GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity

eIF2B is the guanine nucleotide exchange factor (GEF) required for cytoplasmic protein synthesis initiation in eukaryotes and its regulation within the integrated stress response (ISR). It activates its partner factor eIF2, thereby promoting translation initiation. Here we provide evidence through biochemical and genetic approaches that eIF2B can bind directly to GTP and this can enhance its rate of GEF activity toward eIF2-GDP in vitro. GTP binds to a subcomplex of the eIF2B gamma and epsilon subunits. The eIF2Bg amino-terminal domain shares structural homology with hexose sugar phosphate pyrophosphorylase enzymes that bind specific nucleotides. A K66R mutation in eIF2B gamma is especially sensitive to guanine or GTP in a range of functional assays. Taken together, our data suggest eIF2B gamma-may act as a sensor of purine nucleotide availability and thus modulate eIF2B activity and protein synthesis in response to fluctuations in cellular nucleotide levels.

Automated summary

The research revealed that eIF2B can directly bind to GTP, enhancing its GEF activity towards eIF2-GDP. The K66R mutation in eIF2B gamma is particularly sensitive to guanine or GTP, indicating its potential role as a sensor of purine nucleotide availability.