Structure and autoregulation of a P4-ATPase lipid flippase

Milena Timcenko, Joseph A. Lyons, Dovile Januliene, Jakob J. Ulstrup, Thibaud Dieudonné, Cédric Montigny, Miriam Rose Ash, Jesper Lykkegaard Karlsen, Thomas Boesen, Werner Kühlbrandt, Guillaume Lenoir, Arne Moeller, Poul Nissen*

*Corresponding author af dette arbejde

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Abstract

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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind571
Nummer7765
Sider (fra-til)366-370
Antal sider5
ISSN0028-0836
DOI
StatusUdgivet - jul. 2019

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