Journal article
An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation
The Journal of biological chemistry, v 296, 100781
Jan 2021
PMID: 34000298
Featured in Collection : UN Sustainable Development Goals @ Drexel
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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Details
- Title
- An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation
- Creators
- Daniela Ricci - Children's Hospital of PhiladelphiaStephen Tutton - Children's Hospital of PhiladelphiaIlaria Marrocco - Children's Hospital of PhiladelphiaMingjie Ying - Drexel UniversityDaniel Blumenthal - Children's Hospital of PhiladelphiaDaniela Eletto - Children's Hospital of PhiladelphiaJade Vargas - Children's Hospital of PhiladelphiaSarah Boyle - Children's Hospital of PhiladelphiaHossein Fazelinia - Children's Hospital of PhiladelphiaLei Qian - Children's Hospital of PhiladelphiaKrishna Suresh - University of PennsylvaniaDeanne Taylor - Children's Hospital of PhiladelphiaJames C. Paton - University of AdelaideAdrienne W. Paton - University of AdelaideChih-Hang Anthony Tang - The Wistar InstituteChih-Chi Andrew Hu - The Wistar InstituteRavi Radhakrishnan - University of PennsylvaniaTali Gidalevitz - Drexel UniversityYair Argon - Children's Hospital of Philadelphia
- Publication Details
- The Journal of biological chemistry, v 296, 100781
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Web of Science ID
- WOS:000674717300003
- Scopus ID
- 2-s2.0-85108179356
- Other Identifier
- 991020099057704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology