Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations

• Published in: Molecular cell 2016-02, Vol.61 (3), p.341-351
• Main Authors: Buhr, Florian, Jha, Sujata, Thommen, Michael, Mittelstaet, Joerg, Kutz, Felicitas, Schwalbe, Harald, Rodnina, Marina V., Komar, Anton A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; amino acid sequences; Cloning, Molecular; codons; crystallins; Cysteine; energy transfer; eye lens; Fluorescence Resonance Energy Transfer; gamma-Crystallins - biosynthesis; gamma-Crystallins - chemistry; gamma-Crystallins - genetics; Gene Expression Regulation; Genotype; homeostasis; Kinetics; mammals; messenger RNA; nuclear magnetic resonance spectroscopy; Nuclear Magnetic Resonance, Biomolecular; oxidation; Oxidation-Reduction; Peptide Hydrolases - metabolism; Phenotype; Protein Denaturation; Protein Folding; Protein Stability; Protein Structure, Tertiary; proteinases; RNA, Messenger - genetics; RNA, Messenger - metabolism; Silent Mutation; Solubility; spectral analysis; translation (genetics)
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.01.008

In all genomes, most amino acids are encoded by more than one codon. Synonymous codons can modulate protein production and folding, but the mechanism connecting codon usage to protein homeostasis is not known. Here we show that synonymous codon variants in the gene encoding gamma-B crystallin, a mammalian eye-lens protein, modulate 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 have the same amino acid sequence but attain different conformations, as indicated by altered in vivo stability and in vitro protease resistance. 2D NMR spectroscopic data 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. Thus, synonymous codons provide a secondary code for protein folding in the cell. [Display omitted] •Quality of protein folding in cells is guided by synonymous codon usage•NMR reveals multiple conformational and oxidation states of synonymous variants•Synonymous codon usage in mRNA alters translation kinetics•Real-time cotranslational folding is guided by synonymous codon usage Buhr et al. demonstrate how synonymous codon usage guides the real-time kinetics of translation and cotranslational folding of a gamma-B crystallin. Gamma-B crystallins produced from mRNAs with altered codon usage have the same primary sequence but attain different conformations in solution and in the cell.