Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.
Publication Date
2020-12-09Journal Title
eLife
ISSN
2050-084X
Publisher
eLife Sciences Publications Ltd
Volume
9
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Preissler, S., Rato, C., Yan, Y., Perera, L. A., Czako, A., & Ron, D. (2020). Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.. eLife, 9 https://doi.org/10.7554/elife.62601
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.
Sponsorship
Wellcome Trust 200848/Z/16/Z
Funder references
WELLCOME TRUST (200848/Z/16/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.7554/elife.62601
This record's URL: https://www.repository.cam.ac.uk/handle/1810/314982
Rights
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/