Alisa F. Zyryanova
Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B
Zyryanova, Alisa F.; Weis, F�lix; Faille, Alexandre; Abo Alard, Akeel; Crespillo-Casado, Ana; Sekine, Yusuke; Harding, Heather P.; Allen, Felicity; Parts, Leopold; Fromont, Christoph; Fischer, Peter M.; Warren, Alan J.; Ron, David
Authors
F�lix Weis
Alexandre Faille
Akeel Abo Alard
Ana Crespillo-Casado
Yusuke Sekine
Heather P. Harding
Felicity Allen
Leopold Parts
Christoph Fromont
Peter M. Fischer
Alan J. Warren
David Ron
Abstract
The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo–electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the β and δ regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.
Citation
Zyryanova, A. F., Weis, F., Faille, A., Abo Alard, A., Crespillo-Casado, A., Sekine, Y., …Ron, D. (2018). Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359(6383), https://doi.org/10.1126/science.aar5129
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 9, 2018 |
Publication Date | Mar 30, 2018 |
Deposit Date | Apr 6, 2018 |
Publicly Available Date | Mar 29, 2024 |
Journal | Science |
Print ISSN | 0036-8075 |
Electronic ISSN | 1095-9203 |
Publisher | American Association for the Advancement of Science |
Peer Reviewed | Peer Reviewed |
Volume | 359 |
Issue | 6383 |
DOI | https://doi.org/10.1126/science.aar5129 |
Public URL | https://nottingham-repository.worktribe.com/output/922354 |
Publisher URL | http://science.sciencemag.org/content/359/6383/1533.long |
Files
Zyryanova, A.F. et al. Science 2018 author version.pdf
(1.4 Mb)
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