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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
European Molecular Biology Organization
2014
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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. |
format | Online Article Text |
id | pubmed-4188041 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | European Molecular Biology Organization |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kielchristina structureenergybasedpredictionsandnetworkmodellingofrasopathyandcancermissensemutations AT serranoluis structureenergybasedpredictionsandnetworkmodellingofrasopathyandcancermissensemutations |