Reinitiation Protein Synthesis

Reinitiation of Protein and Peptide Synthesis

The encounter of a 80S subunit with a termination codon promotes the dissociation of the ribosomes into 60S and 40S subunit. The possibility that this dissociation is incomplete, with the 40S subunit maintaining its interactin with the mRNA, has led scientists to believe that scanning and reinitiation at a downstream AUG codon is capable. The length of the first open reading frame (ORF) however, limites this reinitiation ability. The ORF must be 30 codons or less, with no visible translation occurring with longer frames, resulting in a small and a large peptide.

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The need for the 40S subunit to reacquire an initiator tRNA-eIF2 to recognize a downstream AUG codon, requires that there be 'some' distance between termination and reinitiation which could provide time for this complexing (Hinnebusch, 1997). It is also believed that once the 60S subunit binds, the dissociation of initiation factors is gradual rather than instantaneous, staying with the complex over a certain period of time. This could explain the decrease in efficiency of reinitiation through extended periods of time (Kozak 1999).

The purpose of reinitiation, which produces one functional large protein and a small non full-length protein, is believed to be for regulatory purposes rather than to produce two proteins (Hinnebusch, 1997). Upstream ORFs might be used to limit the production of proteins which could be harmful if overproduced (Kozak, 1991a), clear ribosomes from viral mRNA before packaging (Moustaksas et al., 1993) or to initiate needed translation, through either splicing or removing the upstream ORF and promoting translation of the downstream ORF (Phelps et al., 1998). This method is depicted in the elevated levels of thrombopoietin in the genetic disease of thrombocythaemia, has been mapped to a defective splicing mutation that removes an upstream ORF and thereby promotes high levels of thrombopoietin (Wiestner et al., 1998).

In concluding, the lack of any concrete experiments and hard data on the mechanism of translation initiation leave any model of initation as a potential for future investigation. I bevieve that 'picture perfect' examples are very rare in science and the universality of the scanning model of translation initiation is one of many examples. According to the scanning model, the initial contact occurs exclusively at the 5'terminus of the mRNA which is capped. To complicate matters even more, the presence of uncapped mRNAs among few plants and animal viruses has started a search for other models of initiation.

The "internal initiation hypothesis" model, as seen in the translation of uncapped mRNAs in picornaviruses, is an "alienated version" of translation initiation, as many of the traditional concrete facts of translation initiation are not valid within this mechanism (Kozak 1992). There are few similarities between the scanning model and internal initiation mechanism, providing evidence I believe, that maybe there is not one universal mechanism of translation initiation within eukaryotes, but a 'mosaic' of different mechanisms, each one evolving to suit its own master's needs.