The genetic architecture of protein interaction affinity and specificity

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• dc.contributor.author Bendel, Alexandra M.
• dc.contributor.author Faure, Andre J.
• dc.contributor.author Klein, Dominique
• dc.contributor.author Shimada, Kenji
• dc.contributor.author Lyautey, Romane
• dc.contributor.author Schiffelholz, Nicole
• dc.contributor.author Kempf, Georg
• dc.contributor.author Cavadini, Simone
• dc.contributor.author Lehner, Ben, 1978-
• dc.contributor.author Diss, Guillaume
• dc.date.accessioned 2024-12-05T07:34:38Z
• dc.date.available 2024-12-05T07:34:38Z
• dc.date.issued 2024
• dc.description.abstract The encoding and evolution of specificity and affinity in protein-protein interactions is poorly understood. Here, we address this question by quantifying how all mutations in one protein, JUN, alter binding to all other members of a protein family, the 54 human basic leucine zipper transcription factors. We fit a global thermodynamic model to the data to reveal that most affinity changing mutations equally affect JUN's affinity to all its interaction partners. Mutations that alter binding specificity are relatively rare but distributed throughout the interaction interface. Specificity is determined both by features that promote on-target interactions and by those that prevent off-target interactions. Approximately half of the specificity-defining residues in JUN contribute both to promoting on-target binding and preventing off-target binding. Nearly all specificity-altering mutations in the interaction interface are pleiotropic, also altering affinity to all partners. In contrast, mutations outside the interface can tune global affinity without affecting specificity. Our results reveal the distributed encoding of specificity and affinity in an interaction interface and how coiled-coils provide an elegant solution to the challenge of optimizing both specificity and affinity in a large protein family.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bendel AM, Faure AJ, Klein D, Shimada K, Lyautey R, Schiffelholz N, et al. The genetic architecture of protein interaction affinity and specificity. Nat Commun. 2024 Oct 14;15(1):8868. DOI: 10.1038/s41467-024-53195-4
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-53195-4
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/68926
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2024 Oct 14;15(1):8868
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
• dc.rights © The Author(s) 2024. 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 Molecular evolution
• dc.subject.keyword Protein–protein interaction networks
• dc.subject.keyword Proteins
• dc.title The genetic architecture of protein interaction affinity and specificity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion