7vsh
Cryo-EM structure of a human ATP11C-CDC50A flippase reconstituted in the Nanodisc in E1P state.
Structural highlights
DiseaseAT11C_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionAT11C_HUMAN Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. In the cell membrane of erythrocytes, it is required to maintain phosphatidylserine (PS) in the inner leaflet preventing its exposure on the surface. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized PS is a phagocytic signal for splenic macrophages (PubMed:26944472). Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (By similarity). Required for B cell differentiation past the pro-B cell stage (By similarity). Seems to mediate PS flipping in pro-B cells (By similarity). May be involved in the transport of cholestatic bile acids (By similarity).[UniProtKB:Q9QZW0][1] Publication Abstract from PubMedATP11C is a member of the P4-ATPase flippase family that mediates translocation of phosphatidylserine (PtdSer) across the lipid bilayer. In order to characterize the structure and function of ATP11C in a model natural lipid environment, we revisited and optimized a quick procedure for reconstituting ATP11C into Nanodiscs using methyl-beta-cyclodextrin as a reagent for the detergent removal. ATP11C was efficiently reconstituted with the endogenous lipid, or the mixture of endogenous lipid and synthetic dioleoylphosphatidylcholine (DOPC)/dioleoylphosphatidylserine (DOPS), all of which retained the ATPase activity. We obtained 3.4 A and 3.9 A structures using single-particle cryo-electron microscopy (cryo-EM) of AlF- and BeF-stabilized ATP11C transport intermediates, respectively, in a bilayer containing DOPS. We show that the latter exhibited a distended inner membrane around ATP11C transmembrane helix 2, possibly reflecting the perturbation needed for phospholipid release to the lipid bilayer. Our structures of ATP11C in the lipid membrane indicate that the membrane boundary varies upon conformational changes of the enzyme and is no longer flat around the protein, a change that likely contributes to phospholipid translocation across the membrane leaflets. Cryo-EM of the ATP11C flippase reconstituted in Nanodiscs shows a distended phospholipid bilayer inner membrane around transmembrane helix 2.,Nakanishi H, Hayashida K, Nishizawa T, Oshima A, Abe K J Biol Chem. 2022 Jan;298(1):101498. doi: 10.1016/j.jbc.2021.101498. Epub 2021 , Dec 17. PMID:34922944[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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