Eukaryotic Initiation Factor - EIF1 & EIF3

EIF1 & EIF3

eIF1, eIF1A, and eIF3 all bind to the ribosome subunit-mRNA complex. They have been implicated in preventing the large ribosomal subunit from binding the small subunit before it is ready to commence elongation.

In mammals, eIF3 is the largest scaffolding initiation factor, made up of 13 subunits (a-m). It is roughly ~750 kDa and it controls the assembly of 40S ribosomal subunit on mRNA that have a 5' cap or an IRES (Internal Ribosomal Entry Site). eIF3 uses the eIF4F complex or IRES from viruses to position the mRNA strand near the exit site of the 40S ribosome subunit, thus promoting the assembly of the pre-initiation complex.

In many cancers, eIF3 is overexpressed. Under serum-deprived conditions (inactive state), eIF3 is bound to S6K1. On stimulation by either mitogens, growth factors, or drugs, mTOR/Raptor complex gets activated and, in turn, binds and phosphorylates S6K1 on T389 (linker region), causing a conformational change that causes the kinase S6K1 to dissociate from eIF3. The T389 phosphorylated S6k1 is then further phosphorylated by PDK1 on T229. This second phosphorylation fully activates the S6K1 kinase, which can then phosphorylate eIF4B, S6, and other protein targets.

Mammalian 17-kDa eukaryotic initiation factor, eIF1A (formerly designated eIF-4C), is essential for transfer of the initiator Met-tRNAf (as Met-tRNAf·eIF2·GTP ternary complex) to 40 S ribosomal subunits in the absence of mRNA to form the 40 S preinitiation complex (40 S·Met-tRNAf·eIF2·GTP). Furthermore, eIF1A acts catalytically in this reaction to mediate highly efficient transfer of the Met-tRNAf·eIF2·GTP ternary complex to 40 S ribosomal subunits. The 40 S complex formed is free of eIF1A which indicates that its role in 40 S preinitiation complex formation is not to stabilize the binding of Met-tRNAf to 40 S ribosomes. Additionally, the eIF1A-mediated 40 S initiation complex formed in the presence of AUG codon efficiently joins 60 S ribosomal subunits in an eIF5-dependent reaction to form a functional 80 S initiation complex. Though found in some reports, eIF1A probably plays no role either in the subunit joining reaction or in the generation of ribosomal subunits from 80 S ribosomes. The major function of eIF1A is to mediate the transfer of Met-tRNAf to 40 S ribosomal subunits to form the 40 S preinitiation complex.