Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations

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• dc.contributor.author Kiel, Cristina
• dc.contributor.author Serrano Pubull, Luis, 1982-
• dc.date.accessioned 2024-02-19T10:08:17Z
• dc.date.available 2024-02-19T10:08:17Z
• dc.date.issued 2014
• dc.description.abstract The Ras/MAPK syndromes (‘RASopathies’) are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen‐activated protein kinase (MAPK) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RASopathies. Here, we shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RASopathy mutations. Through network modelling, we show that partly compensatory mutations in RASopathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations.
• dc.description.sponsorship We thank Marius Ueffing for valuable discussions on the manuscript. This work was supported by the EU (PRIMES under grant agreement number FP7‐HEALTH‐F4‐2011‐278568). This work was supported by the Spanish Ministerio de Economía y Competitividad, Plan Nacional BIO2012‐39754 and the European Fund for Regional Development. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013‐2017’ (SEV‐2012‐0208).
• dc.format.mimetype application/pdf
• dc.identifier.citation Kiel C, Serrano L. Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations. Molecular Systems Biology. 2014 May;10(5):727. DOI: 10.1002/msb.20145092
• dc.identifier.doi http://dx.doi.org/10.1002/msb.20145092
• dc.identifier.issn 1744-4292
• dc.identifier.uri http://hdl.handle.net/10230/59139
• dc.language.iso eng
• dc.publisher EMBO Press
• dc.relation.ispartof Molecular Systems Biology. 2014 May;10(5):727
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/278568
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BIO2012-39754
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SEV-2012-0208
• dc.rights © 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword RASopathy
• dc.subject.keyword FoldX
• dc.subject.keyword MAPK pathway
• dc.subject.keyword Missense mutations
• dc.subject.keyword Enedgetics
• dc.title Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion