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Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

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 2? (eIF2?) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2?, 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 ? and ? 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.

SUBMITTER: Zyryanova AF

PROVIDER: S-EPMC5889100 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

Zyryanova Alisa F AF Weis Félix F Faille Alexandre A Alard Akeel Abo AA Crespillo-Casado Ana A Sekine Yusuke Y Harding Heather P HP Allen Felicity F Parts Leopold L Fromont Christophe C Fischer Peter M PM Warren Alan J AJ Ron David D

Science (New York, N.Y.) 20180301 6383

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-angstro ...[more]

PMID: 29599245

Dataset Information

Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

Publications

Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

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