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

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...

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Published in:Science (American Association for the Advancement of Science) Vol. 365; no. 6458; p. 1149
Main Authors: Hiraizumi, Masahiro, Yamashita, Keitaro, Nishizawa, Tomohiro, Nureki, Osamu
Format: Journal Article
Language:English
Published: United States 13.09.2019
Subjects:
Adenosine Triphosphatases - chemistry
Adenosine Triphosphate - chemistry
Amino Acid Sequence
Binding Sites
Cryoelectron Microscopy
HEK293 Cells
Humans
Membrane Proteins - chemistry
Models, Molecular
Phosphatidylserines
Phospholipid Transfer Proteins - chemistry
Phospholipids - metabolism
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Quaternary
Sequence Alignment
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aay3353