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TitleThe human ribosome modulates multidomain protein biogenesis by delaying cotranslational domain docking.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 11, Page 2296-2307, Year 2025
Publish dateSep 19, 2025
AuthorsGrant A Pellowe / Tomas B Voisin / Laura Karpauskaite / Sarah L Maslen / Alžběta Roeselová / J Mark Skehel / Chloe Roustan / Roger George / Andrea Nans / Svend Kjær / Ian A Taylor / David Balchin /
PubMed AbstractProteins 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 ...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 hydrogen-deuterium exchange mass spectrometry and cryo-electron microscopy to characterize the structure and dynamics of partially synthesized 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.
External linksNat Struct Mol Biol / PubMed:40973728 / PubMed Central
MethodsEM (single particle)
Resolution2.2 Å
Structure data

EMDB-51611, PDB-9gul:
Structure of FLuc-XBP1u+ stalled human 60S ribosome nascent chain complex
Method: EM (single particle) / Resolution: 2.2 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • photinus pyralis (common eastern firefly)
KeywordsTRANSLATION / Ribosome-nascent chain / luciferase / folding

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