Architecture of Human Translation Initiation Factor 3

Eukaryotic translation initiation factor 3 (eIF3) plays a central role in protein synthesis by organizing the formation of the 43S preinitiation complex. Using genetic tag visualization by electron microscopy, we reveal the molecular organization of ten human elF3 subunits, including an octameric core. The structure of elF3 bears a close resemblance to that of the proteasome lid, with a conserved spatial organization of eight core subunits containing PCI and MPN domains that coordinate functional interactions in both complexes. We further show that elF3 subunits a and c interact with initiation factors elF1 and elF1A, which control the stringency of start codon selection. Finally, we find that subunit j, which modulates messenger RNA interactions with the small ribosomal subunit, makes multiple independent interactions with the elF3 octameric core. These results highlight the conserved architecture of elF3 and how it scaffolds key factors that control translation initiation in higher eukaryotes, including humans.