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Li P, Bågenholm V, Hägglund P, Lindkvist-Petersson K, Wang K, Gourdon P
Nat Commun 15 (1) 9605 [2024-11-06; online 2024-11-06]
Endoplasmic reticulum (ER) membrane resident P5A-ATPases broadly affect protein biogenesis and quality control, and yet their molecular function remains debated. Here, we report cryo-EM structures of a P5A-ATPase, CtSpf1, covering multiple transport intermediates of the E1 → E1-ATP → E1P-ADP → E1P → E2P → E2.Pi → E2 → E1 cycle. In the E2P and E2.Pi states a cleft spans the entire membrane, holding a polypeptide cargo molecule. The cargo includes an ER luminal extension, pinpointed as the C-terminus in the E2.Pi state, which reenters the membrane in E2P. The E1 structure harbors a cytosol-facing cavity that is blocked by an insertion we refer to as the Plug-domain. The Plug-domain is nestled to key ATPase features and is displaced in the E1P-ADP and E1P states. Collectively, our findings are compatible with a broad range of proteins as cargo, with the P5A-ATPases serving a role in membrane removal of helices, although insertion/secretion cannot be excluded, as well as with a mechanistic role of the Plug-domain.
PubMed 39505844
DOI 10.1038/s41467-024-53757-6
Crossref 10.1038/s41467-024-53757-6
pii: 10.1038/s41467-024-53757-6