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

  1. Steffen Preissler  Is a corresponding author
  2. Claudia Rato
  3. Yahui Yan
  4. Luke A Perera
  5. Aron Czako
  6. David Ron  Is a corresponding author
  1. 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.

The following data sets were generated

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7936-9836
  2. Claudia Rato

    Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3971-046X
  3. Yahui Yan

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6934-9874
  4. Luke A Perera

    Clinical Biochemistry (CIMR), University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0032-1176
  5. Aron Czako

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3220-2083
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Version history

  1. Received: August 30, 2020
  2. Accepted: December 8, 2020
  3. Accepted Manuscript published: December 9, 2020 (version 1)
  4. 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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  1. Steffen Preissler
  2. Claudia Rato
  3. Yahui Yan
  4. Luke A Perera
  5. Aron Czako
  6. David Ron
(2020)
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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https://doi.org/10.7554/eLife.62601

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