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

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. Synopsis Mutations in Ras/MAPK pathway components can cause either cancer or developmental disorders ('RASopathies'). Combined network-based and structural analyses show that quantitative changes rather than all-or-none rewiring underlie the difference between these classes of mutations. A systematic analysis of 956 RASopathy and cancer mutations based on structures and energy predictions is presented. Even for the same gene, different disease-causing mechanisms exist depending on the type of mutation. Energy changes are higher for cancer compared to RASopathy mutations. In some cases, RASopathy mutations show compensatory changes that, as predicted by network modelling, result only in minor pathway deregulation. Mutations in Ras/MAPK pathway components can cause either cancer or developmental disorders ('RASopathies'). Combined network-based and structural analyses show that quantitative changes rather than all-or-none rewiring underlie the difference between these classes of mutations. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.