7dsh

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Cryo-EM structure of Dnf1 from Saccharomyces cerevisiae in 90PS with AMPPCP (E1-ATP state)

Structural highlights

7dsh is a 2 chain structure with sequence from Saccharomyces cerevisiae and Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.67Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ATC5_YEAST Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of glucosylceramide, phosphatidylcholine, phosphatidylethanolamine, and small amounts of phosphatidylserine from the lumenal to the cytosolic leaflet of the cell membrane and ensures the maintenance of asymmetric distribution of phospholipids (PubMed:12631737, PubMed:22308393, PubMed:22791719, PubMed:23302692, PubMed:31786280, PubMed:33060204, PubMed:33320091, PubMed:35294892). Does not appear to transport sphingomyelin, inositol phosphoceramide, or phosphatidic acid (PubMed:12631737, PubMed:22308393, PubMed:33320091). Required for efficient endocytosis (PubMed:12631737).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Type 4 P-type ATPases (P4-ATPases) actively and selectively translocate phospholipids across membrane bilayers. Driven by ATP hydrolysis, P4-ATPases undergo conformational changes during lipid flipping. It is unclear how the active flipping states of P4-ATPases are regulated in the lipid membranes, especially for phosphatidylcholine (PC)-flipping P4-ATPases whose substrate, PC, is a substantial component of membranes. Here, we report the cryoelectron microscopy structures of a yeast PC-flipping P4-ATPase, Dnf1, in lipid environments. In native yeast lipids, Dnf1 adopts a conformation in which the lipid flipping pathway is disrupted. Only when the lipid composition is changed can Dnf1 be captured in the active conformations that enable lipid flipping. These results suggest that, in the native membrane, Dnf1 may stay in an idle conformation that is unable to support the trans-membrane movement of lipids. Dnf1 may have altered conformational preferences in membranes with different lipid compositions.

Conformational changes of a phosphatidylcholine flippase in lipid membranes.,Xu J, He Y, Wu X, Li L Cell Rep. 2022 Mar 15;38(11):110518. doi: 10.1016/j.celrep.2022.110518. PMID:35294892^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pomorski T, Lombardi R, Riezman H, Devaux PF, van Meer G, Holthuis JC. Drs2p-related P-type ATPases Dnf1p and Dnf2p are required for phospholipid translocation across the yeast plasma membrane and serve a role in endocytosis. Mol Biol Cell. 2003 Mar;14(3):1240-54. PMID:12631737 doi:10.1091/mbc.e02-08-0501
↑ Baldridge RD, Graham TR. Identification of residues defining phospholipid flippase substrate specificity of type IV P-type ATPases. Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):E290-8. PMID:22308393 doi:10.1073/pnas.1115725109
↑ Puts CF, Panatala R, Hennrich H, Tsareva A, Williamson P, Holthuis JC. Mapping functional interactions in a heterodimeric phospholipid pump. J Biol Chem. 2012 Aug 31;287(36):30529-40. PMID:22791719 doi:10.1074/jbc.M112.371088
↑ Baldridge RD, Graham TR. Two-gate mechanism for phospholipid selection and transport by type IV P-type ATPases. Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):E358-67. PMID:23302692 doi:10.1073/pnas.1216948110
↑ Huang Y, Takar M, Best JT, Graham TR. Conserved mechanism of phospholipid substrate recognition by the P4-ATPase Neo1 from Saccharomyces cerevisiae. Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb;1865(2):158581. PMID:31786280 doi:10.1016/j.bbalip.2019.158581
↑ Jain BK, Roland BP, Graham TR. Exofacial membrane composition and lipid metabolism regulates plasma membrane P4-ATPase substrate specificity. J Biol Chem. 2020 Dec 25;295(52):17997-18009. PMID:33060204 doi:10.1074/jbc.RA120.014794
↑ Bai L, You Q, Jain BK, Duan HD, Kovach A, Graham TR, Li H. Transport mechanism of P4 ATPase phosphatidylcholine flippases. Elife. 2020 Dec 15;9:e62163. PMID:33320091 doi:10.7554/eLife.62163
↑ Xu J, He Y, Wu X, Li L. Conformational changes of a phosphatidylcholine flippase in lipid membranes. Cell Rep. 2022 Mar 15;38(11):110518. PMID:35294892 doi:10.1016/j.celrep.2022.110518
↑ Xu J, He Y, Wu X, Li L. Conformational changes of a phosphatidylcholine flippase in lipid membranes. Cell Rep. 2022 Mar 15;38(11):110518. PMID:35294892 doi:10.1016/j.celrep.2022.110518