Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function

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• dc.contributor.author Topolska, Magdalena
• dc.contributor.author Beltran, Antoni
• dc.contributor.author Lehner, Ben, 1978-
• dc.date.accessioned 2025-05-15T06:54:48Z
• dc.date.available 2025-05-15T06:54:48Z
• dc.date.issued 2025
• dc.description.abstract Amino acid insertions and deletions (indels) are an abundant class of genetic variants. However, compared to substitutions, the effects of indels on protein stability are not well understood. To better understand indels here we analyse new and existing large-scale deep indel mutagenesis (DIM) of structurally diverse proteins. The effects of indels on protein stability vary extensively among and within proteins and are not well predicted by existing computational methods. To address this shortcoming we present INDELi, a series of models that combine experimental or predicted substitution effects and secondary structure information to provide good prediction of the effects of indels on both protein stability and pathogenicity. Moreover, quantifying the effects of indels on protein-protein interactions suggests that insertions can be an important class of gain-of-function variants. Our results provide an overview of the impact of indels on proteins and a method to predict their effects genome-wide.
• dc.description.sponsorship This work was funded by a European Research Council (ERC) Advanced (883742) grant, the Spanish Ministry of Science and Innovation (LCF/PR/HR21/52410004, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), and the CERCA Programme/Generalitat de Catalunya. M.T. was funded by a Spanish Ministry of Science and Innovation Severo-Ochoa fellowship PRE2020-093984-SO. T.B. was funded by an EMBO (ALTF 183-2020) and Marie Skłodowska-Curie (101030961) fellowship.
• dc.format.mimetype application/pdf
• dc.identifier.citation Topolska M, Beltran A, Lehner B. Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function. Nat Commun. 2025 Mar 17;16(1):2617. DOI: 10.1038/s41467-025-57510-5
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-025-57510-5
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/70396
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2025 Mar 17;16(1):2617
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/101030961
• dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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 http://creativecommons.org/licenses/by-nc-nd/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Computational biology and bioinformatics
• dc.subject.keyword Genetics
• dc.subject.keyword Proteomics
• dc.title Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion