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

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...

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Detalles Bibliográficos
Autores principales: Kiel, Christina, Serrano, Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Molecular Biology Organization 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188041/
https://www.ncbi.nlm.nih.gov/pubmed/24803665
http://dx.doi.org/10.1002/msb.20145092
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author Kiel, Christina
Serrano, Luis
author_facet Kiel, Christina
Serrano, Luis
author_sort Kiel, Christina
collection PubMed
description 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.
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spelling pubmed-41880412014-10-08 Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations Kiel, Christina Serrano, Luis Mol Syst Biol Articles 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. European Molecular Biology Organization 2014-05-06 /pmc/articles/PMC4188041/ /pubmed/24803665 http://dx.doi.org/10.1002/msb.20145092 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Kiel, Christina
Serrano, Luis
Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title_full Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title_fullStr Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title_full_unstemmed Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title_short Structure‐energy‐based predictions and network modelling of RASopathy and cancer missense mutations
title_sort structure‐energy‐based predictions and network modelling of rasopathy and cancer missense mutations
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188041/
https://www.ncbi.nlm.nih.gov/pubmed/24803665
http://dx.doi.org/10.1002/msb.20145092
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