1. Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations
- Author
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Felicitas Kutz, Joerg Mittelstaet, Harald Schwalbe, Florian Buhr, Sujata Jha, Michael Thommen, Anton A. Komar, and Marina V. Rodnina
- Subjects
0301 basic medicine ,Silent mutation ,Protein Denaturation ,Protein Folding ,Genotype ,Protein domain ,Biology ,Article ,03 medical and health sciences ,Protein structure ,Fluorescence Resonance Energy Transfer ,Amino Acid Sequence ,Cysteine ,RNA, Messenger ,gamma-Crystallins ,Codon degeneracy ,Cloning, Molecular ,Molecular Biology ,Nuclear Magnetic Resonance, Biomolecular ,Silent Mutation ,Genetics ,chemistry.chemical_classification ,Protein Stability ,Cell Biology ,Amino acid ,Protein Structure, Tertiary ,Kinetics ,030104 developmental biology ,Phenotype ,Biochemistry ,chemistry ,Gene Expression Regulation ,Solubility ,Codon usage bias ,Protein folding ,Synonymous substitution ,Oxidation-Reduction ,Peptide Hydrolases - Abstract
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 co-translational 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.
- Published
- 2015