Ongoing efforts are focused on the following three inter-related projects:
Delineating protein kinase design principles using evolutionary-systems approaches
Protein kinases are exquisitely designed molecular machines that display remarkable diversity and complexity in their mechanisms of action. We are mining the wealth of evolutionary information embedded in protein kinase sequences from diverse organisms to obtain an in-depth understanding of the evolutionary rules that govern the structure and regulation of these proteins. Important goals are to quantify the sequence similarities and differences between functionally divergent kinases using statistical and computational approaches, and to experimentally test the role of evolutionarily constrained motifs using biochemical and biophysical techniques. We are also conceptualizing protein kinase knowledge in the form of ontology to facilitate systems level analysis of protein kinase data.
- Oruganty K, Talathi NS, Wood ZA, Kannan N. (2013) Identification of a hidden strain switch provides clues to an ancient structural mechanism in protein kinases. PNAS 110(3):924-9
- Oruganty K, Kannan N. (2012) Design principles underpinning the regulatory diversity of protein kinases. Philos Trans R Soc Lond B Biol Sci 367(1602):2529-39
- Mustafa M, Mirza M, Kannan N. (2011) Conformational regulation of the EGFR kinase core by the Juxtamembrane and COOH-terminal tail. Proteins 79(1):99-114
Predicting the functional impact of cancer mutations in protein kinases
Large scale cancer genome sequencing studies are beginning to reveal the mutational profiles of the 518 protein kinase genes encoded in the human genome from many different cancer types. A detailed understanding of the structural and functional impact of these mutations can potentially lead to new therapies for cancer. We are integrating and analyzing diverse forms of protein kinase data to identify key causative mutations in the cancer kinome. We are using selected receptor tyrosine kinases as our experimental system to predict and test the impact of cancer mutations. We are also developing a computational framework for rapid and consistent annotations of protein kinase mutations identified in cancer genome sequencing studies.
- Gosal G, Kochut K, Kannan N. (2011) ProKinO: An ontology for integrative analysis of protein kinases in cancer. PLoS ONE 6(12):e28782
- Mirza M, Mustafa M, Talevich E, Kannan N. (2010) Co-conserved features associated with cis regulation of ErbB receptor tyrosine kinases. PLoS ONE 5(12):e1431
- Torkamani A, Kannan N, Taylor SS, Schork NJ. (2008) Congenital disease SNPs target lineage specific structural elements in protein kinases. PNAS 105:9011-6
Understanding the divergence and adaptation of protein kinases in apicomplexan parasites
Apicomplexa is an evolutionary divergent phylum of eukaryotic pathogens responsible for human and agricultural diseases. Many cellular functions in apicomplexans are controlled by protein kinases, which have emerged as promising targets for infectious diseases. We are interested in understanding how parasitic kinases structurally and mechanistically differ from their eukaryotic hosts. To this end, we are systematically identifying and classifying kinase sequences in apicomplexan genomes and performing quantitative comparisons of parasite and host kinase sequences and structures. We are also involved in various collaborative efforts to identify and characterize apicomplexan protein kinase substrates.
- Talevich E, Mirza A, Kannan N. (2011) Structural and evolutionary divergence of eukaryotic protein kinases in Apicomplexa. BMC Evol Biol 11:321
- Talevich E, Tobin AB, Kannan N, Doerig C. (2012) An evolutionary perspective on the kinome of malaria parasites. Philos Trans R Soc Lond B Biol Sci 367(1602):2607-18