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Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein C(H)1 to initiate ER stress signaling

Title: Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein C(H)1 to initiate ER stress signaling
Authors: Carrara, M
Prischi, F
Nowak, PR
Kopp, MC
Ali, MMU
Item Type: Journal Article
Abstract: The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. How cells detect the accumulation of misfolded proteins remains unclear. In this study, we identify a noncanonical interaction between the ATPase domain of the ER chaperone BiP and the luminal domains of the UPR sensors Ire1 and Perk that dissociates when authentic ER unfolded protein CH1 binds to the canonical substrate binding domain of BiP. Unlike the interaction between chaperone and substrates, we found that the interaction between BiP and UPR sensors was unaffected by nucleotides. Thus, we discover that BiP is dual functional UPR sensor, sensing unfolded proteins by canonical binding to substrates and transducing this event to noncanonical, signaling interaction to Ire1 and Perk. Our observations implicate BiP as the key component for detecting ER stress and suggest an allosteric mechanism for UPR induction.
Issue Date: 18-Feb-2015
Date of Acceptance: 29-Jan-2015
URI: http://hdl.handle.net/10044/1/21845
DOI: 10.7554/eLife.03522
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd
Start Page: 1
End Page: 16
Journal / Book Title: eLife
Volume: 4
Copyright Statement: © Carrara et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Cancer Research UK
Funder's Grant Number: MR/L007436/1
11161
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
ENDOPLASMIC-RETICULUM STRESS
SENSOR IRE1
ACTIVATION
DIMERIZATION
IRE1-ALPHA
E. coli
ER stress
Ire1
UPR
biochemistry
biophysics
human
perk
structural biology
unfolded protein
Endoribonucleases
Heat-Shock Proteins
Humans
Protein Binding
Protein-Serine-Threonine Kinases
Unfolded Protein Response
eIF-2 Kinase
Humans
Endoribonucleases
Protein-Serine-Threonine Kinases
eIF-2 Kinase
Heat-Shock Proteins
Protein Binding
Unfolded Protein Response
Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
ENDOPLASMIC-RETICULUM STRESS
SENSOR IRE1
ACTIVATION
DIMERIZATION
IRE1-ALPHA
0601 Biochemistry and Cell Biology
Publication Status: Published
Article Number: ARTN e03522
Online Publication Date: 2015-02-18
Appears in Collections:Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons