The eukaryotic translation
initiation factor eIF2 is a
GTPase, which brings the initiator Met-tRNAi to the ribosome as the eIF2-GTP·Met-tRNAi ternary complex (TC). TC regeneration is catalyzed by the
guanine nucleotide exchange factor (GEF)
eIF2B.
eIF2 phosphorylation by several stress-induced
kinases converts it into a competitive inhibitor of
eIF2B. Inhibition of
eIF2B activity lowers cellular TC concentrations, which in turn triggers the integrated stress response (ISR). Depending on its degree of activation and duration, the ISR protects the cell from the stress or can itself induce apoptosis. ISR dysregulation is a causative factor in the pathology of multiple
neurodegenerative disorders, while ISR inhibitors are neuroprotective. The realization that
eIF2B is a promising therapeutic target has triggered significant interest in its structure and its mechanisms of action and regulation. Recently, four groups published the cryo-electron microscopy structures of
eIF2B with its substrate
eIF2 and/or its inhibitor, phosphorylated
eIF2 [
eIF2(α-P)]. While all three structures of the nonproductive eIF2B·eIF2(α-P) complex are similar to each other, there is a sharp disagreement between the published structures of the productive eIF2B·eIF2 complex. One group reports a structure similar to that of the nonproductive complex, whereas two others observe a vastly different eIF2B·eIF2 complex. Here, we discuss the recent reports on the structure, function, and regulation of
eIF2B; the preclinical data on the use of ISR inhibitors for the treatment of
neurodegenerative disorders; and how the new structural and biochemical information can inform and influence the use of
eIF2B as a therapeutic target.