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Structures of ABCB4 provide insight into phosphatidylcholine translocation.

Nosol K, Bang-Sørensen R, Irobalieva RN, Erramilli SK, Stieger B, Kossiakoff AA, Locher KP
Proc Natl Acad Sci U S A 118 (2021)
Related entries: 7niv, 7niw

Cited: 14 times
EuropePMC logo PMID: 34385322

Abstract

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-π 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.

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  2. Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition. Beaudoin JJ, Yang K, Adiwidjaja J, Taneja G, Watkins PB, Siler SQ, Howell BA, Woodhead JL. Front Pharmacol 13 1085621 (2022)
  3. Maternal hyperglycemia induces alterations in hepatic amino acid, glucose and lipid metabolism of neonatal offspring: Multi-omics insights from a diabetic pig model. Shashikadze B, Valla L, Lombardo SD, Prehn C, Haid M, Riols F, Stöckl JB, Elkhateib R, Renner S, Rathkolb B, Menche J, Hrabĕ de Angelis M, Wolf E, Kemter E, Fröhlich T. Mol Metab 75 101768 (2023)
  4. PGP-14 establishes a polar lipid permeability barrier within the C. elegans pharyngeal cuticle. Kamal M, Tokmakjian L, Knox J, Han D, Moshiri H, Magomedova L, Nguyen KC, Zheng H, Burns AR, Cooke B, Lacoste J, Yeo M, Hall DH, Cummins CL, Roy PJ. PLoS Genet 19 e1011008 (2023)
  5. Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Zöllner J, Finer S, Linton KJ, Genes and Health Research Team, van Heel DA, Williamson C, Dixon PH. Sci Rep 13 8120 (2023)
  6. Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport. Rahman H, Ware MJ, Sajid A, Lusvarghi S, Durell SR, Ambudkar SV. Cancers (Basel) 15 3459 (2023)
  7. Structural and functional investigation of ABC transporter STE6-2p from Pichia pastoris reveals unexpected interaction with sterol molecules. Schleker ESM, Buschmann S, Xie H, Welsch S, Michel H, Reinhart C. Proc Natl Acad Sci U S A 119 e2202822119 (2022)
  8. Letter Structural basis of acyl-CoA transport across the peroxisomal membrane by human ABCD1. Wang R, Qin Y, Li X. Cell Res 32 214-217 (2022)
  9. Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP. Liu H, Irobalieva RN, Kowal J, Ni D, Nosol K, Bang-Sørensen R, Lancien L, Stahlberg H, Stieger B, Locher KP. Nat Commun 14 7296 (2023)


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