Native Fold Delay and its implications for co-translational chaperone binding and protein aggregation

Ramon Duran-Romaña, Bert Houben, Paula Fernández Migens, Ying Zhang, Frederic Rousseau () and Joost Schymkowitz ()
Additional contact information
Ramon Duran-Romaña: VIB-KU Leuven Center for Brain and Disease Research
Bert Houben: VIB-KU Leuven Center for Brain and Disease Research
Paula Fernández Migens: VIB-KU Leuven Center for Brain and Disease Research
Ying Zhang: University of Freiburg
Frederic Rousseau: VIB-KU Leuven Center for Brain and Disease Research
Joost Schymkowitz: VIB-KU Leuven Center for Brain and Disease Research

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Because of vectorial protein translation, residues that interact in the native protein structure but are distantly separated in the primary sequence are unavailable simultaneously. Instead, there is a temporal delay during which the N-terminal interaction partner is unsatisfied and potentially vulnerable to non-native interactions. We introduce “Native Fold Delay” (NFD), a metric that integrates protein topology with translation kinetics to quantify such delays. We found that many proteins exhibit residues with NFDs in the range of tens of seconds. These residues, predominantly in well-structured, buried regions, often coincide with aggregation-prone regions. NFD correlates with co-translational engagement by the yeast Hsp70 chaperone Ssb, suggesting that native fold-delayed regions have a propensity to misfold. Supporting this, we show that proteins with long NFDs are more frequently co-translationally ubiquitinated and prone to aggregate upon Ssb deletion.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57033-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57033-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57033-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().