Research Article

Cryo-EM structures capture the transport cycle of the P4-ATPase flippase

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Science  13 Sep 2019:
Vol. 365, Issue 6458, pp. 1149-1155
DOI: 10.1126/science.aay3353

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Flipping a lipid

The membranes of eukaryotic cells have different lipid compositions in their inner and outer leaflets. Enzymes known as flippases and floppases use the energy from adenosine triphosphate (ATP) hydrolysis to translocate lipids against a concentration gradient from the outer to inner or inner to outer leaflets, respectively. Flippases are P4-type ATPases that are important in processes such as membrane trafficking, signaling, and apoptosis. Hiraizumi et al. report the cryo–electron microscopy structure of six intermediates of the human flippase ATP8A1 bound to the partner protein it requires for function, CDC50. ATP binding and autophosphorylation of ATP8A1 drive a cycle of conformations in which lipids bind differently, powering translocation.

Science, this issue p. 1149


In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is critical for membrane trafficking and signaling pathways. Here, we report the cryo–electron microscopy structures of six distinct intermediates of the human ATP8A1-CDC50a heterocomplex at resolutions of 2.6 to 3.3 angstroms, elucidating the lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site in the phosphorylation domain, accompanied by lateral shifts of the first and second transmembrane helices, thereby allowing phosphatidylserine binding. The phospholipid head group passes through the hydrophilic cleft, while the acyl chain is exposed toward the lipid environment. These findings advance our understanding of the flippase mechanism and the disease-associated mutants of P4-ATPases.

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