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

Abstract
Data availability
Article and author information
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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.

Data availability

Diffraction data have been deposited in PDB under the accession codes 6ZYH, 6ZYI, 6ZYJ, 7A4U, 7A4V.

The following data sets were generated

1. Yan Y
2. Preissler S
3. Ron D
(2020) Crystal structure of GRP78 (70kDa heat shock protein 5 / BiP) ATPase domain in complex with ADP and calcium
Protein Data Bank, 6ZYH.

https://www.rcsb.org/structure/6ZYH
1. Yan Y
2. Preissler S
3. Ron D
(2020) Crystal structure of HSP70 ATPase domain in complex with ADP and calcium
Protein Data Bank, 6ZYI.

https://www.rcsb.org/structure/6ZYI
1. Yan Y
2. Preissler S
3. Ron D
(2020) Crystal structure of Hsc70 ATPase domain in complex with ADP and calcium
Protein Data Bank, 6ZYJ.

https://www.rcsb.org/structure/6ZYJ
1. Yan Y
2. Preissler S
3. Ron D
(2020) Crystal structure of lid-truncated apo BiP in an oligomeric state
Protein Data Bank, 7A4U.

https://www.rcsb.org/structure/7A4U
1. Yan Y
2. Preissler S
3. Ron D
(2020) Crystal structure of lid-truncated ADP-bound BiP in an oligomeric state
Protein Data Bank, 7A4V.

https://www.rcsb.org/structure/7A4V

Article and author information

Author details

Steffen Preissler

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

For correspondence
sp693@cam.ac.uk

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7936-9836
Claudia Rato

Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3971-046X
Yahui Yan

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6934-9874
Luke A Perera

Clinical Biochemistry (CIMR), University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-0032-1176
Aron Czako

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3220-2083
David Ron

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

For correspondence
dr360@medschl.cam.ac.uk

Competing interests
David Ron, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-3014-5636

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.

Copyright

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.