Journal
NATURE
Volume 571, Issue 7765, Pages 366-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1344-7
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Funding
- Danish National Research Foundation
- Lundbeck Foundation
- EMBO
- Danish Council for Independent Research [0602-02912B]
- Lundbeck Foundation [R171-2014-663, R209-2015-2704]
- Boehringer-Ingelheim Fonds
- ANR [ANR-14-CE09-0022]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05]
- Centre National de la Recherche Scientifique (CNRS)
- German Research Foundation [Mo2752/2]
- Lundbeck Foundation [R248-2016-2518, R155-2015-2666, R208-2015-3225] Funding Source: researchfish
- Agence Nationale de la Recherche (ANR) [ANR-14-CE09-0022] Funding Source: Agence Nationale de la Recherche (ANR)
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Type 4 P-type ATPases (P4-ATPases) are lipid flippases that drive the active transport of phospholipids from exoplasmic or luminal leaflets to cytosolic leaflets of eukaryotic membranes. The molecular architecture of P4-ATPases and the mechanism through which they recognize and transport lipids have remained unknown. Here we describe the cryo-electron microscopy structure of the P4-ATPase Drs2p-Cdc50p, a Saccharomyces cerevisiae lipid flippase that is specific to phosphatidylserine and phosphatidylethanolamine. Drs2p-Cdc50p is autoinhibited by the C-terminal tail of Drs2p, and activated by the lipid phosphatidylinositol-4-phosphate (PtdIns4P or PI4P). We present three structures that represent the complex in an autoinhibited, an intermediate and a fully activated state. The analysis highlights specific features of P4-ATPases and reveals sites of autoinhibition and PI4P-dependent activation. We also observe a putative lipid translocation pathway in this flippase that involves a conserved PISL motif in transmembrane segment 4 and polar residues of transmembrane segments 2 and 5, in particular Lys1018, in the centre of the lipid bilayer.
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