title: Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations.
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 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.
authors: Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany.
authors: Florian
authors: F
authors: Buhr
authors: Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio 44115, USA.
authors: Sujata
authors: S
authors: Jha
authors: Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
authors: Michael
authors: M
authors: Thommen
authors: Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
authors: Joerg
authors: J
authors: Mittelstaet
authors: Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany.
authors: Felicitas
authors: F
authors: Kutz
authors: Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Germany.
authors: Harald
authors: H
authors: Schwalbe
authors: Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
authors: Marina V
authors: MV
authors: Rodnina
authors: Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio 44115, USA.|Department of Biochemistry and Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, Ohio 44106, USA.|Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
authors: Anton A
authors: AA
authors: Komar
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D003545:Cysteine; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D005838:Genotype; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D011489:Protein Denaturation; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000069456:Silent Mutation; D012995:Solubility; D038222:gamma-Crystallins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C107738:crystallin, gammaB; D038222:gamma-Crystallins; D010447:Peptide Hydrolases; D003545:Cysteine