FIGURE 1.
Met-tRNAiMet binding step in translation initiation. The eIF2·GTP complex binds to Met-tRNAiMet to form a ternary complex (step 1) that associates with the 40 S ribosomal subunit (step 2). During a late step in initiation, the GTP bound to eIF2 is hydrolyzed, and eIF2·GDP is released (step 3). A guanine nucleotide exchange factor, eIF2B, mediates exchange of GDP bound to eIF2 for GTP (steps 5–7), permitting reassembly of the ternary complex. Phosphorylation of serine 51 on the α-subunit of eIF2 by any of four known kinases leads to sequestration of eIF2B into an inactive complex (step 10), repressing the translation of most mRNAs but stimulating the translation of a selected group of mRNAs, such as the one encoding the transcription factor ATF4. GCN2 is activated when it binds to deacylated tRNA; HRI is activated both by heme deficiency and under conditions of heat shock and oxidative stress; PERK is activated in response to the accumulation of misfolded proteins in the lumen of the endoplasmic reticulum; and PKR is activated by double-stranded RNA. The binding of mRNA to the 40 S ribosomal subunit is mediated by the eIF4F complex, consisting of eIF4A, eIF4E, and eIF4G (step 8). Assembly of the eIF4F complex is regulated in part through the binding of eIF4E to 4E-BP1 (step 9).