ArticleProceedings of the National Academy of Sciences of the United States of America2020
Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers, 2 of them syntheses that pooled it.
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Who cites it
118 citing papers in PubMed, 2 syntheses or guidelines pooled it, 241 citations in OpenAlex.
- How soluble misfolded proteins bypass chaperones at the molecular level.Nature communications · 2023Pooled it
- Synonymous but Not Silent: The Codon Usage Code for Gene Expression and Protein Folding.Annual review of biochemistry · 2021Pooled it
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Co-mutation Based Genetic Networks to Infer Temporal Mutation Dynamics in Ancient Human Mitochondrial Genomes.Journal of molecular evolution · 2026Article
- VeloHARMO: a deep learning framework for mRNA coding sequence generation and design via translation velocity harmonization.Briefings in bioinformatics · 2026Article
- The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair inRNA (New York, N.Y.) · 2026Article
- Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1.Molecular cell · 2026Article
- Synonymous Codons as Potential Contributors to Chromatin Stability and Gene Body Methylation in Plants.Journal of molecular evolution · 2026Article
- Multilayered nucleotide organization reveals purifying selection and host-driven adaptation in CPV and FPV.BMC veterinary research · 2026Article
- Evolution of Resistance to Avian Malaria Infection in an Endemic Hawaiian Honeycreeper.Ecology and evolution · 2026Article
- Prime editor-based high-throughput screening reveals functional synonymous mutations in human cells.Nature biotechnology · 2026Article
- Identification of the Mutations Spectrum in the Fumarylacetoacetate Hydrolase Gene in Tyrosinemia Type 1 Patients in Northeastern Iran.Biochemical genetics · 2026Article
- SyMetrics: an integrated machine learning model for evaluating the pathogenicity of synonymous variants in the human genome.NAR genomics and bioinformatics · 2026Article
- Live-attenuated foot-and-mouth disease virus vaccine engineered by codon deoptimization induces a strong protective immune response in cattle.NPJ vaccines · 2026Article
- Availability of Charged tRNAs Drives Maximal Protein Synthesis at Intermediate Levels of Codon Usage Bias.Bulletin of mathematical biology · 2026Article
- Hurdles to horizontal gene transfer: species-specific effects of synonymous variation and plasmid copy number determine antibiotic resistance phenotype.Microbiology (Reading, England) · 2026Article
- A viral codon usage strategy enhances antigen production and protection in SFTSV mRNA vaccination.NPJ vaccines · 2025Article
- Functional synonymous mutations and their evolutionary consequences.Nature reviews. Genetics · 2025Review
- DRP-PSM: Multi-Level Feature Integration Reveals Hierarchical Contributions to Pathogenic Synonymous Mutation Prediction.ACS omega · 2025Article
- Cotranslational protein folding through non-native structural intermediates.Science advances · 2025Article
58 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
In the cell, proteins are synthesized from N to C terminus and begin to fold during translation. Cotranslational folding mechanisms are therefore linked to elongation rate, which varies as a function of synonymous codon usage. However, synonymous codon substitutions can affect many distinct cellular processes, which has complicated attempts to deconvolve the extent to which synonymous codon usage can promote or frustrate proper protein folding in vivo. Although previous studies have shown that some synonymous changes can lead to different final structures, other substitutions will likely be more subtle, perturbing predominantly the protein folding pathway without radically altering the final structure. Here we show that synonymous codon substitutions encoding a single essential enzyme lead to dramatically slower cell growth. These mutations do not prevent active enzyme formation; instead, they predominantly alter the protein folding mechanism, leading to enhanced degradation in vivo. These results support a model in which synonymous codon substitutions can impair cell fitness by significantly perturbing cotranslational protein folding mechanisms, despite the chaperoning provided by the cellular protein homeostasis network.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.