Abstract
The precise interplay between the mRNA codon and the tRNA anticodon is crucial for ensuring efficient and accurate translation by the ribosome. The insertion of RNA nucleobase derivatives in the mRNA allowed us to modulate the stability of the codon-anticodon interaction in the decoding site of bacterial and eukaryotic ribosomes, allowing an in-depth analysis of codon recognition. We found the hydrogen bond between the N1 of purines and the N3 of pyrimidines to be sufficient for decoding of the first two codon nucleotides, whereas adequate stacking between the RNA bases is critical at the wobble position. Inosine, found in eukaryotic mRNAs, is an important example of destabilization of the codon-anticodon interaction. Whereas single inosines are efficiently translated, multiple inosines, e.g., in the serotonin receptor 5-HT2C mRNA, inhibit translation. Thus, our results indicate that despite the robustness of the decoding process, its tolerance toward the weakening of codon-anticodon interactions is limited.
Highlights
The precise interplay between the messenger RNAs (mRNAs) codon and the Transfer RNAs (tRNAs) anticodon is crucial for ensuring efficient and accurate translation by the ribosome
The codon–anticodon interaction is without doubt one of the most crucial interactions in molecular biology
Decades of research have evaluated numerous aspects and factors contributing to the speed and accuracy of the decoding process during protein synthesis
Summary
The precise interplay between the mRNA codon and the tRNA anticodon is crucial for ensuring efficient and accurate translation by the ribosome. Since inosine has been revealed in coding sequences (CDSs) of mRNAs, it is remarkable that, so far, inosine has not been observed to impair protein synthesis This potentially implies that the number of H-bonds between codon and anticodon is less critical during translation than previously assumed or that a loss in stability of the codon–anticodon interaction can be compensated for by other means[29,30]. By specific insertions of various non-natural modifications into mRNA codons (Fig. 1), we intended to define the limits for the stability of the W–C interaction in the ribosomal decoding site during protein synthesis. It is not the number of H-bonds, but rather the contact interactions that maintain the overall geometry and shape of the base pair that are critical for translation
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