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PreprintCited by 13RNA and protein synthesis mechanismsProtein Structure and DynamicsHeat shock proteins research

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The human ribosome modulates multidomain protein biogenesis by delaying cotranslational domain docking

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Pellowe, Grant A., Voisin, Tomas B., Karpauskaite, Laura, Maslen, Sarah L., Roeselová, Alžběta, Skehel, J. Mark, Roustan, Chloe, George, Roger, Nans, Andrea, Kjær, Svend, Taylor, Ian A., Balchin, David·2024·Nature Structural & Molecular Biology
DOI 10.1101/2024.09.19.613857PMC PMC12618258

Preprint — published as 10.1038/s41594-025-01676-5 · Paper page

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Abstract

Proteins with multiple domains are intrinsically prone to misfold, yet fold efficiently during their synthesis on the ribosome. This is especially important in eukaryotes, where multidomain proteins predominate. Here, we sought to understand how multidomain protein folding is modulated by the eukaryotic ribosome. We used cryo-electron microscopy and hydrogen/deuterium exchange-mass spectrometry to characterise the structure and dynamics of partially-synthesised intermediates of a model multidomain protein. We find that nascent subdomains fold progressively during synthesis on the human ribosome, templated by interactions across domain interfaces. The conformational ensemble of the nascent chain is tuned by its unstructured C-terminal segments, which keep interfaces between folded domains in dynamic equilibrium until translation termination. This contrasts with the bacterial ribosome, on which domain interfaces form early and remain stable during synthesis. Delayed domain docking may avoid interdomain misfolding to promote the maturation of multidomain proteins in eukaryotes.

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Metadata

Authors
Pellowe, G. A., Voisin, T. B., Karpauskaite, L., Maslen, S. L., Roeselová, A., Skehel, J. M., Roustan, C., George, R., Nans, A., Kjær, S., Taylor, I. A., & Balchin, D.
Affiliations
  • Aston University (GB)
  • The Francis Crick Institute (GB)
Corresponding author
Balchin, David
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2024-09-19
Volume
32
Issue
11
Pages
2296-2307
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2024.09.19.613857
PMC
PMC12618258
OpenAlex
W4414358293
Cited by
13
References
1
Citations by year
2026: 11 · 2025: 2
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aston Publications Explorer (Aston University) (acceptedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Wellcome Trust (CC2025, CC1063, CC1068)
  • Francis Crick Institute
  • UK Research and Innovation
  • Cancer Research UK (CC1068, CC1063)
  • Medical Research Council (CC1068, CC1063)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
co-translational folding, ribosome, nascent chain, interdomain interface, protein maturation, human ribosome, bacterial ribosome, translation termination, hydrogen-deuterium exchange
MeSH terms
Protein Domains, Humans, Models, Molecular, Ribosomes, Protein Biosynthesis, Protein Folding, Cryoelectron Microscopy

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