Role of the initiation factor 3 in the fidelity of initiator tRNA selection on ribosome

Initiation factors play critical roles in fine-tuning translation initiation, which is the first and the rate-limiting step in protein synthesis. In bacteria, initiation factors, IF1, IF2 and IF3 work in concert to accurately position the initiator tRNA (i-tRNA) in its formyl-aminoacyl form, and the mRNA start codon at the ribosomal P-site, setting the stage for accommodation of the aminoacyl-tRNA in response to the second codon, and formation of the first peptide bond. Among these, IF3 is particularly crucial in ensuring the fidelity of translation initiation as it is involved in the accuracy of the selection of i-tRNA and the start codon. The two-domains (N- and C-terminal) dumbbell shaped structure and dynamics of IF3 significantly influence its fidelity function. This review explores how the N- and C-terminal domains of IF3 communicate with each other and how their interaction with i-tRNA helps to maintain the fidelity of translation initiation.