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Structure and autoregulation of a P4-ATPase lipid flippase.

Nature. 2019 Jul;571(7765):366-370. Epub 2019 Jun 26
Milena Timcenko 1 , Joseph A Lyons 1 , Dovile Januliene 2 , Jakob J Ulstrup 1 , Thibaud Dieudonné 3 , Cédric Montigny 3 , Miriam-Rose Ash 1 , Jesper Lykkegaard Karlsen 1 , Thomas Boesen 4 , Werner Kühlbrandt 2 , Guillaume Lenoir 5 , Arne Moeller 6 , Poul Nissen 7
Milena Timcenko 1 , Joseph A Lyons 1 , Dovile Januliene 2 , Jakob J Ulstrup 1 , Thibaud Dieudonné 3 , Cédric Montigny 3 , Miriam-Rose Ash 1 , Jesper Lykkegaard Karlsen 1 , Thomas Boesen 4 , Werner Kühlbrandt 2 , Guillaume Lenoir 5 , Arne Moeller 6 , Poul Nissen 7
+ et al

[No authors listed]

Author information
  • 1 DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • 2 Max Planck Institute for Biophysics, Frankfurt, Germany.
  • 3 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 4 Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark.
  • 5 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France. guillaume.lenoir@i2bc.paris-saclay.fr.
  • 6 Max Planck Institute for Biophysics, Frankfurt, Germany. arne.moeller@biophys.mpg.de.
  • 7 DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. pn@mbg.au.dk.

摘要


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.