Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B
الباحث الأول:
Alisa F Zyryanova
الباحثين الآخرين:
Félix Weis 2 3 4 5, Alexandre Faille 2 3 4, Akeel Abo Alard 6, Ana Crespillo-Casado 2, Yusuke Sekine 2, Heather P Harding 2, Felicity Allen 7, Leopold Parts 7, Christophe Fromont 6, Peter M Fischer 6, Alan J Warren 1 3 4 5, David Ron
المجلة:
Science
تاريخ النشر:
30 مارس، 2018
مختصر البحث:
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) th…
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.
