Skip to content
DraconiticResearch
Search Sources API
201,683 studies31 sourcesUpdated 50 min ago
Peer-reviewedCC BYNature Structural & Molecular Biology

Structures of protein folding intermediates on the ribosome

  • Sammy H. S. Chan1
  • Julian O. Streit1
  • Tomasz Włodarski2,1
  • Alkistis N. Mitropoulou1
  • Anaïs M. E. Cassaignau1
  • Ivana V. Bukvin1
  • Christopher A. Waudby3,1
  • Lisa D. Cabrita1
  • John C. Christodoulou4,5
5 affiliations
  1. 1Institute of Structural and Molecular Biology, Department of Structural and Molecular Biology, University College London, London, UK
  2. 2Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
  3. 3Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College London, London, UK
  4. 4Institute of Structural and Molecular Biology, Department of Structural and Molecular Biology, University College London, London, UK. [email protected]
  5. 5School of Natural Sciences, Birkbeck College, London, UK. [email protected]
Open at sourceDOICite

Abstract

The ribosome biases the conformations sampled by nascent polypeptide chains along folding pathways towards biologically active states. A hallmark of the co-translational folding (coTF) of many proteins are highly stable folding intermediates that are absent or only transiently populated off the ribosome, yet persist during translation well-beyond complete emergence of the domain from the ribosome exit tunnel. Intermediates are important for folding fidelity; however, their structures have remained elusive. Here, we have structurally characterised two coTF intermediates of an immunoglobulin-like domain by developing comprehensive 19 F NMR analyses using chemical shifts, paramagnetic relaxation enhancement (PRE), and protein engineering. We integrated these experimental data with extensive molecular dynamics (MD) simulations to obtain atomistic structures of the folding intermediates on the ribosome. The resulting intermediate structures are distinguished by native-like folds initiated from either their N-or C-termini, and reveal parallel folding pathways, which are structurally conserved within the protein domain family, in contrast to their in vitro refolding mechanisms. By redirecting proteins to fold along hierarchical, parallel routes, the ribosome may promote efficient folding by avoiding kinetic traps, and regulate nascent chain assembly and targeting by auxiliary factors to maintain cellular proteostasis.

Related

  1. Predicting protein structures at any folding stage from sequence
    Lisheng Zhang, Qingsong Li, Zinan Xie +7
    arXivPreprintCC BY 4.0Full textBiophysicsarXiv
  2. The structures of two intermediates en route to DNA repair within a (6-4) photolyase
    C. Yang, Q. Yu, X. Cao +6
    bioRxivPreprintAll rights reservedFull textGeneral biochemistrybioRxiv
  3. Transition Intermediates Encode Ligand Efficacy at the μ-Opioid Receptor-Gi Protein Complex
    K. Konovalov, S. Novack, D. Provasi +3
    bioRxivPreprintAll rights reservedFull text1 citedBiophysicsbioRxiv
  4. Mass spectrometric detection of protein nanoclusters: the invisible intermediates of phase separation
    Christina Glen Robb, Anisha Haris, Thuy P Dao +3
    bioRxivPreprintAll rights reservedFull textBiophysicsbioRxivPMC
  5. The ssDNA-binding protein MEIOB sustains synaptonemal complex integrity by stabilizing recombination intermediates during male meiosis
    Haiwei Feng, Binjie Jiang, Yanling Gao +9
    iSciencePeer-reviewedCC BY 4.0Molecular biology & gene regulationCell biologyCrossrefCell Press

Cite

BibTeXRIS
BibTeX
@article{chan2026structures,
  title = {{Structures of protein folding intermediates on the ribosome}},
  author = {Sammy H. S. Chan and Julian O. Streit and Tomasz Włodarski and Alkistis N. Mitropoulou and Anaïs M. E. Cassaignau and Ivana V. Bukvin and Christopher A. Waudby and Lisa D. Cabrita and John C. Christodoulou},
  journal = {Nature Structural \& Molecular Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41594-026-01814-7},
  url = {https://doi.org/10.1038/s41594-026-01814-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Structures of protein folding intermediates on the ribosome
AU  - Sammy H. S. Chan
AU  - Julian O. Streit
AU  - Tomasz Włodarski
AU  - Alkistis N. Mitropoulou
AU  - Anaïs M. E. Cassaignau
AU  - Ivana V. Bukvin
AU  - Christopher A. Waudby
AU  - Lisa D. Cabrita
AU  - John C. Christodoulou
PY  - 2026
DA  - 2026/06/01
JO  - Nature Structural & Molecular Biology
DO  - 10.1038/s41594-026-01814-7
UR  - https://doi.org/10.1038/s41594-026-01814-7
AB  - The ribosome biases the conformations sampled by nascent polypeptide chains along folding pathways towards biologically active states. A hallmark of the co-translational folding (coTF) of many proteins are highly stable folding intermediates that are absent or only transiently populated off the ribosome, yet persist during translation well-beyond complete emergence of the domain from the ribosome exit tunnel. Intermediates are important for folding fidelity; however, their structures have remained elusive. Here, we have structurally characterised two coTF intermediates of an immunoglobulin-like domain by developing comprehensive 19 F NMR analyses using chemical shifts, paramagnetic relaxation enhancement (PRE), and protein engineering. We integrated these experimental data with extensive molecular dynamics (MD) simulations to obtain atomistic structures of the folding intermediates on the ribosome. The resulting intermediate structures are distinguished by native-like folds initiated from either their N-or C-termini, and reveal parallel folding pathways, which are structurally conserved within the protein domain family, in contrast to their in vitro refolding mechanisms. By redirecting proteins to fold along hierarchical, parallel routes, the ribosome may promote efficient folding by avoiding kinetic traps, and regulate nascent chain assembly and targeting by auxiliary factors to maintain cellular proteostasis.
SN  - 1545-9985
SN  - 1545-9993
ER  -