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-Structure paper
タイトル | Structures of ABCB4 provide insight into phosphatidylcholine translocation. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 118, Issue 33, Year 2021 |
掲載日 | 2021年8月17日 |
著者 | Kamil Nosol / Rose Bang-Sørensen / Rossitza N Irobalieva / Satchal K Erramilli / Bruno Stieger / Anthony A Kossiakoff / Kaspar P Locher / |
PubMed 要旨 | 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 ...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. |
リンク | Proc Natl Acad Sci U S A / PubMed:34385322 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.6 - 4.2 Å |
構造データ | EMDB-12365, PDB-7niu: EMDB-12366, PDB-7niv: EMDB-12367, PDB-7niw: |
化合物 | ChemComp-CLR: ChemComp-DLP: ChemComp-X2N: |
由来 |
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キーワード | PROTEIN TRANSPORT / ABCB4 / MDR3 / nanodisc / lipid transporter / transporter / phosphatidylcholine |