Why is start codon selection so precise in eukaryotes?

Abstract

Translation generally initiates with the AUG codon. While initiation at GUG and UUG is permitted in prokaryotes (Archaea and Bacteria), cases of CUG initiation were recently reported in human cells. The varying stringency in translation initiation between eukaryotic and prokaryotic domains largely stems from a fundamental problem for the ribosome in recognizing a codon at the peptidyl-tRNA binding site. Initiation factors specific to each domain of life evolved to confer stringent initiation by the ribosome. The mechanistic basis for high accuracy in eukaryotic initiation is described based on recent findings concerning the role of the multifactor complex (MFC) in this process. Also discussed are whether non-AUG initiation plays any role in translational control and whether start codon accuracy is regulated in eukaryotes.

Mechanism of Cytoplasmic mRNA Translation

“…The selection of the initiation codon depends upon its nucleotide sequence context and possibly other features in the mRNA. Upon selection of the initiation codon, a series of molecular events occurs that transforms the open scanning form of the 48S scanning complex to the closed form that is ready to engage the 60S subunit (Asano, 2014). This completes the initiation phase with an elongation competent 80S ribosome at the start of the desired ORF.…”

“…Once the 43S PIC associates at the 5' end of the mRNA, scanning proceeds from 5' to 3' until a start codon is selected (Kozak, 1986;Asano, 2014). This is facilitated by binding of eIF1 to the "open" or scanning form of the 43S PIC that is stabilized by contacts with the N-terminal tail of eIF2β (Nanda et al, 2013).…”

“…It is thought that nucleotides surrounding the start codon help to engage the closed PIC conformation as the AUG codon is recognized Asano, 2014;Hinnebusch, 2014). The A at position -3 corresponds to the first nucleotide of the E-site of the 40S subunit and is occupied by eIF2 as the codon-anticodon interaction is established in the P-site.…”

“…The eIF2β N-terminal tail then interacts with the C-terminal domain of eIF5. The N-terminal domain of eIF5 is then able to interact with the C-terminal tail of eIF1A, which promotes the release of P i from the ternary complex resulting in scanning arrest at a suitable initiation codon and conversion to a "closed" PIC (Asano, 2014;Hinnebusch, 2014;Saini et al, 2014).…”

DHX29 and eIF3 cooperate in ribosomal scanning on structured mRNAs during translation initiation

“…After attachment, the 43S PIC scans the 5 ′ -untranslated region (5 ′ -UTR) for the initiation codon, where it stops and forms the 48S initiation complex (48S IC), thereby establishing the codon-anticodon interaction in the P-site of the 40S subunit. Finally, the 48S IC, with the help of eIF5 and eIF5B, binds to the 60S subunit to form the 80S initiation complex and initiate elongation (Jackson et al 2010;Hinnebusch and Lorsch 2012;Asano 2014).…”