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Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling

Carrara, Marta and Prischi, Filippo and Nowak, Piotr R and Kopp, Megan C and Ali, Maruf MU (2015) 'Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling.' eLife, 4 (4). ISSN 2050-084X

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Abstract

<jats:p>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.</jats:p>

Item Type: Article
Uncontrolled Keywords: Humans; Endoribonucleases; eIF-2 Kinase; Heat-Shock Proteins; Protein Binding; Unfolded Protein Response; Endoplasmic Reticulum Chaperone BiP; Protein Serine-Threonine Kinases
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 22 Oct 2015 11:22
Last Modified: 07 Jan 2022 19:02
URI: http://repository.essex.ac.uk/id/eprint/15341

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