Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 62-70 |
| Number of pages | 9 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 27 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2020 |
Bibliographical note
Funding Information:This research was supported by the Swiss National Science Foundation (grant nos. 310030B_166672 and 310030_189111 to K.P.L.) and by The Danish Council for Independent Research (grant no. DFF-4181-00021 to J.A.O.). Cryo-EM data were collected at the electron microscopy facility at ETH Zürich (ScopeM) and the authors thank the ScopeM staff for technical support.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.