CAREER: Leveraging a fast-evolving kinase family to gain fundamental understanding of kinase evolution

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Kinases are critical components of cells that work by modifying proteins. This process is finely tuned and regulated, as changes in kinase activity can be lethal or lead to a variety of diseases. This means that signaling molecules like them tend to evolve very slowly, because they must maintain both the ability to perform the chemistry as well as identify the right target. For this reason, it has been difficult to study kinases and their signaling networks. The research goals of this project are based on developing a large family of fast-evolving kinases from a parasite as an experimental system that can be compared to more typical animal model systems. This will allow us to better define the biochemical rules that govern the functional elements of kinases. This project's educational goals will (1) develop a new course to use bioinformatics and evolutionary concepts to teach undergraduates scientific critical thinking skills and (2) adapt these course materials to train high school teachers from local schools that enroll students who traditionally are underrepresented in science in engineering. The goal of introducing high school students to inquiry-based science The educational goals will empower students, both undergraduate and high school, to use bioinformatic tools to ask and quickly answer questions of their own devising. This will train them in the critical thinking that is the foundation of scientific inquiry. Such critical thinking skills are a fundamental part of modern education, and will further empower the students as they grow as citizensAs opposed to normal intracellular signaling kinases, effector kinases of the coccidian parasites such Toxoplasma gondii evolve at rates that dwarf normal enzymes. These coccidian kinases evolve quickly, but act on well-studied vertebrate signaling networks. We will harness this system to discover new biochemistry and the forces that govern its evolution. This research will (1) determine the biochemical and structural mechanism by which a family of coccidian kinases is able to retain its catalytic activity in spite of missing a Gly-loop, which is a motif that has been presumed to be absolutely required for kinase activity, (2) use the reconstruction of ancestral gene sequences to define the residues that enable active kinases that require ATP for stability to evolve into catalytically inactive pseudokinases that are stable without nucleotide, and (3) determine how sets of orthologous coccidian kinases have changed their specificity to target completely different vertebrate pathways.