Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes
- University of Cambridge, United Kingdom
Abstract
The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.
Data availability
Diffraction data have been deposited in PDB under the accession codes 6ZYH, 6ZYI, 6ZYJ, 7A4U, 7A4V.
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Crystal structure of lid-truncated apo BiP in an oligomeric stateProtein Data Bank, 7A4U.
Article and author information
Author details
Funding
Wellcome (200848/Z/16/Z)
- David Ron
Wellcome (996 100140)
- David Ron
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
Version history
- Received: August 30, 2020
- Accepted: December 8, 2020
- Accepted Manuscript published: December 9, 2020 (version 1)
- Version of Record published: December 23, 2020 (version 2)
Copyright
© 2020, Preissler et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes
eLife 9:e62601.
https://doi.org/10.7554/eLife.62601
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