Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Impact of cancer mutations on protein binding and activity
Missense mutations play an important role in carcinogenesis, however, their effect on biomolecular interactions remains unclear. We describe a new framework that uses experimental evidence on structural complexes, the atomic details of binding interfaces and evolutionary conservation to map the set of human protein-biomolecular interactions (Benjamin et al. 2012; Tyagi etal. 2012). To analyze the impact of missense cancer mutations on protein interactions, we model the affected protein complexes and estimate the change in binding energy upon mutations. We find that although some missense mutations over-stabilize protein complexes, overall they are destabilizing, mostly affecting the electrostatic component of binding energy. Our analysis allows stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers. Furthermore we observe that interactions of proteins with mutations mapped on interfaces have higher bottleneck properties compared to interactions with mutations elsewhere on the protein. This suggests that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks.
Next we study the mechanisms of aberrant activation of receptor tyrosine kinases in cancer and estimate the effects of single and double cancer mutations on the stability of active and inactive states (Hashimoto et al. 2012). We show that singleton cancer mutations destabilize active and inactive states, however, inactive states are destabilized more than the active ones, potentially leading to kinase activation. In addition, more frequent mutations have a higher activating effect. The activation mechanisms of double mutations are found to be quite different from those of single mutations.
Manoj Tyagi, Kosuke Hashimoto, Benjamin Shoemaker, Stefan Wuchty and Anna R. Panchenko “Large-scale mapping of human protein interactions using structural complexes”, EMBO Reports, Jan 20. doi: 10.1038 (2012).
Kosuke Hashimoto, Igor Rogozin and Anna R. Panchenko “Effect of cancer single and double somatic mutations on stability and activity of receptor tyrosine kinases”, Human Mutation, Jun 29. doi: 10.1002/humu.22145 (2012).
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