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Journal Article

Structure and autoregulation of a P4-ATPase lipid flippase

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Januliene,  Dovilé
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Kühlbrandt,  Werner       
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Möller,  Arne
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Timcenko, M., Lyons, J. A., Januliene, D., Ulstrup, J. J., Dieudonné, T., Montigny, C., et al. (2019). Structure and autoregulation of a P4-ATPase lipid flippase. Nature, 571(7765), 366-370. doi:10.1038/s41586-019-1344-7.


Cite as: https://hdl.handle.net/21.11116/0000-0003-E71F-7
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.