Structure of the human lipid exporter ABCB4 in a lipid environment.

Olsen JA; Alam A; Kowal J; Stieger B; Locher KP

doi:10.1038/s41594-019-0354-3

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Journal article

Structure of the human lipid exporter ABCB4 in a lipid environment.

Olsen JA Department of Biology, ETH Zürich, Zürich, Switzerland.
Alam A Department of Biology, ETH Zürich, Zürich, Switzerland.
Kowal J Department of Biology, ETH Zürich, Zürich, Switzerland.
Stieger B Department of Clinical Pharmacology and Toxicology, University Hospital Zürich, Zürich, Switzerland.
Locher KP Department of Biology, ETH Zürich, Zürich, Switzerland. locher@mol.biol.ethz.ch.

2019-12-25

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Nature structural & molecular biology. - 2020

ATP Binding Cassette Transporter, Subfamily B

English ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 Å. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.

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