Related Experiment Video
Updated: Apr 30, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations
1EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona, Spain.
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.
Insights
RASopathies and cancer arise from mutations in the Ras/MAPK pathway. This study reveals quantitative network differences, not qualitative ones, distinguish these conditions, impacting protein activation and downstream signaling.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- RASopathies are developmental disorders linked to germline mutations in genes of the Ras/mitogen-activated protein kinase (MAPK) pathway.
- The molecular basis for differing outcomes (RASopathy vs. cancer) from mutations in the same protein remains unclear.
Purpose of the Study:
- To investigate the molecular mechanisms differentiating RASopathy-associated mutations from cancer-associated mutations within the Ras/MAPK pathway.
- To analyze the impact of missense mutations on protein structure, stability, and network activity.
Main Methods:
- Analysis of 956 missense mutations in RASopathy and cancer contexts.
- Utilized protein network data and 3D structural analysis.
- Employed the FoldX protein design algorithm to predict mutation effects on protein stability (destabilizing energies).
- Network modeling to assess downstream pathway deregulation.
Main Results:
- Most destabilizing mutations affect protein activation regions, not protein folding.
- Cancer-associated mutations showed a trend towards higher energy changes than RASopathy mutations.
- RASopathy mutations often involve compensatory mechanisms leading to minor downstream pathway deregulation.
- Quantitative differences in network effects distinguish RASopathy from cancer mutations.
Conclusions:
- Suggests that quantitative network differences, rather than qualitative ones, determine the phenotypic outcome of RASopathy versus cancer mutations.
- Highlights the role of protein activation and network compensation in RASopathy development.
Related Concept Videos
02:38The Ras Gene
Ras is a...
02:38The Ras Gene
01:24Small GTPases - Ras and Rho
Three regulatory proteins control their activity:
02:26Protein Networks
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
02:23Abnormal Proliferation