Structure and autoregulation of a P4-ATPase lipid flippase

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Structure and autoregulation of a P4-ATPase lipid flippase. / Timcenko, Milena; Lyons, Joseph A.; Januliene, Dovile; Ulstrup, Jakob J.; Dieudonné, Thibaud; Montigny, Cédric; Ash, Miriam Rose; Karlsen, Jesper Lykkegaard; Boesen, Thomas; Kühlbrandt, Werner; Lenoir, Guillaume; Moeller, Arne; Nissen, Poul.

In: Nature, Vol. 571, No. 7765, 07.2019, p. 366-370.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Timcenko, M, Lyons, JA, Januliene, D, Ulstrup, JJ, Dieudonné, T, Montigny, C, Ash, MR, Karlsen, JL, Boesen, T, Kühlbrandt, W, Lenoir, G, Moeller, A & Nissen, P 2019, 'Structure and autoregulation of a P4-ATPase lipid flippase', Nature, vol. 571, no. 7765, pp. 366-370. https://doi.org/10.1038/s41586-019-1344-7

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Timcenko, Milena ; Lyons, Joseph A. ; Januliene, Dovile ; Ulstrup, Jakob J. ; Dieudonné, Thibaud ; Montigny, Cédric ; Ash, Miriam Rose ; Karlsen, Jesper Lykkegaard ; Boesen, Thomas ; Kühlbrandt, Werner ; Lenoir, Guillaume ; Moeller, Arne ; Nissen, Poul. / Structure and autoregulation of a P4-ATPase lipid flippase. In: Nature. 2019 ; Vol. 571, No. 7765. pp. 366-370.

Bibtex

@article{af5c7181a4c64ad793c2936001bb90f6,
title = "Structure and autoregulation of a P4-ATPase lipid flippase",
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.",
author = "Milena Timcenko and Lyons, {Joseph A.} and Dovile Januliene and Ulstrup, {Jakob J.} and Thibaud Dieudonn{\'e} and C{\'e}dric Montigny and Ash, {Miriam Rose} and Karlsen, {Jesper Lykkegaard} and Thomas Boesen and Werner K{\"u}hlbrandt and Guillaume Lenoir and Arne Moeller and Poul Nissen",
year = "2019",
month = "7",
doi = "10.1038/s41586-019-1344-7",
language = "English",
volume = "571",
pages = "366--370",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7765",

}

RIS

TY - JOUR

T1 - Structure and autoregulation of a P4-ATPase lipid flippase

AU - Timcenko, Milena

AU - Lyons, Joseph A.

AU - Januliene, Dovile

AU - Ulstrup, Jakob J.

AU - Dieudonné, Thibaud

AU - Montigny, Cédric

AU - Ash, Miriam Rose

AU - Karlsen, Jesper Lykkegaard

AU - Boesen, Thomas

AU - Kühlbrandt, Werner

AU - Lenoir, Guillaume

AU - Moeller, Arne

AU - Nissen, Poul

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068223301&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1344-7

DO - 10.1038/s41586-019-1344-7

M3 - Journal article

VL - 571

SP - 366

EP - 370

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7765

ER -