Structural features in eukaryotic mRNAs that modulate the initiation of translation.

Abstract

In higher eukaryotes, translation is modulated at the level of initiation by five aspects of mRNA structure: (i) the m7G cap; (ii) the primary sequence or context surrounding the AUG codon; (iii) the position of the AUG codon, i.e. whether or not it s “first”; (iv) secondary structure both upstream and downstream from the AUG codon; and (v) leader length. Here I briefly discuss how experimental manipulation of these features affects the fidelity and/or efficiency of initiation. Elsewhere (1) I discuss the extent to which natural mRNA leader sequences conform to these experimentally determined requirements for initiation. Although my primary concern is to document the occurrence and consequences of the five structural elements in mRNAs, I will allude now and then to why each feature has the effect it does. The explanations will invariably hark back to the scanning process by which ribosomes are thought to initiate translation. In its simplest form, the scanning model (2) postulates that a 40 S ribosomal subunit, carrying MettRNA? and an imperfectly defined set of initiation factors (3), enters at the 5‘-end of the mRNA and migrates linearly until it reaches the first AUG codon, whereupon a 60 S ribosomal subunit joins and the first peptide bond is formed (Fig. 1). Evidence in support of the scanning model has been adduced previously (2, 4, 5). The most recent evidence includes the apparent queuing of 40 S ribosomal subunits on a long, unstructured leader sequence (6) and the demonstration that 40 S subunits stall on the 5’-side of a stable hairpin structure introduced between the cap and the AUG codon (7).