Eukaryotic translation initiation factor 2B (eIF2B), a heterodecameric complex of two sets of the alpha, beta, gamma, delta, and epsilon subunits, is the guanine nucleotide exchange factor (GEF) specific for eIF2, a heterotrimeric G protein consisting of the alpha, beta, and gamma subunits. The eIF2 protein binds GTP on the gamma subunits and delivers an initiator methionyl-tRNA (Met-tRNA(i)(Met)) to the ribosome. The GEF activity of eIF2B is inhibited by stress-induced phosphorylation of Ser51 in the alpha subunit of eIF2, which leads to lower amounts of active eIF2 and a limited quantity of Met-tRNA(i)(Met) for the ribosome, resulting in global repression of translation. However, the structural mechanism of the GEF activity inhibition remained enigmatic, and therefore the three-dimensional structure of the entire eIF2B molecule had been awaited. Recently, we determined the crystal structure of Schizosaccharomyces pombe eIF2B. In this Structural Snapshot, we present the structural features of eIF2B and the mechanism underlying the GEF activity inhibition by the phosphorylation of eIF2 alpha, elucidated from structure-based in vitro analyses.
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