Effects of single synonymous substitutions on fold efficiency demonstrate the influence of rare codons and protein structure
Otsuka, Felipe A.M. LU and André, Ingemar LU
(2026)
In Cell Reports
45(4).
- Abstract
Summary: Codon sequences can influence proteins to misfold during cotranslational folding. Here, we develop an in vivo assay in E. coli to comprehensively study the impact of single synonymous substitutions on protein folding efficiency and apply it to the N-terminal domain of ddlA. By mapping the influence of codons along the sequence, we show that codon identity can substantially influence folding efficiency in a manner depending on structure and topology. We found that a cluster of codons in the N-terminal domain strongly impacts ddlA folding. Further analysis revealed that substitutions to rarer codons generally lead to increased folding efficiency. Consistent with this, an mRNA composed exclusively of rare codons yields higher... (More)
Summary: Codon sequences can influence proteins to misfold during cotranslational folding. Here, we develop an in vivo assay in E. coli to comprehensively study the impact of single synonymous substitutions on protein folding efficiency and apply it to the N-terminal domain of ddlA. By mapping the influence of codons along the sequence, we show that codon identity can substantially influence folding efficiency in a manner depending on structure and topology. We found that a cluster of codons in the N-terminal domain strongly impacts ddlA folding. Further analysis revealed that substitutions to rarer codons generally lead to increased folding efficiency. Consistent with this, an mRNA composed exclusively of rare codons yields higher expression and folding efficiency than one containing only commons codons. Our results highlight the importance of rare codons in cotranslational folding and the relationship between codon sequence and protein structure.
(Less)
- author
- Otsuka, Felipe A.M.
LU
and André, Ingemar
LU
- organization
- publishing date
- 2026-04
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cotranslational folding, folding efficiency assay, gene expression, synonymous codon substitutions
- in
- Cell Reports
- volume
- 45
- issue
- 4
- article number
- 117266
- publisher
- Cell Press
- external identifiers
-
- scopus:105035682721
- pmid:41989916
- ISSN
- 2639-1856
- DOI
- 10.1016/j.celrep.2026.117266
- language
- English
- LU publication?
- yes
- id
- 48e83b93-3293-42b8-b8f4-92c401e5ec09
- date added to LUP
- 2026-06-24 09:05:58
- date last changed
- 2026-07-23 17:53:27
@article{48e83b93-3293-42b8-b8f4-92c401e5ec09,
abstract = {{<p>Summary: Codon sequences can influence proteins to misfold during cotranslational folding. Here, we develop an in vivo assay in E. coli to comprehensively study the impact of single synonymous substitutions on protein folding efficiency and apply it to the N-terminal domain of ddlA. By mapping the influence of codons along the sequence, we show that codon identity can substantially influence folding efficiency in a manner depending on structure and topology. We found that a cluster of codons in the N-terminal domain strongly impacts ddlA folding. Further analysis revealed that substitutions to rarer codons generally lead to increased folding efficiency. Consistent with this, an mRNA composed exclusively of rare codons yields higher expression and folding efficiency than one containing only commons codons. Our results highlight the importance of rare codons in cotranslational folding and the relationship between codon sequence and protein structure.</p>}},
author = {{Otsuka, Felipe A.M. and André, Ingemar}},
issn = {{2639-1856}},
keywords = {{cotranslational folding; folding efficiency assay; gene expression; synonymous codon substitutions}},
language = {{eng}},
number = {{4}},
publisher = {{Cell Press}},
series = {{Cell Reports}},
title = {{Effects of single synonymous substitutions on fold efficiency demonstrate the influence of rare codons and protein structure}},
url = {{http://dx.doi.org/10.1016/j.celrep.2026.117266}},
doi = {{10.1016/j.celrep.2026.117266}},
volume = {{45}},
year = {{2026}},
}