摘要：SummaryeIF2B 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–GDPin vitro. GTP binds to a subcomplex of the eIF2Bγ and ε subunits. The eIF2Bγ amino-terminal domain shares structural homology with hexose sugar phosphate pyrophosphorylase enzymes that bind specific nucleotides. A K66R mutation in eIF2Bγ is especially sensitive to guanine or GTP in a range of functional assays. Taken together, our data suggest eIF2Bγ 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.Graphical abstractDisplay OmittedHighlights•eIF2B, the GDP exchange factor for eIF2 in translation and its control, binds GTP•GTP binding enhances the rate of eIF2B GEF activity toward eIF2–GDPin vitro•A K66R mutation in yeast eIF2Bγ is sensitive to guaninein vivoor GTPin vitro•eIF2B may act as a sensor of purine nucleotide availabilityBiological sciences; Molecular biology; Cell biology; Biomechanics
