Research in the Stock laboratory focuses on understanding molecular mechanisms of receptor-mediated signal transduction. In particular, research is focused on elucidating structure/function relationships in proteins involved in information processing, with special interest directed towards investigating the role of covalent modifications of proteins in signaling pathways. The laboratory uses a combination of molecular genetic, biochemical, and X-ray crystallographic methods to correlate function and structure in signal transduction proteins.
Similar molecular strategies are used in stimulus/response coupling in all cells. The process generally involves transmembrane receptors located at the cell surface and a set of intracellular signal transduction proteins that carry information from the receptors to the target proteins that carry out the specific responses. In an attempt to elucidate the molecular mechanism of receptor-mediated signal transduction, this laboratory has been studying the proteins that comprise a simple model sensory system, bacterial chemotaxis. The system is composed of a small number of components: a family of transmembrane receptor proteins, two receptor modifying enzymes, the flagellar motor apparatus, and four cytoplasmic signal transduction proteins that function in a phosphotransfer pathway that links receptor signaling to the motor response.
Several research projects in the laboratory are focused on receptor modification enzymes. The chemotaxis receptors, like all transmembrane receptors, are subject to reversible covalent modifications that modulate their signaling activities. The bacterial chemoreceptors are reversibly methylated at specific glutamate residues within their conserved cytoplasmic domains. We are studying the enzymes that catalyze these reactions: the S-adenosylmethionine-dependent methyltransferase, CheR, and the methylesterase, CheB. Research focuses on understanding their mechanisms of catalysis, regulation of their enzymatic activities and interactions that allow recognition of the receptor substrates.
Other research projects focus on "two-component" proteins involved in phosphotransfer signaling systems. Transfer of a high energy phosphoryl group from a histidine protein kinase to an aspartyl residue of a response regulator represents a general mechanism of signal transduction that is widespread throughout nature, having been identified in hundreds of systems in numerous prokaryotes and some eukaryotic organisms. We are investigating the mechanism of activation of representative response regulator proteins including the bacterial chemotaxis regualtor of the flagellar motor CheY, the methylesterase CheB, the winged-helix transcription factor OmpR and Drr proteins, members of the OmpR subfamily from the hyperthermophilic bacterium Thermotoga maritima.