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Structure and autoregulation of a P4-ATPase lipid flippase

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  • Milena Timcenko
  • ,
  • Joseph A. Lyons
  • Dovile Januliene, Max Planck Institute of Biophysics
  • ,
  • Jakob J. Ulstrup
  • ,
  • Thibaud Dieudonné, Université Paris-Sud 11
  • ,
  • Cédric Montigny, Université Paris-Sud 11
  • ,
  • Miriam Rose Ash
  • ,
  • Jesper Lykkegaard Karlsen
  • Thomas Boesen
  • Werner Kühlbrandt, Max Planck Institute of Biophysics
  • ,
  • Guillaume Lenoir, Université Paris-Sud 11
  • ,
  • Arne Moeller, Max Planck Institute of Biophysics
  • ,
  • Poul Nissen

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.

Original languageEnglish
Pages (from-to)366-370
Number of pages5
Publication statusPublished - Jul 2019

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