An unfolded protein-induced conformational switch activates mammalian IRE1

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 stres...

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Autores principales: Karagöz, G Elif, Acosta-Alvear, Diego, Nguyen, Hieu T, Lee, Crystal P, Chu, Feixia, Walter, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699868/
https://www.ncbi.nlm.nih.gov/pubmed/28971800
http://dx.doi.org/10.7554/eLife.30700
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author Karagöz, G Elif
Acosta-Alvear, Diego
Nguyen, Hieu T
Lee, Crystal P
Chu, Feixia
Walter, Peter
author_facet Karagöz, G Elif
Acosta-Alvear, Diego
Nguyen, Hieu T
Lee, Crystal P
Chu, Feixia
Walter, Peter
author_sort Karagöz, G Elif
collection PubMed
description 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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spelling pubmed-56998682017-11-24 An unfolded protein-induced conformational switch activates mammalian IRE1 Karagöz, G Elif Acosta-Alvear, Diego Nguyen, Hieu T Lee, Crystal P Chu, Feixia Walter, Peter eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2017-10-03 /pmc/articles/PMC5699868/ /pubmed/28971800 http://dx.doi.org/10.7554/eLife.30700 Text en © 2017, Karagöz et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Karagöz, G Elif
Acosta-Alvear, Diego
Nguyen, Hieu T
Lee, Crystal P
Chu, Feixia
Walter, Peter
An unfolded protein-induced conformational switch activates mammalian IRE1
title An unfolded protein-induced conformational switch activates mammalian IRE1
title_full An unfolded protein-induced conformational switch activates mammalian IRE1
title_fullStr An unfolded protein-induced conformational switch activates mammalian IRE1
title_full_unstemmed An unfolded protein-induced conformational switch activates mammalian IRE1
title_short An unfolded protein-induced conformational switch activates mammalian IRE1
title_sort unfolded protein-induced conformational switch activates mammalian ire1
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699868/
https://www.ncbi.nlm.nih.gov/pubmed/28971800
http://dx.doi.org/10.7554/eLife.30700
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