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Synonymous Codon Usage—a Guide for Co-Translational Protein Folding in the Cell

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Abstract—In the cell, protein folding begins during protein synthesis/translation and thus is a co-translational process. Co-translational protein folding is tightly linked to translation elongation, which is not a uniform process. While there are many reasons for translation non-uniformity, it is generally believed that non-uniform synonymous codon usage is one of the key factors modulating translation elongation rates. Frequent/optimal codons as a rule are translated more rapidly than infrequently used ones and vice versa. Over 30 years ago, it was hypothesized that changes in synonymous codon usage affecting translation elongation rates could im**e on co-translation protein folding and that many synonymous codons are strategically placed within mRNA to ensure a particular translation kinetics facilitating productive step-by-step co-translational folding of proteins. It was suggested that this particular translation kinetics (and, specifically, translation pause sites) may define the window of opportunity for the protein parts to fold locally, particularly at the critical points where folding is far from equilibrium. It was thus hypothesized that synonymous codons may provide a secondary code for protein folding in the cell. Although, mostly accepted now, this hypothesis appeared to be difficult to prove and many convincing results were obtained only relatively recently. Here, I review the progress in the field and explain, why this simple idea appeared to be so challenging to prove.

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ACKNOWLEDGMENTS

This work would not be possible without the original contribution of Ivan A. Adzhubei and Igor A. Krasheninnikov, further support from Slava Kolb, Aigar Kommer, Lev P. Ovchinnikov and Alexander S. Spirin, followed by collaborations with Rainer Jaenicke, Claude Reiss and more recently with Chava Kimchi-Sarfaty, Harald Schwalbe and Marina V. Rodnina.

I am indebted to all my colleagues and collaborators for their extremely generous and inspiring discussions and invaluable contributions.

I also apologize to those whose work or original publications could not be cited in this short review article.

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Authors and Affiliations

  1. Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State University, 44115, Cleveland, Ohio, USA

    A. A. Komar

  2. Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, 44106, Cleveland, Ohio, USA

    A. A. Komar

  3. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 44195, Cleveland, Ohio, USA

    A. A. Komar

  4. DAPCEL, Inc., 44106, Cleveland, Ohio, USA

    A. A. Komar

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  1. A. A. Komar
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Correspondence to A. A. Komar.

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FUNDING

In recent years, this work in my laboratory was supported by grants from the Human Frontier Science Program Organization [HFSP grant #RGP0024/2010], the American Heart Association [AHA grant 13GRNT17070025], the National Institutes of Health [NIH grant HL121779], the Center for Gene Regulation in Health and Disease (GRHD) at CSU, and the biotechnology company, DAPCEL, Inc, that for more that 10 years has been successfully utilizing ideas developed during this study for synonymous gene optimization aimed at production (in any desired host organism) of correctly folded, soluble proteins.

COMPLIANCE WITH ETHICAL STANDARDS

The author declares that he has no conflict of interest. This article does not contain any studies involving animals or human participants performed by the author.

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Komar, A.A. Synonymous Codon Usage—a Guide for Co-Translational Protein Folding in the Cell. Mol Biol 53, 777–790 (2019). https://doi.org/10.1134/S0026893319060098

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