Dynamic Interaction of Eukaryotic Initiation Factor 4G1 (eIF4G1) with eIF4E and eIF1 Underlies Scanning-Dependent and -Independent Translation

Translation initiation of most mRNAs involves m 7G-cap binding, ribosomal scanning and AUG selection. Initiation from a m 7G-cap-proximal AUG can be bypassed resulting in leaky-scanning, except for mRNAs bearing the Translation Initiator of Short 5'UTR (TISU) element. m 7G-cap-binding is mediated by eIF4E-eIF4G1 complex. eIF4G1 also associates with eIF1 and both promote scanning and AUG selection. Understanding the dynamics and significance of these interactions is lacking. We report that eIF4G1 exists in two complexes, either with eIF4E or with eIF1. Using an eIF1 mutant impaired in eIF4G1 binding, we demonstrate that eIF1-eIF4G1 interaction is important for leaky scanning and for avoiding m 7G-cap-proximal initiation. Intriguingly, eIF4E-eIF4G1 antagonizes the scanning promoted by eIF1-eIF4G1 and is required for TISU. Mapping eIF1-binding site on eIF4G1 we unexpectedly found that eIF4E also binds it indirectly. These findings uncover the RNA features underlying regulation by eIF4E-eIF4G1 and eIF1-eIF4G1 and suggest that 43S ribosome transition from the m 7G-cap to scanning involves relocation of eIF4G1 from eIF4E to eIF1.