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 () and Poul Nissen ()
Additional contact information
Milena Timcenko: Aarhus University
Joseph A. Lyons: Aarhus University
Dovile Januliene: Max Planck Institute for Biophysics
Jakob J. Ulstrup: Aarhus University
Thibaud Dieudonné: Université Paris-Sud, Université Paris-Saclay
Cédric Montigny: Université Paris-Sud, Université Paris-Saclay
Miriam-Rose Ash: Aarhus University
Jesper Lykkegaard Karlsen: Aarhus University
Thomas Boesen: Aarhus University
Werner Kühlbrandt: Max Planck Institute for Biophysics
Guillaume Lenoir: Université Paris-Sud, Université Paris-Saclay
Arne Moeller: Max Planck Institute for Biophysics
Poul Nissen: Aarhus University

Nature, 2019, vol. 571, issue 7765, 366-370

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1344-7

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