Structural Insights into the Mechanism of Scanning and Start Codon Recognition in Eukaryotic Translation Initiation

Initiation of translation on eukaryotic mRNAs generally follows the scanning mechanism, wherein a preinitiation complex (PIC) assembled on the small (40S) ribosomal subunit and containing initiator methionyl tRNA_i (Met-tRNA_i) scans the mRNA leader for an AUG codon. In a current model, the scanning PIC adopts an open conformation and rearranges to a closed state, with fully accommodated Met-tRNA_i, upon AUG recognition. Evidence from recent high-resolution structures of PICs assembled with different ligands supports this model and illuminates the molecular functions of eukaryotic initiation factors eIF1, eIF1A, and eIF2 in restricting to AUG codons the transition to the closed conformation. They also reveal that the eIF3 complex interacts with multiple functional sites in the PIC, rationalizing its participation in numerous steps of initiation.