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The structure and function of P5A-ATPases

Li, Ping LU ; Bågenholm, Viktoria LU ; Hägglund, Per LU ; Lindkvist-Petersson, Karin LU ; Wang, Kaituo and Gourdon, Pontus LU (2024) In Nature Communications 15(1).
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.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... (More)

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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
9605
publisher
Nature Publishing Group
external identifiers
  • scopus:85208688903
  • pmid:39505844
ISSN
2041-1723
DOI
10.1038/s41467-024-53757-6
language
English
LU publication?
yes
id
f817713e-5f4c-4b7c-8fde-e6b4a1ba81d1
date added to LUP
2025-01-09 10:36:39
date last changed
2025-07-11 15:20:54
@article{f817713e-5f4c-4b7c-8fde-e6b4a1ba81d1,
  abstract     = {{<p>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.</p>}},
  author       = {{Li, Ping and Bågenholm, Viktoria and Hägglund, Per and Lindkvist-Petersson, Karin and Wang, Kaituo and Gourdon, Pontus}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The structure and function of P5A-ATPases}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-53757-6}},
  doi          = {{10.1038/s41467-024-53757-6}},
  volume       = {{15}},
  year         = {{2024}},
}