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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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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. |
format | Online Article Text |
id | pubmed-5699868 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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