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Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response

By Aditya A. Anand, Lillian R. Kenner, Henry C. Nguyen, Alexander G. Myasnikov, Carolin J Klose, Lea A McGeever, Jordan C Tsai, Lakshmi E. Miller-Vedam, Peter Walter, Adam Frost

Posted 22 Dec 2018
bioRxiv DOI: 10.1101/504654

The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a GTPase, that becomes activated by eIF2B, a large two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from substrate into an inhibitor of eIF2B. We report cryoEM structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's catalytic centers to catalyze guanine nucleotide exchange. Phosphorylation refolds eIF2, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequesters it into a non-productive complex.

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