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

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 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.

Publication DOI: https://doi.org/10.1038/s41594-025-01676-5
Divisions: College of Health & Life Sciences
Aston University (General)
Funding Information: This work was supported by funding from UK Research and Innovation (FoldingMap, EP/X020428/1, to D.B.) and the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2025, CC1063 and CC1068), the UK Medical Research Council (C
Additional Information: Copyright © The Author(s) 2025. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/
Publication ISSN: 1545-9985
Last Modified: 07 Oct 2025 07:21
Date Deposited: 23 Sep 2025 08:09
Full Text Link:
Related URLs: https://www.nat ... 594-025-01676-5 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2025-09-19
Published Online Date: 2025-09-19
Accepted Date: 2025-08-14
Authors: Pellowe, Grant (ORCID Profile 0000-0003-4314-5261)
Voisin, Tomas
Karpauskaite, Laura
Maslen, Sarah L
Roeselova, Alzbeta
Skehel, J Mark
Roustan, Chloe
George, Roger
Nans, Andrea
Kjaer, Svend
Taylor, Ian A.
Balchin, David

Download

[img]

Version: Published Version

License: Creative Commons Attribution


Export / Share Citation


Statistics

Additional statistics for this record