An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation.
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Date
2021
Authors
Ricci, D.
Tutton, S.
Marrocco, I.
Ying, M.
Blumenthal, D.
Eletto, D.
Vargas, J.
Boyle, S.
Fazelinia, H.
Qian, L.
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Journal article
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Journal of Biological Chemistry, 2021; 296:100781-1-100781-16
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Daniela Ricci, Stephen Tutton, Ilaria Marrocco, Mingjie Ying, Daniel Blumenthal, Daniela Eletto, Jade Vargas, Sarah Boyle, Hossein Fazelinia, Lei Qian, Krishna Suresh, Deanne Taylor, James C. Paton, Adrienne W. Paton, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Ravi Radhakrishnan, Tali Gidalevitz, and Yair Argon
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Abstract
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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© 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).