An unfolded protein-induced conformational switch activates mammalian IRE1

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0002-3392-2250
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.
Hieu T Nguyen

Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States

Competing interests
No competing interests declared.
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.
Feixia Chu

Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States

Competing interests
No competing interests declared.
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.

"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.

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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.