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Quality of protein folding in cells is guided by synonymous codon usage

February 2016. A team of scientists from Goethe University Frankfurt, Max Planck Institute for Biophysical Chemistry and Cleveland State University have shown that synonymous codons direct cotranslational folding toward different protein conformations.

Protein translation involves a set of amino acids, each of which is coded for by a sequence of three DNA base pairs called a codon. The genetic code determines which codon is translated into which amino acid. There are more possible codons than amino acids and some amino acids are coded for by several different codons. The occurrence of such synonymous codons in protein-coding open reading frames of genes is not random, so there must have been evolutionary selection for specific codon choice.

Synonymous codons can modulate protein production and folding, but the mechanism connecting codon usage to protein homeostasis is not known. The new study, published in the journal Molecular Cell, revealed that the quality of protein folding in cells is guided by synonymous codon usage and that there are multiple conformational and oxidation states of synonymous variants. Synonymous codon usage in mRNA was shown to alter translation kinetics and real-time cotranslational folding to be guided by synonymous codon usage.

The new study demonstrated that synonymous codon variants in the gene encoding gamma-B crystallin, a mammalian eye-lens protein, modulated the rates of translation and cotranslational folding of protein domains monitored in real time by Förster resonance energy transfer and fluorescence-intensity changes. Gamma-B crystallins produced from mRNAs with changed codon bias had the same amino acid sequence but attain different conformations, as indicated by altered in vivo stability and in vitro protease resistance. Data from 2D NMR spectroscopy suggest that structural differences are associated with different cysteine oxidation states of the purified proteins, providing a link between translation, folding and the structures of isolated proteins. Synonymous codons thus provide a secondary code for protein folding in the cell. More

Harald Schwalbe
Institute of organic Chemistry and chemical Biology
Center for Biomolecular Magnetic Resonance (BMRZ)
Campus Riedberg
Goethe University Frankfurt


Buhr F, Jha S, Thommen M, Mittelstaet J, Kutz F, Schwalbe H, Rodnina M V, Komar A A (2016) Synonymous codons direct cotranslational folding toward different protein conformations. Molecular Cell 61:341-351. Link