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Towards the understanding of the transport mechanism of membrane lipids

Flippases are membrane proteins that help maintain lipid asymmetry between the two "layers" of cell membranes. In humans, some mutations of these proteins lead to rare genetic diseases. The work of scientists from the Institute for Integrative Biology of the Cell (University of Paris-Sud/CEA/CNRS), the University of Aarhus (Denmark) and the Max Planck Institute in Frankfurt (Germany) reveals the first high-resolution structures of one of these proteins.

Biological membranes are organized as two layers of lipids in which proteins are partially or totally embedded. The lipid composition of the two leaflets is different, thereby controlling many biological processes such as membrane trafficking or cell signaling. This lipid asymmetry results from many mechanisms whose main contributors are transmembrane lipid transport proteins. Floppases catalyse the transport of lipids from the inner (cytosolic) to the outer (exoplasmic) membrane leaflet and flippases do the opposite. In humans, mutations of several flippase homologs are involved in rare forms of intrahepatic cholestasis or neurological disease (cerebellar ataxia syndrome associated with intellectual disability).

The teams of Guillaume Lenoir (I2BC), Poul Nissen (University of Aarhus, Denmark) and Arne Möller (Max Planck Institute in Frankfurt, Germany) have collaborated to determine the structure of the Drs2p-Cdc50p flippase from S. cerevisiae by cryo-electron microscopy. More precisely, the structure of this flippase was studied in three different conformations : a conformation in which it is auto-inhibited, a conformation in which it is fully active and a third intermediate conformation.

Proposed autoregulation mechanism
Proposed mechanism for the regulation of the Drs2p-Cdc50p lipid flippase

PI4P binding triggers formation of an amphipathic helix in the membrane domain, partially disrupts the binding of the auto-inhibitory C-terminus of Drs2p and induces a rigid-body movement of the catalytic A, N, and P domains. For activation to be complete, the C-terminus must be fully displaced, for instance through the binding of the regulatory Gea2p protein. The catalytic domains subsequently operate further rearrangements which are transmitted to transmembrane helices, resulting in the opening of a putative lipid-entry site.

The three structures obtained at resolutions of 2.8 to 3.7 Å reveal the mechanism by which the C-terminal end of Drs2p inhibits complex activity and the first steps in auto-inhibition relief by PI4P. Comparison of the three structures also reveals the existence of a cavity through which the polar headgroup of the substrate lipid (mainly phosphatidylserine) might be transported, as it travels from one layer of the cell membrane to the other.

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Reference : Structure and autoregulation of a P4-ATPase lipid flippase
M. Timcenko, J. A. Lyons, D. Januliene, J. Ulstrup, T. Dieudonné, C. Montigny, M. R. Ash, Jesper Lykkegaard Karlsen, T. Boesen, W. Kühlbrandt, G. Lenoir, A. Möller, P. Nissen
Nature - DOI : 10.1038/s41586-019-1344-7

Contact : Guillaume Lenoir

par Communication - publié le