Model for eukaryotic translation initiation

Eukaryotic translation initiation and ribosomal subunit recycling are depicted as a nine-stage process. In stage 1, ribosome recycling occurs to yield separated 40S and 60S ribosomal subunits. In stage 2, eukaryotic initiation factor 2 (eIF2), GTP, and an initiator methionine tRNA (Met-tRNA^Met_i) form a ternary complex called eIF2–GTP–Met-tRNA^Met_i. In stage 3, the 43S preinitiation complex forms. This complex includes a 40S subunit, eIF1, eIF1A, eIF3, eIF2–GTP–Met-tRNAMeti and probably eIF5. In stage 4, mRNA activation occurs, during which the mRNA cap-proximal region is unwound in an ATP-dependent manner by eIF4F with eIF4B. The mRNA loops into a circular configuration. In stage 5, the 43S preinitiation complex attaches to the unwound mRNA region. In stage 6, the 43S complex scans the 5′ UTR in a 5′ to 3′ direction. In stage 7, the initiation codon is recognized, and the 48S initiation complex forms, which switches the scanning complex to a 'closed' conformation. This leads to the displacement of eIF1 to allow eIF5-mediated hydrolysis of eIF2-bound GTP and inorganic phosphate (Pi) release. In stage 8, the 60S subunit joins the 48S complex, and there is concomitant displacement of GDP-bound eIF2 and other factors (eIF1, eIF3, eIF4B, eIF4F, and eIF5) mediated by eIF5B. In stage 9, hydrolysis of eIF5B-bound GTP occurs, and eIF1A and GDP-bound eIF5B are released from the assembled elongation-competent 80S ribosomes. Translation is a cyclical process. Following elongation, termination occurs, followed by recycling (stage 1), which generates separated ribosomal subunits, and the process begins again.