A central helical fulcrum in eIF2B coordinates allosteric regulation of Integrated Stress Response signaling

The Integrated Stress Response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling down-regulates 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. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions are unknown. Using hydrogen deuterium exchange-mass spectrometry and cryo-EM, we identified a single alpha-helix whose orientation allosterically controls eIF2B conformation and assembly. Biochemical and signaling assays show that this 'Switch-Helix' controls eIF2B activity and signaling in cells. In sum, the Switch-Helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a novel allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases. ### Competing Interest Statement PW is an inventor of ISRIB, patent held by the Regents of the University of California that describes ISRIB and its analogs. Rights to the invention have been licensed by UCSF to Calico. For the remaining authors, no competing financial interests exist.