 2. DR InterPro; IPR003593; AAA+_ATPase. DR InterPro; IPR011527; ABC1_TM_dom. DR InterPro; IPR003439; ABC_transporter-like. DR InterPro; IPR017871; ABC_transporter_CS. DR InterPro; IPR027417; P-loop_NTPase. DR Pfam; PF00664; ABC_membrane; 2. DR Pfam; PF00005; ABC_tran; 2. DR SMART; SM00382; AAA; 2. DR SUPFAM; SSF52540; SSF52540; 2. DR SUPFAM; SSF90123; SSF90123; 2. DR PROSITE; PS50929; ABC_TM1F; 2. DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2. DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Cell membrane; Complete proteome; KW Cytoplasm; Cytoplasmic vesicle; Disease mutation; Glycoprotein; KW Hydrolase; Intrahepatic cholestasis; Lipid transport; Membrane; KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome; KW Repeat; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1 1286 Phosphatidylcholine translocator ABCB4. FT /FTId=PRO_0000093333. FT TOPO_DOM 1 50 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 51 73 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 74 118 Extracellular. {ECO:0000250}. FT TRANSMEM 119 139 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 140 188 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 189 210 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 211 217 Extracellular. {ECO:0000250}. FT TRANSMEM 218 238 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 239 296 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 297 318 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 319 332 Extracellular. {ECO:0000250}. FT TRANSMEM 333 354 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 355 711 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 712 732 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 733 755 Extracellular. {ECO:0000250}. FT TRANSMEM 756 776 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 777 831 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 832 852 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 853 853 Extracellular. {ECO:0000250}. FT TRANSMEM 854 873 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 874 933 Cytoplasmic. {ECO:0000250}. FT TRANSMEM 934 956 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 957 972 Extracellular. {ECO:0000250}. FT TRANSMEM 973 994 Helical. {ECO:0000255|PROSITE- FT ProRule:PRU00441}. FT TOPO_DOM 995 1286 Cytoplasmic. {ECO:0000250}. FT DOMAIN 57 359 ABC transmembrane type-1 1. FT {ECO:0000255|PROSITE-ProRule:PRU00441}. FT DOMAIN 394 630 ABC transporter 1. {ECO:0000255|PROSITE- FT ProRule:PRU00434}. FT DOMAIN 711 999 ABC transmembrane type-1 2. FT {ECO:0000255|PROSITE-ProRule:PRU00441}. FT DOMAIN 1034 1279 ABC transporter 2. {ECO:0000255|PROSITE- FT ProRule:PRU00434}. FT NP_BIND 429 436 ATP 1. {ECO:0000255|PROSITE- FT ProRule:PRU00434}. FT NP_BIND 1069 1076 ATP 2. {ECO:0000255|PROSITE- FT ProRule:PRU00434}. FT REGION 625 647 Interaction with HAX1. {ECO:0000250}. FT MOD_RES 27 27 Phosphoserine. FT {ECO:0000250|UniProtKB:P21440}. FT MOD_RES 34 34 Phosphothreonine. FT {ECO:0000269|PubMed:24723470}. FT CARBOHYD 91 91 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 97 97 N-linked (GlcNAc...). {ECO:0000255}. FT VAR_SEQ 929 975 Missing (in isoform 3). {ECO:0000305}. FT /FTId=VSP_046258. FT VAR_SEQ 1094 1100 Missing (in isoform 2 and isoform 3). FT {ECO:0000303|PubMed:2906314}. FT /FTId=VSP_023263. FT VARIANT 34 34 T -> M (in GBD1; reduces efflux activity FT for PC in a phosphorylation-dependent FT manner). {ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:24723470}. FT /FTId=VAR_073728. FT VARIANT 47 47 R -> G (in GBD1; partly retained FT intracellularly; reduces efflux activity FT for PC in a phosphorylation-dependent FT manner). {ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|PubMed:24723470}. FT /FTId=VAR_073729. FT VARIANT 47 47 R -> Q (found in patients with FT cholangitis; unknown pathological FT significance). FT {ECO:0000269|PubMed:22331132}. FT /FTId=VAR_073730. FT VARIANT 68 68 G -> R (in PFIC3; retained in the FT reticulum endoplasmic; greatly reduced FT expression). FT {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073731. FT VARIANT 70 70 G -> R (in PFIC3). FT {ECO:0000269|PubMed:21119540}. FT /FTId=VAR_073732. FT VARIANT 71 71 L -> H (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073733. FT VARIANT 73 73 L -> V (in PFIC3 and GBD1). FT {ECO:0000269|PubMed:21119540, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073734. FT VARIANT 78 78 F -> C (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073735. FT VARIANT 87 87 D -> E. {ECO:0000269|PubMed:16763017}. FT /FTId=VAR_043078. FT VARIANT 95 95 P -> S. {ECO:0000269|PubMed:16763017}. FT /FTId=VAR_043079. FT VARIANT 99 99 S -> F (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073736. FT VARIANT 124 124 G -> S (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073737. FT VARIANT 126 126 G -> E (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073738. FT VARIANT 138 138 W -> R (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043080. FT VARIANT 150 150 R -> K (in ICP3). FT {ECO:0000269|PubMed:12746424}. FT /FTId=VAR_043081. FT VARIANT 154 154 F -> S (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073739. FT VARIANT 165 165 F -> I (in GBD1). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_043082. FT VARIANT 175 175 T -> A (found in patients with FT gallbladder and cholestasis; unknown FT pathological significance; FT dbSNP:rs58238559). FT {ECO:0000269|PubMed:11313316, FT ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:15077010, FT ECO:0000269|PubMed:16763017, FT ECO:0000269|PubMed:17264802, FT ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_023501. FT VARIANT 201 201 T -> M (in PFIC3; greatly reduced FT expression; alters efflux activity for FT PC). {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073740. FT VARIANT 238 238 L -> V (in dbSNP:rs45596335). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_020223. FT VARIANT 250 250 A -> P (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073741. FT VARIANT 263 263 I -> V (in dbSNP:rs45547936). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_030763. FT VARIANT 286 286 A -> V (in PFIC3 and GBD1; does not alter FT plasma membrane location; inhibits efflux FT activity for PC). FT {ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|PubMed:24806754}. FT /FTId=VAR_073742. FT VARIANT 301 301 M -> T (in GBD1). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_043083. FT VARIANT 320 320 S -> F (in ICP3, GBD1 and PFIC3; unknown FT pathological significance; does not alter FT plasma membrane location; does not FT inhibit efflux activity for PC). FT {ECO:0000269|PubMed:11313316, FT ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:15077010, FT ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:21119540, FT ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|PubMed:24806754}. FT /FTId=VAR_023502. FT VARIANT 346 346 S -> I (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043084. FT VARIANT 357 357 F -> L (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073743. FT VARIANT 364 364 A -> V (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073744. FT VARIANT 367 367 I -> V. {ECO:0000269|PubMed:16763017}. FT /FTId=VAR_043085. FT VARIANT 395 395 E -> G (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043086. FT VARIANT 403 403 Y -> H (in PFIC3; does not alter FT cytoplasmic and cell membrane location; FT inhibits efflux activity for PC and FT cholesterol). FT {ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:21119540, FT ECO:0000269|PubMed:24045840}. FT /FTId=VAR_073745. FT VARIANT 406 406 R -> G (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073746. FT VARIANT 406 406 R -> Q (found in patients with FT cholangitis; unknown pathological FT significance). FT {ECO:0000269|PubMed:22331132}. FT /FTId=VAR_073747. FT VARIANT 424 424 T -> A (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043087. FT VARIANT 425 425 V -> M (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043088. FT VARIANT 450 450 E -> G. {ECO:0000269|PubMed:16763017}. FT /FTId=VAR_043089. FT VARIANT 459 459 D -> H (in PFIC3; retained in the FT reticulum endoplasmic; greatly reduced FT expression). FT {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073748. FT VARIANT 475 475 V -> A (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073749. FT VARIANT 479 479 P -> L (in PFIC3; greatly reduced FT expression; alters efflux activity for FT PC). {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073750. FT VARIANT 481 481 L -> R (in PFIC3; does not alter FT cytoplasmic and cell membrane location; FT inhibits efflux activity for PC and FT cholesterol). FT {ECO:0000269|PubMed:24045840}. FT /FTId=VAR_073751. FT VARIANT 510 510 N -> S (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073752. FT VARIANT 511 511 A -> T (in PFIC3 and GBD1). FT {ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073753. FT VARIANT 513 513 E -> K (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073754. FT VARIANT 528 528 E -> D (in GBD1; unknown pathological FT significance; dbSNP:rs8187797). