Walter Lab

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  • Research
    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
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Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response

Anand AA, Walter P. Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response. FEBS J. Review. 10.1111/febs.15073, 2019
(PMID : 31550413) (PDF)

Abstract

The integrated stress response regulates protein synthesis under conditions of stress. Phosphorylation of translation initiation factor eIF2 by stress-sensing kinases converts eIF2 from substrate to competitive inhibitor of its dedicated nucleotide exchange factor, eIF2B, arresting translation. A drug-like molecule called ISRIB reverses the effects of eIF2 phosphorylation and restores translation by targeting eIF2B. When administered to mice, ISRIB enhances cognition and limits cognitive decline due to brain injury. To determine ISRIB’s mechanism of action we solved an atomic structure of ISRIB bound to the human eIF2B decamer. We found that ISRIB acts as a molecular staple, pinning together tetrameric subcomplexes of eIF2B along the assembly path to a fully-active, decameric enzyme. In this Structural Snapshot, we discuss ISRIB’s mechanism, its ability to rescue disease mutations in eIF2B and conservation of the enzyme and ISRIB binding pocket.

 


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