Structure and autoregulation of a P4-ATPase lipid flippase.
Binding Sites
Biological Transport
Calcium-Transporting ATPases
/ antagonists & inhibitors
Cryoelectron Microscopy
Enzyme Activation
Lipid Bilayers
/ metabolism
Models, Biological
Models, Molecular
Phosphatidylethanolamines
/ metabolism
Phosphatidylinositol Phosphates
/ chemistry
Phosphatidylserines
/ metabolism
Protein Domains
Saccharomyces cerevisiae
/ enzymology
Saccharomyces cerevisiae Proteins
/ antagonists & inhibitors
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
14
01
2019
accepted:
28
05
2019
pubmed:
28
6
2019
medline:
8
10
2019
entrez:
28
6
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31243363
doi: 10.1038/s41586-019-1344-7
pii: 10.1038/s41586-019-1344-7
doi:
Substances chimiques
CDC50 protein, S cerevisiae
0
DRS2 protein, S cerevisiae
0
Lipid Bilayers
0
Phosphatidylethanolamines
0
Phosphatidylinositol Phosphates
0
Phosphatidylserines
0
Saccharomyces cerevisiae Proteins
0
phosphatidylinositol 4-phosphate
0
phosphatidylethanolamine
39382-08-6
Calcium-Transporting ATPases
EC 7.2.2.10
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
366-370Références
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