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Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes

Published version
Peer-reviewed

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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.

Description

Keywords

Research Article, Biochemistry and Chemical Biology, Cell Biology, BiP, Grp78, calcium, endoplasmic reticulum, oligomerisation, None

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X

Volume Title

9

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Wellcome (200848/Z/16/Z)
Wellcome (996 100140)