Translation Initiation by Internal Ribosome Binding of Eukaryotic mRNA Molecules

Abstract

A unique feature of all eukaryotic mRNA molecules is the presence of a m⁷GpppN (where N can be any nucleotide) “cap” structure at the 5’ end of the RNAs (Shatkin, 1976; Banerjee, 1980). This cap structure interacts with eukaryotic initiation factor (elF) 4F, a three subunit protein complex composed of elF-4E, eIF4A and p220 (Tahara et al. 1981; Edery et al., 1983; Grifo et al., 1983). It is thought that binding of elF-4F to the 5’- terminal cap-structure facilitates the recruitment of the 40S ribosomal subunit to the 5’ end of the mRNA (Ray et al., 1985; Rozen et al., 1990).Subsequently, the 40S ribosomal subunit, carrying factors elF2-GTP, elF3 and the initiator tRNA (tRNA^meti), is postulated to move in a 5’ to 3’ direction along the mRNA until an appropriate AUG codon is encountered, which is then used to start protein synthesis. This model is known as the “scanning mechanism” for translation initiation (Kozak, 1989a). Evidence supporting this model includes the inability of circular RNAs to bind eukaryotic ribosomes (Kozak, 1979; Konarska et al., 1981), suggesting that the 40S subunit can enter the mRNA only at its free 5’ end. Furthermore, 40S subunits can be trapped both upstream of the AUG start codon if ATP is depleted (Kozak, 1980) and upstream of stable RNA hairpin structures (Kozak, 1989b). Thus, the scanning mechanism can explain translation initiation of most vertebrate mRNAs containing short 5’ noncoding regions (5’NCRs), harboring one or only a few AUG codons.