The structure and function of P5A-ATPases.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39505844.
- Also identified by DOI 10.1038/s41467-024-53757-6 and PMC identifier 11541931.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.P<sub>i</sub> → E2 → E1 cycle. In the E2P and E2.P<sub>i</sub> 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.P<sub>i</sub> 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.
Medical subject headings
- Cryoelectron Microscopy
- Endoplasmic Reticulum
- Adenosine Triphosphatases