Molecular mechanisms of translation initiation in eukaryotes

Translation initiation is a complex process in which initiator tRNA, 40S, a nd 60S ribosomal subunits are assembled by eukaryotic initiation factors (e IFs) into an 805 ribosome at the initiation codon of mRNA, The cap-binding complex eIF4F and the factors eIF4A and eIF4B are required for binding of 4 3S complexes (comprising a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5 ' end of capped mRNA but are not sufficient to promote ribosomal scannin g to the initiation codon, eIF1A enhances the ability of eIF1 to dissociate aberrantly assembled complexes from mRNA, and these factors synergisticall y mediate 48S complex assembly at the initiation codon, Joining of 48S comp lexes to 60S subunits to form 805 ribosomes requires eIF5B, which has an es sential ribosome-dependent GTPase activity and hydrolysis of eIF2-bound GTP induced by eIF5. Initiation on a few mRNAs is cap-independent and occurs i nstead by internal ribosomal entry. Encephalomyocarditis virus (EMCV) and h epatitis C virus epitomize distinct mechanisms of internal ribosomal entry site (IRES)-mediated initiation. The eIF4A and eIF4G subunits of eIF4F bind immediately upstream of the EMCV initiation codon and promote binding of 4 3S complexes. EMCV initiation does not involve scanning and does not requir e eIF1, eIF1A. and the eIF4E subunit of eIF4F, Initiation on some EMCV-like IRESs requires additional noncanonical initiation factors, which alter IRE S conformation and promote binding of eIF4A/4G. Initiation on the hepatitis C virus IRES is even simpler: 43S complexes containing only eIF2 and eIF3 bind directly to the initiation codon as a result of specific interaction o f the IRES and the 40S subunit.