| Structural highlights
Disease
MDR3_HUMAN Low phospholipid-associated cholelithiasis;Progressive familial intrahepatic cholestasis type 3;Intrahepatic cholestasis of pregnancy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
MDR3_HUMAN Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, PubMed:17523162, PubMed:23468132, PubMed:24806754, PubMed:24723470, PubMed:24594635, PubMed:21820390). Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes (PubMed:23468132). Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner (PubMed:24045840). Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane (PubMed:9366571, PubMed:28012258). In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts (PubMed:21820390). Does not confer multidrug resistance (By similarity).[UniProtKB:P21440][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
ABCB4 is expressed in hepatocytes and translocates phosphatidylcholine into bile canaliculi. The mechanism of specific lipid recruitment from the canalicular membrane, which is essential to mitigate the cytotoxicity of bile salts, is poorly understood. We present cryogenic electron microscopy structures of human ABCB4 in three distinct functional conformations. An apo-inward structure reveals how phospholipid can be recruited from the inner leaflet of the membrane without flipping its orientation. An occluded structure reveals a single phospholipid molecule in a central cavity. Its choline moiety is stabilized by cation-pi interactions with an essential tryptophan residue, rationalizing the specificity of ABCB4 for phosphatidylcholine. In an inhibitor-bound structure, a posaconazole molecule blocks phospholipids from reaching the central cavity. Using a proteoliposome-based translocation assay with fluorescently labeled phosphatidylcholine analogs, we recapitulated the substrate specificity of ABCB4 in vitro and confirmed the role of the key tryptophan residue. Our results provide a structural basis for understanding an essential translocation step in the generation of bile and its sensitivity to azole drugs.
Structures of ABCB4 provide insight into phosphatidylcholine translocation.,Nosol K, Bang-Sorensen R, Irobalieva RN, Erramilli SK, Stieger B, Kossiakoff AA, Locher KP Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2106702118. doi: , 10.1073/pnas.2106702118. PMID:34385322[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Morita SY, Kobayashi A, Takanezawa Y, Kioka N, Handa T, Arai H, Matsuo M, Ueda K. Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4. Hepatology. 2007 Jul;46(1):188-99. doi: 10.1002/hep.21591. PMID:17523162 doi:http://dx.doi.org/10.1002/hep.21591
- ↑ Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J, Van den Oever K, Mok KS, Paulusma CC, Linton KJ, Oude Elferink RP. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology. 2011 Nov;141(5):1927-37.e1-4. doi:, 10.1053/j.gastro.2011.07.042. Epub 2011 Aug 4. PMID:21820390 doi:http://dx.doi.org/10.1053/j.gastro.2011.07.042
- ↑ Morita SY, Tsuda T, Horikami M, Teraoka R, Kitagawa S, Terada T. Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized in nonraft membranes. J Lipid Res. 2013 May;54(5):1221-30. doi: 10.1194/jlr.M032425. Epub 2013 Mar 6. PMID:23468132 doi:http://dx.doi.org/10.1194/jlr.M032425
- ↑ Degiorgio D, Corsetto PA, Rizzo AM, Colombo C, Seia M, Costantino L, Montorfano G, Tomaiuolo R, Bordo D, Sansanelli S, Li M, Tavian D, Rastaldi MP, Coviello DA. Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. Eur J Hum Genet. 2014 May;22(5):633-9. doi: 10.1038/ejhg.2013.214. Epub 2013 Sep , 18. PMID:24045840 doi:http://dx.doi.org/10.1038/ejhg.2013.214
- ↑ Gordo-Gilart R, Andueza S, Hierro L, Martinez-Fernandez P, D'Agostino D, Jara P, Alvarez L. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut. 2015 Jan;64(1):147-55. doi: 10.1136/gutjnl-2014-306896. Epub 2014 Mar 4. PMID:24594635 doi:http://dx.doi.org/10.1136/gutjnl-2014-306896
- ↑ Gautherot J, Delautier D, Maubert MA, Ait-Slimane T, Bolbach G, Delaunay JL, Durand-Schneider AM, Firrincieli D, Barbu V, Chignard N, Housset C, Maurice M, Falguieres T. Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology. 2014 Aug;60(2):610-21. doi: 10.1002/hep.27170. Epub 2014 May 19. PMID:24723470 doi:http://dx.doi.org/10.1002/hep.27170
- ↑ Andress EJ, Nicolaou M, Romero MR, Naik S, Dixon PH, Williamson C, Linton KJ. Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology. 2014 May;59(5):1921-31. doi: 10.1002/hep.26970. Epub 2014 Apr 1. PMID:24806754 doi:http://dx.doi.org/10.1002/hep.26970
- ↑ Delaunay JL, Bruneau A, Hoffmann B, Durand-Schneider AM, Barbu V, Jacquemin E, Maurice M, Housset C, Callebaut I, Ait-Slimane T. Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology. 2017 Feb;65(2):560-570. doi: 10.1002/hep.28929. Epub 2016 Dec 24. PMID:28012258 doi:http://dx.doi.org/10.1002/hep.28929
- ↑ Smith AJ, Timmermans-Hereijgers JL, Roelofsen B, Wirtz KW, van Blitterswijk WJ, Smit JJ, Schinkel AH, Borst P. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett. 1994 Nov 14;354(3):263-6. doi: 10.1016/0014-5793(94)01135-4. PMID:7957936 doi:http://dx.doi.org/10.1016/0014-5793(94)01135-4
- ↑ van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel AH, Borst P, van Meer G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996 Nov 1;87(3):507-17. doi: 10.1016/s0092-8674(00)81370-7. PMID:8898203 doi:http://dx.doi.org/10.1016/s0092-8674(00)81370-7
- ↑ Crawford AR, Smith AJ, Hatch VC, Oude Elferink RP, Borst P, Crawford JM. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. J Clin Invest. 1997 Nov 15;100(10):2562-7. doi: 10.1172/JCI119799. PMID:9366571 doi:http://dx.doi.org/10.1172/JCI119799
- ↑ Nosol K, Bang-Sørensen R, Irobalieva RN, Erramilli SK, Stieger B, Kossiakoff AA, Locher KP. Structures of ABCB4 provide insight into phosphatidylcholine translocation. Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2106702118. PMID:34385322 doi:10.1073/pnas.2106702118
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