My laboratory studies how signal transducing proteins are regulated by protein conformational changes. The ubiquitous protein kinase family of signaling proteins offers rich diversity in regulatory mechanisms. Our laboratory, with Melanie Cobb, Ph.D., solved the structures of the first pair of active and inactive kinase structures – that of the phosphorylated and unphosphorylated MAP kinase ERK2. We continue to study MAP kinase pathway enzymes and have recently solved the structure of the MAP3K TAO2. MAP kinase cascades carry out two double phosphorylation events, and we are studying the mechanism of these events and the implications for the sigmoid switch embodied in MAP kinase cascades.
As part of this study, we determined that the MAP kinase p38, in addition to being activated by phosphorylation, is regulated allosterically by interactions with its activator, the MAP2K MEK3. Other protein kinases under study are WNK1, which is linked to familial hypoaldosteronism, and Aurora B, which participates in cell-cycle regulation. We are also working on several Ste20 homologs in collaboration with the Cobb lab.
A second focus in our group is on the serpin family of protease inhibitors. These molecules undergo the most dramatic conformational changes presently known to occur in proteins. These changes function in the activity of serpins to inhibit and clear target proteases from the blood. The conformational changes are irreversible, and reflect the irreversible pathway in which they function. We are interested in locating other proteins that might have the feature of irreversible conformational changes functioning in either cell division or apoptosis.
In other work, we are collaborating with Cognition Technologies, Inc., to develop an improved search of Medline biomedical content using their natural language technology.