Locating the Initiation Codon

How is a ribosome capable of finding the exact initiation position in order to produce the correct and complete protein from a messenger ribonucleic acid (mRNA) which consists of an immense array of nucleotides ? To find such a 'start site,' initiation factors must be implied to help, however, there would have to be a distinct structure capable of differentiating the start region compared to the entire mRNA sequence. This distinctiveness in structure was what Yahuhiro Furuichi and colleagues determined (Furuichi and Miura 1975). They revealed the presence of a 7-methyl guanosine (m7G) cap at the 5' end of eukaryotic mRNA which could act as a signal for primary attachment of the translation machinery (Furuichi and Miura, 1975). Further studies have displayed that a variety of methylated 5'-cap structures have been found in a variety of eukaryotic species, as well as viruses.

A hypothesis was subsequently put forth indicating that caps enhance the translation ability of mRNAs, by providing a marker which is apart from the uniform sequences of mRNA capable of acting as an initiator for translation. The purpose of the cap is to act as a flag for incoming translation factors which are thought to be 'flagged' onto the mRNA to begin translation initiation (Gallie 1991).

Nevertheless, once these factors are bound to the 5' end of the mRNA, these factors are not positioned at the correct location for translation, the AUG start codon, which is known to be approximately 50-100 nucleotides away from the cap. Many models have been postulated to explain the relocating process of ribosomes onto the AUG codon, each with the goal of effectively unraveling three questions:

1) Which factors are required for attachment to the mRNA ?
2) How does the 43S complex move on the mRNA ?
3) How do components of the 43S complex interact with and read mRNA triplets during the search for the correct initiation codon, with the rejection of mismatched codons ?

These questions are of prime importance, as many different hypothesis exist to explain an initiation mechanism. The scanning model of eukaryotic translation initiation, put forth by Marilyn Kozak (Kozak 1980), seems presently to have the most followers and will therefore begin our discussion of initiation mechanisms.