Ann M. Stock
	Associate Director Center for Advanced Biotechnology and Medicine Professor Department of Biochemistry UMDNJ-Robert Wood Johnson Medical School Investigator Howard Hughes Medical Institute Member Cancer Institute of New Jersey Ph.D., 1986, University of California, Berkeley Tel:  [732] 235-4844 Fax: [732] 235-5289 stock@cabm.rutgers.edu Stock Lab Website

Signal transduction, protein kinases, response regulators, receptor modification, X-ray crystallography.

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.

The ability to respond to environmental changes is essential for single-celled organisms to survive and thrive. Because adaptive responses are essential for general metabolic functions as well as for host-pathogen interactions, signal transduction proteins are key targets for development of anti-microbial drugs. The majority of signal transduction in bacteria occurs through pathways known as "two-component" systems. These 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. Response regulator proteins typically contain two domains: a conserved regulatory domain and a variable effector domain. The regulatory domains of response regulator proteins can be thought of as phosphorylation-activated switches that are turned on and off by phosphorylation and dephosphorylation. In the phosphorylated state, the conserved regulatory domains activate their associated effector domains to elicit specific responses such as flagellar rotation, regulation of transcription, or enzymatic catalysis. Using a combination of biophysical and biochemical approaches, our laboratory is investigating how these molecular switch proteins function to regulate cellular activities.

The majority of bacterial response regulators are transcription factors that regulate expression of specific sets of genes in response to environmental cues. Response regulator transcription factors can be classed into subfamilies based on structural similarity within their DNA-binding effector domains. The OmpR/PhoB subfamily, characterized by a winged-helix DNA-binding domain, is the largest subfamily and accounts for approximately one third of all response regulators. The genome of a single bacterium typically encodes 10-40 different OmpR/PhoB family transcription factors. Over 5000 different OmpR/PhoB family proteins have been identified to date. This large family allows us to pose a very basic question of broad relevance. Do homologous signaling proteins with structurally similar domains use common mechanisms to regulate function?

Within the OmpR/PhoB family of response regulators, the short answer to this question is "no". There is a limit to the extent that sequence and structural similarity can be used to predict mechanisms of function. In well-characterized members of the OmpR/PhoB family, phosphorylation-mediated activation involves a transition from inactive monomers to active dimers (and/or higher order oligomers) and this dimerization promotes DNA binding to direct repeat half-sites located within the promoters of regulated genes. Our recent studies, indicate that OmpR/PhoB family members have different inactive states but adopt a common active state upon phosphorylation. The different inactive conformations provide the basis for different regulatory strategies that are optimized for the specific needs of each individual two-component signaling system.

Additional projects pursued in collaboration with the laboratory of Dr. Peter Lobel are focused on characterization of proteins involved in lysosomal storage diseases, including Niemann-Pick type C2 and Batten disease.

Inactive and active domain arrangements in OmpR/PhoB subfamily members.  OmpR/PhoB response regulators havae different domain orientations in the inactive state yet all adopt a common structure in the active state.

Selected Publications1