The integrated stress response affects cell survival or death under stress conditions, and depends on the activity of the eukaryotic translation initiation factor eIF2B. New research identifies a protein helix that modulates this response by controlling the structural states of eIF2B.

The integrated stress response (ISR) is a highly conserved translational control mechanism in eukaryotes that detects, and enables adaptation to, diverse stress stimuli1. However, this pathway is chronically activated in various neurodegenerative disorders and contributes to neuronal death2. Therefore, the prevention of a chronic ISR is considered a potential therapeutic approach for these disorders. One promising target in the ISR is the eukaryotic translation-initiation factor eIF2B. Activation of the ISR depends on inhibition of eIF2B, which involves a conformational change within eIF2B from a catalytically active to an inactive state3,4. Modulation of this transition is an attractive target for drug development, but it is unclear which part of eIF2B controls the process. In this issue of Nature Chemical Biology, Lawrence et al.5 identify the responsible element in eIF2B, revealing a new allosteric control mechanism.