ArticleNature communications2021
Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 56 citations in OpenAlex.
- The Shape of Things to Come: α-Helical Membrane Protein Folding on the Ribosome.Chemical reviews · 2026Review
- Structures of protein folding intermediates on the ribosome.Nature structural & molecular biology · 2026Article
- Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis.JCI insight · 2026Article
- Unavailability of experimental 3D structural data on protein folding dynamics and necessity for a new generation of structure prediction methods in this context.Bioinformatics (Oxford, England) · 2026Article
- Native CFTR codon bias controls translation rate to balance off-pathway aggregation and channel function by conformational imprinting.Scientific reports · 2025Article
- The mechanism of pathogenic αProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Molecular insights on the mechanism of α1-antitrypsin condensate formation and maturation.PLoS computational biology · 2025Article
- Cotranslational protein folding through non-native structural intermediates.Science advances · 2025Article
- Top-Down Ion Mobility Mass Spectrometry Reveals a Disease Associated Conformational Ensemble of Alpha-1-antitrypsin.Journal of the American Chemical Society · 2025Article
- Proteome-wide determinants of co-translational chaperone binding in bacteria.Nature communications · 2025Article
- High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy.Science advances · 2025Article
- Making Proteins with Electricity.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Pulling Forces Differentially Affect Refolding Pathways Due to Entangled Misfolded States in SARS-CoV-1 and SARS-CoV-2 Receptor Binding Domain.Biomolecules · 2024Article
- Article
- Thermodynamic profiles for cotranslational trigger factor substrate recognition.Science advances · 2024Article
- How the ribosome shapes cotranslational protein folding.Current opinion in structural biology · 2024Review
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- Is Posttranslational Folding More Efficient Than Refolding from a Denatured State: A Computational Study.The journal of physical chemistry. B · 2023Article
- The conformational landscape of a serpin N-terminal subdomain facilitates folding and in-cell quality control.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
8 authors at 1 institution in 1 country.
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Abstract
During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z's misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease.
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