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Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding

Nature Structural & Molecular Biology volume 20, pages 237–243 (2013)Cite this article

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Abstract

The choice of codons can influence local translation kinetics during protein synthesis. Whether codon preference is linked to cotranslational regulation of polypeptide folding remains unclear. Here, we derive a revised translational efficiency scale that incorporates the competition between tRNA supply and demand. Applying this scale to ten closely related yeast species, we uncover the evolutionary conservation of codon optimality in eukaryotes. This analysis reveals universal patterns of conserved optimal and nonoptimal codons, often in clusters, which associate with the secondary structure of the translated polypeptides independent of the levels of expression. Our analysis suggests an evolved function for codon optimality in regulating the rhythm of elongation to facilitate cotranslational polypeptide folding, beyond its previously proposed role of adapting to the cost of expression. These findings establish how mRNA sequences are generally under selection to optimize the cotranslational folding of corresponding polypeptides.

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Figure 1: A normalized translational efficiency scale that balances tRNA supply and demand.
Figure 2: A conserved short dip of low translational efficiency at the beginning of mRNAs.
Figure 3: Site-specific evolutionary conservation of codon optimality.
Figure 4: Conserved codon optimality associates with signatures of cotranslational folding.
Figure 5: Conserved codon optimality maps onto known protein structures.
Figure 6: Optimal and nonoptimal codons in protein synthesis and cotranslational folding.

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Acknowledgements

We thank the Frydman lab for helpful discussions. We gratefully acknowledge support from an European Molecular Biology Organization Long-Term Fellowship (ALTF 1334-2010) to S.P. and US National Institutes of Health grants GM56433 and AI91575 to J.F.

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Authors and Affiliations

  1. Department of Biology, Stanford University, Stanford, California, USA

    Sebastian Pechmann & Judith Frydman

  2. BioX Program, Stanford University, Stanford, California, USA

    Sebastian Pechmann & Judith Frydman

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  1. Sebastian Pechmann
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  2. Judith Frydman
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S.P. performed all analyses; S.P. and J.F. designed research, interpreted the data and wrote the manuscript.

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Correspondence to Judith Frydman.

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Pechmann, S., Frydman, J. Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding. Nat Struct Mol Biol 20, 237–243 (2013). https://doi.org/10.1038/nsmb.2466

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