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The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.

ABSTRACT: Missense mutations at protein-protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, "core" and "rim", which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues ("hot spots") is crucial for the binding free energy of the protein-protein complex. We performed a large-scale structural analysis of human single amino acid variations (SAVs) and demonstrated that disease-causing mutations are preferentially located within the interface core, as opposed to the rim (p<0.01). In contrast, the interface rim is significantly enriched in polymorphisms, similar to the remaining non-interacting surface. Energetic hot spots tend to be enriched in disease-causing mutations compared to non-hot spots (p=0.05), regardless of their occurrence in core or rim residues. For individual amino acids, the frequency of substitution into a polymorphism or disease-causing mutation differed to other amino acids and was related to its structural location, as was the type of physicochemical change introduced by the SAV. In conclusion, this study demonstrated the different distribution and properties of disease-causing SAVs and polymorphisms within different structural regions and in relation to the energetic contribution of amino acid in protein-protein interfaces, thus highlighting the importance of a structural system biology approach for predicting the effect of SAVs.

SUBMITTER: David A

PROVIDER: S-EPMC4548493 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.

David Alessia A Sternberg Michael J E MJ

Journal of molecular biology 20150711 17

Missense mutations at protein-protein interaction sites, called interfaces, are important contributors to human disease. Interfaces are non-uniform surface areas characterized by two main regions, "core" and "rim", which differ in terms of evolutionary conservation and physicochemical properties. Moreover, within interfaces, only a small subset of residues ("hot spots") is crucial for the binding free energy of the protein-protein complex. We performed a large-scale structural analysis of human ...[more]

PMID: 26173036

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Project description:Recently it has been shown that cancer mutations selectively target protein-protein interactions. We hypothesized that mutations affecting distinct protein interactions involving established cancer genes could contribute to tumor heterogeneity, and that novel mechanistic insights might be gained into tumorigenesis by investigating protein interactions under positive selection in cancer. To identify protein interactions under positive selection in cancer, we mapped over 1.2 million nonsynonymous somatic cancer mutations onto 4,896 experimentally determined protein structures and analyzed their spatial distribution. In total, 20% of mutations on the surface of known cancer genes perturbed protein-protein interactions (PPIs), and this enrichment for PPI interfaces was observed for both tumor suppressors (Odds Ratio 1.28, P-value < 10(-4)) and oncogenes (Odds Ratio 1.17, P-value < 10(-3)). To study this further, we constructed a bipartite network representing structurally resolved PPIs from all available human complexes in the Protein Data Bank (2,864 proteins, 3,072 PPIs). Analysis of frequently mutated cancer genes within this network revealed that tumor-suppressors, but not oncogenes, are significantly enriched with functional mutations in homo-oligomerization regions (Odds Ratio 3.68, P-Value < 10(-8)). We present two important examples, TP53 and beta-2-microglobulin, for which the patterns of somatic mutations at interfaces provide insights into specifically perturbed biological circuits. In patients with TP53 mutations, patient survival correlated with the specific interactions that were perturbed. Moreover, we investigated mutations at the interface of protein-nucleotide interactions and observed an unexpected number of missense mutations but not silent mutations occurring within DNA and RNA binding sites. Finally, we provide a resource of 3,072 PPI interfaces ranked according to their mutation rates. Analysis of this list highlights 282 novel candidate cancer genes that encode proteins participating in interactions that are perturbed recurrently across tumors. In summary, mutation of specific protein interactions is an important contributor to tumor heterogeneity and may have important implications for clinical outcomes.

Dataset Information

The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.

Publications

The Contribution of Missense Mutations in Core and Rim Residues of Protein-Protein Interfaces to Human Disease.

Similar Datasets

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