Understanding protein structural changes for oncogenic missense variants

Understanding and predicting the changes of protein structure and function upon mutation and their relationship to human health is a critical element to translate the genomic revolution into actionable interventions. Therefore, it is pertinent to explore how mutations result in structural changes leading to pathogenic proteins, but due to the protein structural knowledge gap, experimental approaches are lacking. Protein structure prediction methods, such as I-TASSER, have made it possible to predict the structure of a given amino acid sequence, thus opening a new way to explore protein structure changes upon mutations when experimental information is not available. Using known mutations from the Catalogue of Somatic Mutation in Cancer (COSMIC) and ClinVar databases, we compare predicted structure-derived properties from wild type (WT) and mutated proteins and find differences between the local and global 3D protein structures of the WT and the mutants. The studies in this relatively small sample reveal that the structural changes are quite diverse.