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:15077010, FT ECO:0000269|PubMed:22331132, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|Ref.2}. FT /FTId=VAR_043090. FT VARIANT 535 535 G -> D (in PFIC3). FT {ECO:0000269|PubMed:12671900}. FT /FTId=VAR_043091. FT VARIANT 541 541 I -> F (in PFIC3 and GBD1). FT {ECO:0000269|PubMed:11313315, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_043092. FT VARIANT 545 545 R -> H (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073755. FT VARIANT 546 546 A -> D (in ICP3; disruption of protein FT trafficking with subsequent lack of FT functional protein at the cell surface). FT {ECO:0000269|PubMed:10767346}. FT /FTId=VAR_023503. FT VARIANT 549 549 R -> H (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073756. FT VARIANT 556 556 L -> R (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043093. FT VARIANT 558 558 E -> K (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073757. FT VARIANT 564 564 D -> G (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043094. FT VARIANT 589 589 H -> T (in GBD1; requires 2 nucleotide FT substitutions). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073758. FT VARIANT 590 590 R -> Q (found in patients with FT gallbladder and cholestasis; unknown FT pathological significance; FT dbSNP:rs45575636). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:16763017, FT ECO:0000269|PubMed:17264802, FT ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:19261551, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|Ref.2}. FT /FTId=VAR_043095. FT VARIANT 591 591 L -> Q (in GBD1). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_043096. FT VARIANT 593 593 T -> A (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073759. FT VARIANT 593 593 T -> M (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073760. FT VARIANT 630 630 M -> V (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073761. FT VARIANT 647 647 E -> K (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073762. FT VARIANT 651 651 T -> N (in dbSNP:rs45476795). FT {ECO:0000269|Ref.2}. FT /FTId=VAR_030765. FT VARIANT 652 652 R -> G (found in patients with FT gallbladder and cholestasis; unknown FT pathological significance; FT dbSNP:rs2230028). FT {ECO:0000269|PubMed:11313315, FT ECO:0000269|PubMed:12746424, FT ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:15077010, FT ECO:0000269|PubMed:16763017, FT ECO:0000269|PubMed:17264802, FT ECO:0000269|PubMed:19261551, FT ECO:0000269|PubMed:21119540, FT ECO:0000269|Ref.2}. FT /FTId=VAR_020225. FT VARIANT 701 701 L -> P (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073763. FT VARIANT 711 711 F -> S (in PFIC3). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043097. FT VARIANT 715 715 T -> I (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073764. FT VARIANT 723 723 G -> E (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073765. FT VARIANT 726 726 P -> L (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073766. FT VARIANT 726 726 P -> T (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073767. FT VARIANT 729 729 S -> L (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073768. FT VARIANT 737 737 A -> V (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073769. FT VARIANT 742 742 G -> S. {ECO:0000269|PubMed:12891548}. FT /FTId=VAR_043098. FT VARIANT 762 762 G -> E (in ICP3). FT {ECO:0000269|PubMed:15077010}. FT /FTId=VAR_043099. FT VARIANT 764 764 I -> L (in a heterozygous patient with FT risperidone-induced cholestasis). FT {ECO:0000269|PubMed:17264802}. FT /FTId=VAR_043100. FT VARIANT 775 775 T -> M (found in patients with FT cholangitis; unknown pathological FT significance). FT {ECO:0000269|PubMed:15077010, FT ECO:0000269|PubMed:17726488, FT ECO:0000269|PubMed:22331132}. FT /FTId=VAR_043101. FT VARIANT 788 788 R -> Q (found in patients with FT gallbladder and cholestasis; unknown FT pathological significance; FT dbSNP:rs8187801). