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Structure paper

TitleStructure and autoregulation of a P4-ATPase lipid flippase.
Journal, issue, pagesNature, Vol. 571, Issue 7765, Page 366-370, Year 2019
Publish dateJun 26, 2019
AuthorsMilena 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 /
PubMed AbstractType 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 ...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.
External linksNature / PubMed:31243363
MethodsEM (single particle)
Resolution2.8 - 3.7 Å
Structure data

EMDB-4972, PDB-6roh:
Cryo-EM structure of the autoinhibited Drs2p-Cdc50p
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-4973, PDB-6roi:
Cryo-EM structure of the partially activated Drs2p-Cdc50p
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-4974, PDB-6roj:
Cryo-EM structure of the activated Drs2p-Cdc50p
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-PSF:
1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE / Phosphatidylserine

ChemComp-MG:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-HOH:
WATER / Water

ChemComp-2Y5:
(2R)-1-{[(R)-hydroxy{[(1R,2R,3R,4R,5S,6R)-2,3,5,6-tetrahydroxy-4-(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate

Source
  • Saccharomyces cerevisiae S288C (yeast)
  • saccharomyces cerevisiae (strain atcc 204508 / s288c) (yeast)
  • klebsiella pneumoniae (bacteria)
KeywordsLIPID TRANSPORT / Lipid Flippase / P-type ATPase / PS Transport.

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