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A Code Within a Code: How Codons Fine-Tune Protein Folding in the Cell

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Abstract

The genetic code sets the correspondence between the sequence of a given nucleotide triplet in an mRNA molecule, called a codon, and the amino acid that is added to the growing polypeptide chain during protein synthesis. With four bases (A, G, U, and C), there are 64 possible triplet codons: 61 sense codons (encoding amino acids) and 3 nonsense codons (so-called, stop codons that define termination of translation). In most organisms, there are 20 common/standard amino acids used in protein synthesis; thus, the genetic code is redundant with most amino acids (with the exception of Met and Trp) are being encoded by more than one (synonymous) codon. Synonymous codons were initially presumed to have entirely equivalent functions, however, the finding that synonymous codons are not present at equal frequencies in mRNA suggested that the specific codon choice might have functional implications beyond coding for amino acid. Observation of nonequivalent use of codons in mRNAs implied a possibility of the existence of auxiliary information in the genetic code. Indeed, it has been found that genetic code contains several layers of such additional information and that synonymous codons are strategically placed within mRNAs to ensure a particular translation kinetics facilitating and fine-tuning co-translational protein folding in the cell via step-wise/sequential structuring of distinct regions of the polypeptide chain emerging from the ribosome at different points in time. This review summarizes key findings in the field that have identified the role of synonymous codons and their usage in protein folding in the cell.

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Abbreviations

ADAMTS13:

a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13

CAT:

chloramphenicol acetyltransferase

FRET:

fluorescence resonance energy transfer

mRNA:

messenger RNA

NMR:

Nuclear magnetic resonance

PGK:

phosphoglycerate kinase

P-gp:

P-glycoprotein

RNase A:

Ribonuclease A

tRNA:

transport RNA

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Acknowledgments

This work would not be possible without the original contribution of Ivan Adzhubei and Igor A. Krasheninnikov, further support from Slava Kolb, Aigar Kommer, Valentin M. Stepanov, 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 teachers, 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.

Funding

In recent years, the work in my laboratory was financially supported by the Human Frontier Science Program Organization [HFSP grant #RGP0024/2010], the American Heart Association [AHA grant 13GRNT17070025], the National Institutes of Health [NIH grants HL121779; HL151392 and GM128981], the Center for Gene Regulation in Health and Disease (GRHD) at CSU, and the biotechnology company, DAPCEL, Inc.

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

    Anton A. Komar

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

    Anton A. Komar

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

    Anton A. Komar

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

    Anton A. Komar

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Correspondence to Anton A. Komar.

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I am co-founder and Chief Scientific Officer of DAPCEL, Inc., a biotechnology company that develops innovative approaches for gene redesign for protein production in any desired host organism. This article does not contain any studies with human participants or animals performed by the author.

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Komar, A.A. A Code Within a Code: How Codons Fine-Tune Protein Folding in the Cell. Biochemistry Moscow 86, 976–991 (2021). https://doi.org/10.1134/S0006297921080083

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