{"title":"Effects of single synonymous substitutions on fold efficiency demonstrate the influence of rare codons and protein structure.","authors":"Felipe A M Otsuka, Ingemar André","doi":"10.1016/j.celrep.2026.117266","DOIUrl":null,"url":null,"abstract":"<p><p>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>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 4","pages":"117266"},"PeriodicalIF":6.9000,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2026.117266","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership.
The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.
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