Abstract
AbstractThe search for mechanisms of translational regulation has yielded many experimentally identified internal ribosome entry sites (IRES). Because of the lack of sequence similarity among the experimentally IRESs, it is widely assumed that IRESs posses stable secondary structure allowing them to interact with the components of the translation machinery. Contrary to this view, here we show that IRES activity in nine yeast IRESs, mapped to 60 nt immediately upstream of the initiation AUG, is strongly associated with the lack of secondary structure of IRESs. Furthermore, the reverse complements of these IRESs, with their secondary structure more stable than those of the IRESs, exhibit little IRES activity. The generality of this association is exemplified by the observation that, in the natural vpu-env bicistronic mRNA in HIV-1, the mRNA segment (60 nt) immediately upstream of the initiation AUG of env has the weakest secondary structure among all dominant HIV-1 mRNA species. These results suggest a unified model of alternative translation initiation.
Highlights
Our finding that yeast internal ribosome entry sites (IRES) are sequence segments devoid of secondary structure explains the lack of sequence or structural similarity among IRESs, i.e., sequence segments devoid of secondary structure do not need to have any sequence or structural similarity
To test the generality of the observation that structure-less sequence segments immediately upstream of the initiation AUG can facilitate internal ribosome entry, we examined the natural vpu-env bicistronic mRNA in HIV-1 to see whether the 60 nt immediately upstream of the initiation AUG of the downstream env gene lacks secondary structure relative to other dominant HIV-1 mRNA species
The 60 nt immediately upstream of the initiation AUG of other major mRNA species all have more stable secondary structure (Table 1). These results suggest a unified model of alternative translation initiation from yeast to mammalian cells
Summary
Past effort in searching for structure conservation among IRESs, especially among eukaryotic IRESs has essentially come to nothing 1. The lack of sequence and structure conservation among reported IRESs has become one of the main reasons for IRES to be the target of ridicule 5. Our finding that yeast IRESs are sequence segments devoid of secondary structure explains the lack of sequence or structural similarity among IRESs, i.e., sequence segments devoid of secondary structure do not need to have any sequence or structural similarity. To test the generality of the observation that structure-less sequence segments immediately upstream of the initiation AUG can facilitate internal ribosome entry, we examined the natural vpu-env bicistronic mRNA in HIV-1 to see whether the 60 nt immediately upstream of the initiation AUG of the downstream env gene lacks secondary structure relative to other dominant HIV-1 mRNA species.
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