Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations
Open accessAbstract
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.
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Researchers usually performed codon optimization on the antigen-coding sequence to enhance translation efficiency.
“To improve the safety, efficacy, and stability of mRNA vaccines, researchers usually performed codon optimization172,239–243 on the antigen-coding sequence to enhance translation efficiency.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [241]
Silent substitutional changes in the third position Wobble Site in a codon can have functional consequences affecting replication and infective efficacy through cotranslational pausing/delays.
“Silent substitutional changes in the 3rd position 'Wobble Site' in a codon can have functional consequence affecting replication and infective ef fi cacy caused by cotranslational pausing/delays as the polypeptide exits the Ribosome.”
From Cause of Cambrian Explosion - Terrestrial or Cosmic? (2018) · cites this paper as Buhr et al., 2016
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- Authors
- Buhr, F., Jha, S., Thommen, M., Mittelstaet, J., Kutz, F., Schwalbe, H., Rodnina, M. V., & Komar, A. A.
- Affiliations
- Goethe University Frankfurt (DE)
- Cleveland State University (US)
- Max Planck Institute for Biophysical Chemistry (DE)
- Corresponding author
- Schwalbe, Harald
- Rodnina, Marina V.
- Komar, Anton A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 61
- Issue
- 3
- Pages
- 341-351
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4745992
- OpenAlex
- W2257602426
- Cited by
- 395
- References
- 66
- Citations by year
- 2026: 21 · 2025: 33 · 2024: 48 · 2023: 38 · 2022: 47 · 2021: 35 · 2020: 48 · 2019: 36 · 2018: 37 · 2017: 37 · 2016: 15
- FWCI
- 21.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- GRO (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R15HL121779)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- synonymous codons, codon usage bias, co-translational folding, protein folding, protein conformation, translation rate, protein stability, protease resistance, lens proteins, proteostasis
- MeSH terms
- Silent Mutation, Amino Acid Sequence, Cloning, Molecular, Cysteine, Gene Expression Regulation, Genotype, Kinetics, Oxidation-Reduction, Peptide Hydrolases, Phenotype, Protein Denaturation, RNA, Messenger, Solubility, Protein Structure, Tertiary, Protein Folding, Nuclear Magnetic Resonance, Biomolecular, Fluorescence Resonance Energy Transfer, gamma-Crystallins, Protein Stability
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