9vq2
Cryo-EM structure of a human flippase mutant ATP11C Q79A-CDC50A in the PtdSer-occluded E2-AlF 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 PubMedClosely related P4-ATPases, ATP11A and ATP11C, act as major phospholipid flippases in the plasma membrane of mammalian cells, with strict substrate specificity for phosphatidylserine (PS) and phosphatidylethanolamine (PE), but not for phosphatidylcholine (PC), thereby contributing to the asymmetric distribution of PS and PE across bilayers. A previously reported disease-associated Q84E mutation in ATP11A confers the ability to flip PC, implicating the involvement of this conserved residue in substrate specificity. We performed cryo-EM analysis for the equivalent mutant Q79E of ATP11C to address the structural basis for its unusual substrate specificity. Measurement of ATPase activity revealed that the ATP11C Q79E mutant retained PS-dependent activity, whilst gaining robust PC-dependent activity, indicative of expanded substrate specificity, consistent with reported properties in ATP11A Q84E. The cryo-EM structure of ATP11C Q79E mutant in the PC-occluded E2-P(i) state revealed a PC molecule in a reshaped binding pocket. Due to the Q79E mutation and associated conformational changes in its surrounding residues, including Ser91and Asn352, the binding pocket has additional space to accommodate the bulky choline headgroup. Our results provide structural and functional insights into how a single point mutation can alter substrate specificity in a P4-ATPase. Cryo-EM Structure of the ATP11C Q79E Mutant Reveals the Structural Basis for Altered Phospholipid Recognition.,Qian Y, Gopalasingam CC, Gerle C, Shigematsu H, Abe K, Oshima A J Biol Chem. 2025 Nov 12:110935. doi: 10.1016/j.jbc.2025.110935. PMID:41237907[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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