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Vol 53(2019) N 6 p. 777-790; DOI 10.1134/S0026893319060098 Full Text

A.A. Komar1,2,3,4*

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

1Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio, 44115 USA
2Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, Ohio, 44106 USA
3Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195 USA
4DAPCEL, Inc., Cleveland, Ohio, 44106 USA

*a.komar@csuohio.edu
Received - 2019-04-21; Revised - 2019-05-07; Accepted - 2019-05-14

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 impinge 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.

genetic code, codon usage, synonymous codons, translation kinetics, nascent peptides, co-translational protein folding



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