The goal of research in our laboratory is to understand the molecular mechanisms of receptor-mediated signal transduction. In particular, research is focused on elucidating structure/function relationships in proteins involved in information processing using a combination of molecular genetic, biochemical, and X-ray crystallographic methods. Specific interest is directed toward investigating the role of covalent modifications of proteins in signaling pathways. A large fraction of bacterial signal transduction systems commonly known as two-component systems utilize a common mechanism involving transfer of a high-energy phosphoryl group from a histidine protein kinase to an aspartate residue of a response regulator protein. The regulatory domains of the response regulator proteins can be thought of as phosphorylation-activated switches that are turned on and off by phosphorylation and dephosphorylation. In the active, phosphorylated state, the conserved regulatory domains interact productively with other protein domains to activate specific effector functions such as flagellar rotation, regulation of transcription, or enzymatic catalysis. We have solved the crystal structures of several representative members of the response regulator family. These structures and correlated biochemical studies have provided insight into the mechanism of function of response regulators. Phosphorylation alters the conformation of the regulatory domain and the altered molecular surface is exploited for regulatory protein-protein interactions.
Current efforts are focused on extending our understanding of the molecular mechanisms of regulation of response regulator function to systems-level analysis of specific two-component signaling systems in bacterial cells. Our efforts are focused both on model regulatory systems in E. coli and on signaling systems involved in virulence of the human pathogen Staphylococcus aureus.
