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The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR drives disease via incompletely understood metabolic mechanisms. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. I will present on the discovery of eIF2B’s allosteric mechanism: using hydrogen–deuterium exchange–mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this ‘switch-helix’ controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. To conclude the talk, I will discuss future directions leveraging our understanding of the eIF2B Switch-Helix to gain rational control over signaling in cultured cells, opening up the ability to define precise mechanisms of metabolic mechanisms of chronic stress-induced disease.
