1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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An unfolded protein-induced conformational switch activates mammalian IRE1

  1. Gülsün Elif Karagöz  Is a corresponding author
  2. Diego Acosta-Alvear
  3. Hieu T Nguyen
  4. Crystal P Lee
  5. Feixia Chu
  6. Peter Walter
  1. University of California, San Francisco, United States
  2. University of New Hampshire, United States
Research Article
  • Cited 64
  • Views 4,515
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Cite this article as: eLife 2017;6:e30700 doi: 10.7554/eLife.30700

Abstract

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.

Article and author information

Author details

  1. Gülsün Elif Karagöz

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    elif@walterlab.ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3392-2250
  2. Diego Acosta-Alvear

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Hieu T Nguyen

    Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States
    Competing interests
    No competing interests declared.
  4. Crystal P Lee

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    Crystal P Lee, Currently an employee of BioMarin Pharmaceutical Inc., but the research was conducted at UCSF. The author has no competing interests to declare.
  5. Feixia Chu

    Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States
    Competing interests
    No competing interests declared.
  6. Peter Walter

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

Funding

Howard Hughes Medical Institute

  • Peter Walter

National Science Foundation (CLF #1307367)

  • Feixia Chu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lewis E Kay, University of Toronto, Canada

Publication history

  1. Received: July 27, 2017
  2. Accepted: October 2, 2017
  3. Accepted Manuscript published: October 3, 2017 (version 1)
  4. Version of Record published: November 22, 2017 (version 2)

Copyright

© 2017, Karagöz 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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