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:23533021, FT ECO:0000269|Ref.2}. FT /FTId=VAR_024359. FT VARIANT 840 840 A -> D (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073770. FT VARIANT 934 934 A -> T (found in patients with FT gallbladder and cholestasis; unknown FT pathological significance; FT dbSNP:rs61730509). FT {ECO:0000269|PubMed:12891548, FT ECO:0000269|PubMed:23533021}. FT /FTId=VAR_043102. FT VARIANT 954 954 G -> S (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073771. FT VARIANT 964 964 V -> T (requires 2 nucleotide FT substitutions; found in patients with FT cholangitis; unknown pathological FT significance). FT {ECO:0000269|PubMed:22331132}. FT /FTId=VAR_073772. FT VARIANT 975 975 L -> V (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073773. FT VARIANT 978 978 S -> P (in PFIC3; alters efflux activity FT for PC). {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073774. FT VARIANT 983 983 G -> S (in PFIC3; dbSNP:rs56187107). FT {ECO:0000269|PubMed:11313315}. FT /FTId=VAR_043103. FT VARIANT 1082 1082 L -> Q (in a heterozygous patient with FT amoxicillin/clavulanic acid-induced FT cholestasis). FT {ECO:0000269|PubMed:17264802}. FT /FTId=VAR_043104. FT VARIANT 1084 1084 R -> W (in GBD1). FT {ECO:0000269|PubMed:23533021}. FT /FTId=VAR_073775. FT VARIANT 1125 1125 E -> K (in PFIC3; alters efflux activity FT for PC). {ECO:0000269|PubMed:24594635}. FT /FTId=VAR_073776. FT VARIANT 1161 1161 Missing (in GBD1). FT /FTId=VAR_043105. FT VARIANT 1168 1168 P -> S (in GBD1). FT {ECO:0000269|PubMed:11313316, FT ECO:0000269|PubMed:12891548}. FT /FTId=VAR_023504. FT VARIANT 1193 1193 A -> T (in PFIC3). FT {ECO:0000269|PubMed:17726488}. FT /FTId=VAR_073777. FT MUTAGEN 34 34 T->D: Does not inhibit efflux activity FT for PC. {ECO:0000269|PubMed:24723470}. FT MUTAGEN 44 44 T->A: Reduces efflux activity for PC. FT Does not alter apical membrane location. FT {ECO:0000269|PubMed:24723470}. FT MUTAGEN 49 49 S->A: Reduces efflux activity for PC. FT Does not alter apical membrane location. FT {ECO:0000269|PubMed:24723470}. FT MUTAGEN 435 435 K->M: Inhibits efflux activity for PC and FT cholesterol, but does not alter FT glycosylation and surface expression in FT the presence of taurocholate. FT {ECO:0000269|PubMed:17523162}. FT MUTAGEN 953 953 A->D: Accumulates predominantly in FT intracellular compartments with only a FT small fraction at the plasma membrane and FT inhibits partially the efflux activity FT for PC. {ECO:0000269|PubMed:24806754}. FT MUTAGEN 1075 1075 K->M: Inhibits efflux activity for PC and FT cholesterol, but does not alter FT glycosylation and surface expression in FT the presence of taurocholate. FT {ECO:0000269|PubMed:17523162}. SQ SEQUENCE 1286 AA; 141523 MW; 9A9066F2292F2CCF CRC64; MDLEAAKNGT AWRPTSAEGD FELGISSKQK RKKTKTVKMI GVLTLFRYSD WQDKLFMSLG TIMAIAHGSG LPLMMIVFGE MTDKFVDTAG NFSFPVNFSL SLLNPGKILE EEMTRYAYYY SGLGAGVLVA AYIQVSFWTL AAGRQIRKIR QKFFHAILRQ EIGWFDINDT TELNTRLTDD ISKISEGIGD KVGMFFQAVA TFFAGFIVGF IRGWKLTLVI MAISPILGLS AAVWAKILSA FSDKELAAYA KAGAVAEEAL GAIRTVIAFG GQNKELERYQ KHLENAKEIG IKKAISANIS MGIAFLLIYA SYALAFWYGS TLVISKEYTI GNAMTVFFSI LIGAFSVGQA APCIDAFANA RGAAYVIFDI IDNNPKIDSF SERGHKPDSI KGNLEFNDVH FSYPSRANVK ILKGLNLKVQ SGQTVALVGS SGCGKSTTVQ LIQRLYDPDE GTINIDGQDI RNFNVNYLRE IIGVVSQEPV LFSTTIAENI CYGRGNVTMD EIKKAVKEAN AYEFIMKLPQ KFDTLVGERG AQLSGGQKQR IAIARALVRN PKILLLDEAT SALDTESEAE VQAALDKARE GRTTIVIAHR LSTVRNADVI AGFEDGVIVE QGSHSELMKK EGVYFKLVNM QTSGSQIQSE EFELNDEKAA TRMAPNGWKS RLFRHSTQKN LKNSQMCQKS LDVETDGLEA NVPPVSFLKV LKLNKTEWPY FVVGTVCAIA NGGLQPAFSV IFSEIIAIFG PGDDAVKQQK CNIFSLIFLF LGIISFFTFF LQGFTFGKAG EILTRRLRSM AFKAMLRQDM SWFDDHKNST GALSTRLATD AAQVQGATGT RLALIAQNIA NLGTGIIISF IYGWQLTLLL LAVVPIIAVS GIVEMKLLAG NAKRDKKELE AAGKIATEAI ENIRTVVSLT QERKFESMYV EKLYGPYRNS VQKAHIYGIT FSISQAFMYF SYAGCFRFGA YLIVNGHMRF RDVILVFSAI VFGAVALGHA SSFAPDYAKA KLSAAHLFML FERQPLIDSY SEEGLKPDKF EGNITFNEVV FNYPTRANVP VLQGLSLEVK KGQTLALVGS SGCGKSTVVQ LLERFYDPLA GTVFVDFGFQ LLDGQEAKKL NVQWLRAQLG IVSQEPILFD CSIAENIAYG DNSRVVSQDE IVSAAKAANI HPFIETLPHK YETRVGDKGT QLSGGQKQRI AIARALIRQP QILLLDEATS ALDTESEKVV QEALDKAREG RTCIVIAHRL STIQNADLIV VFQNGRVKEH GTHQQLLAQK GIYFSMVSVQ AGTQNL //