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An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation
Journal article   Open access   Peer reviewed

An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation

Daniela Ricci, Stephen Tutton, Ilaria Marrocco, Mingjie Ying, Daniel Blumenthal, Daniela Eletto, Jade Vargas, Sarah Boyle, Hossein Fazelinia, Lei Qian, …
The Journal of biological chemistry, v 296, 100781
Jan 2021
DOI: https://doi.org/10.1016/j.jbc.2021.100781
PMID: 34000298
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
http://www.jbc.org/article/S0021925821005743/pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1016/j.jbc.2021.100781View
Published, Version of Record (VoR) Open

Abstract

conformational change differential autophosphorylation IRE1 oligomerization kinase RNase interdomain helix RNase activity
The unfolded protein response plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its endoplasmic reticulum luminal domain, IRE1α dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1α, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix αK, located between the kinase and RNase domains of IRE1α, in conveying this critical conformational change. Using constructs containing mutations within this interdomain helix, we show that distinct substitutions affect oligomerization, kinase activity, and the RNase activity of IRE1α differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Of importance, an RNase-inactive mutant, L827P, can still dimerize with wildtype monomers, but this mutation inactivates the wildtype molecule and renders leukemic cells more susceptible to stress. We surmise that helix αK is a conduit for the activation of IRE1α in response to stress.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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