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Structure and autoregulation of a P4-ATPase lipid flippase.
- Source :
-
Nature [Nature] 2019 Jul; Vol. 571 (7765), pp. 366-370. Date of Electronic Publication: 2019 Jun 26. - Publication Year :
- 2019
-
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.
- Subjects :
- Binding Sites
Biological Transport
Calcium-Transporting ATPases antagonists & inhibitors
Calcium-Transporting ATPases ultrastructure
Enzyme Activation
Lipid Bilayers metabolism
Models, Biological
Models, Molecular
Phosphatidylethanolamines metabolism
Phosphatidylinositol Phosphates chemistry
Phosphatidylinositol Phosphates metabolism
Phosphatidylserines metabolism
Protein Domains
Saccharomyces cerevisiae Proteins antagonists & inhibitors
Saccharomyces cerevisiae Proteins ultrastructure
Calcium-Transporting ATPases chemistry
Calcium-Transporting ATPases metabolism
Cryoelectron Microscopy
Saccharomyces cerevisiae enzymology
Saccharomyces cerevisiae Proteins chemistry
Saccharomyces cerevisiae Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 571
- Issue :
- 7765
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 31243363
- Full Text :
- https://doi.org/10.1038/s41586-019-1344-7