eIF2B conformation and assembly state regulates the integrated stress response
Abstract
The integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2's nucleotide exchange factor eIF2B, a two-fold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assembly in vitro and in vivo. In the absence of eIF2B's α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-EM structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into 'conjoined tetramers' with diminished substrate binding and enzymatic activity. Canonical eIF2-P-driven ISR activation thus arises due to this change in eIF2B's conformational state.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Howard Hughes Medical Institute (Investigator Grant)
- Peter Walter
Howard Hughes Medical Institute (HHMI Faculty Scholar Grant)
- Adam Frost
Calico Life Sciences LLC
- Peter Walter
The George and Judy Marcus Family Foundation
- Peter Walter
Damon Runyon Cancer Research Foundation (Postdoctoral Fellowship)
- Lan Wang
Jane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)
- Rosalie Lawrence
Belgian-American Educational Foundation (Postdoctoral Fellowship)
- Morgane Boone
Chan Zuckerberg Initiative (Investigator Grant)
- Adam Frost
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Schoof et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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