The ribosome stabilizes partially folded intermediates of a nascent multi-domain protein
- PMID: 35927328
- PMCID: PMC7613651
- DOI: 10.1038/s41557-022-01004-0
The ribosome stabilizes partially folded intermediates of a nascent multi-domain protein
Abstract
Co-translational folding is crucial to ensure the production of biologically active proteins. The ribosome can alter the folding pathways of nascent polypeptide chains, yet a structural understanding remains largely inaccessible experimentally. We have developed site-specific labelling of nascent chains to detect and measure, using 19F nuclear magnetic resonance (NMR) spectroscopy, multiple states accessed by an immunoglobulin-like domain within a tandem repeat protein during biosynthesis. By examining ribosomes arrested at different stages during translation of this common structural motif, we observe highly broadened NMR resonances attributable to two previously unidentified intermediates, which are stably populated across a wide folding transition. Using molecular dynamics simulations and corroborated by cryo-electron microscopy, we obtain models of these partially folded states, enabling experimental verification of a ribosome-binding site that contributes to their high stabilities. We thus demonstrate a mechanism by which the ribosome could thermodynamically regulate folding and other co-translational processes.
© 2022. The Author(s).
Conflict of interest statement
The authors declare no competing interests.
Figures
















Similar articles
-
Structure and dynamics of a ribosome-bound nascent chain by NMR spectroscopy.Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16516-21. doi: 10.1073/pnas.0704664104. Epub 2007 Oct 10. Proc Natl Acad Sci U S A. 2007. PMID: 17940046 Free PMC article.
-
The ribosome and its role in protein folding: looking through a magnifying glass.Acta Crystallogr D Struct Biol. 2017 Jun 1;73(Pt 6):509-521. doi: 10.1107/S2059798317007446. Epub 2017 May 31. Acta Crystallogr D Struct Biol. 2017. PMID: 28580913 Free PMC article. Review.
-
Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.Nat Commun. 2021 Nov 8;12(1):6447. doi: 10.1038/s41467-021-26531-1. Nat Commun. 2021. PMID: 34750347 Free PMC article.
-
The ribosome lowers the entropic penalty of protein folding.Nature. 2024 Sep;633(8028):232-239. doi: 10.1038/s41586-024-07784-4. Epub 2024 Aug 7. Nature. 2024. PMID: 39112704 Free PMC article.
-
Protein folding on the ribosome studied using NMR spectroscopy.Prog Nucl Magn Reson Spectrosc. 2013 Oct;74(100):57-75. doi: 10.1016/j.pnmrs.2013.07.003. Epub 2013 Jul 27. Prog Nucl Magn Reson Spectrosc. 2013. PMID: 24083462 Free PMC article. Review.
Cited by
-
Arrest Peptide Profiling resolves co-translational folding pathways and chaperone interactions in vivo.Nat Commun. 2025 Jul 24;16(1):6833. doi: 10.1038/s41467-025-61398-6. Nat Commun. 2025. PMID: 40707494 Free PMC article.
-
How the ribosome shapes cotranslational protein folding.Curr Opin Struct Biol. 2024 Feb;84:102740. doi: 10.1016/j.sbi.2023.102740. Epub 2023 Dec 9. Curr Opin Struct Biol. 2024. PMID: 38071940 Free PMC article. Review.
-
Mechanistic Insights into Protein Biogenesis and Maturation on the Ribosome.J Mol Biol. 2025 Feb 28:169056. doi: 10.1016/j.jmb.2025.169056. Online ahead of print. J Mol Biol. 2025. PMID: 40024436 Review.
-
How ribosomes shape protein folding.Nature. 2024 Oct 9. doi: 10.1038/d41586-024-03251-2. Online ahead of print. Nature. 2024. PMID: 39384923 No abstract available.
-
Genetic Code Expansion: Recent Developments and Emerging Applications.Chem Rev. 2025 Jan 22;125(2):523-598. doi: 10.1021/acs.chemrev.4c00216. Epub 2024 Dec 31. Chem Rev. 2025. PMID: 39737807 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources