ArticleProceedings of the National Academy of Sciences of the United States of America2020
Cotranslational folding allows misfolding-prone proteins to circumvent deep kinetic traps.
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 38 papers.
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38 citing papers in PubMed.
- A detailed molecular picture of protein folding during active translation.bioRxiv : the preprint server for biology · 2026Article
- Live-cell co-translational folding tracking reveals bidirectional coupling between translation and folding.bioRxiv : the preprint server for biology · 2026Article
- Prolines in linkers of multi-domain proteins: Intrinsic regulators of misfolding and aggregation.PLoS computational biology · 2026Article
- The Shape of Things to Come: α-Helical Membrane Protein Folding on the Ribosome.Chemical reviews · 2026Review
- Hydrogen/deuterium exchange mass spectrometry analysis of ribosome-nascent chain complexes to study protein biogenesis at the peptide level.Nature protocols · 2026Article
- Cis-Acting Chaperoning by Macromolecular Tethering: A Built-In Layer of Cellular Chaperoning.International journal of molecular sciences · 2026Review
- Phosphoglycerate Kinase Can Adopt Topologically Misfolded Forms That Are More Stable Than Its Native State.Journal of the American Chemical Society · 2026Article
- Physics Determines and Evolution Shapes Basic Units of Protein Function and Allosteric Regulation.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Native CFTR codon bias controls translation rate to balance off-pathway aggregation and channel function by conformational imprinting.Scientific reports · 2025Article
- Cotranslational protein folding through non-native structural intermediates.Science advances · 2025Article
- A ribosome-associating chaperone mediates GTP-driven vectorial folding of nascent eEF1A.Nature communications · 2025Article
- Protein Quality Control is a Master Modulator of Molecular Evolution in Bacteria.Genome biology and evolution · 2025Review
- Translation Rates and Protein Folding.Journal of molecular biology · 2024Review
- The Effects of Codon Usage on Protein Structure and Folding.Annual review of biophysics · 2024Review
- How the ribosome shapes cotranslational protein folding.Current opinion in structural biology · 2024Review
- Nuclear Hsp104 safeguards the dormant translation machinery during quiescence.Nature communications · 2024Article
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- Viral Evolution Shaped by Host Proteostasis Networks.Annual review of virology · 2023Review
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- Learning to learn by using nonequilibrium training protocols for adaptable materials.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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4 authors.
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Abstract
Many large proteins suffer from slow or inefficient folding in vitro. It has long been known that this problem can be alleviated in vivo if proteins start folding cotranslationally. However, the molecular mechanisms underlying this improvement have not been well established. To address this question, we use an all-atom simulation-based algorithm to compute the folding properties of various large protein domains as a function of nascent chain length. We find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by nonnative interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins' sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modeling, we show that under certain conditions, such a slowdown indeed improves cotranslational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from cotranslational folding due to a lack of significant nonnative interactions, and indeed these proteins' sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell and how biomolecular self-assembly may be optimized evolutionarily.
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