Faculty

The primary goal of the Tesmer laboratory is to understand molecular mechanisms of signal transduction. The primary tool is X-ray crystallography, which enables us to examine macromolecular structure at atomic resolution. In order to decipher how one protein transfers a biological signal to another, atomic structures are determined of signaling proteins individually and in complex. These structures help decipher existing biochemical data, spawn new hypotheses for future research and can aid in the design of therapeutic agents.

Current studies span three signal transduction systems thought to be important in human physiology and disease. Each system involves the activation of G protein-coupled receptors, which constitute the largest receptor family in the human genome and are involved in nearly all known physiological processes. The first signaling system involves the structure and function of G protein-coupled receptor kinases (GRKs), a family of enzymes responsible for the rapid desensitization of cells to extracellular signals. Members of this protein family have been implicated in the progression of heart disease and opiate addiction, and include ß-adrenergic receptor kinase 1 and rhodopsin kinase. The second signaling system is that of leukemia-associated Rho guanine nucleotide exchange factor (LARG), a protein that links extracellular signals to the rearrangement of the actin cytoskeleton. The third signaling system is that of a heterotrimeric G protein known as Gaq, whose activity regulates cardiac hypertrophy, blood pressure and platelet activation.

In each of these systems, there is strong evidence that the proteins involved are organized into higher order signaling complexes at the cell membrane, and a major goal of the Tesmer lab is to isolate these complexes for structural analysis. Students joining the lab will therefore experience techniques from a diverse range of disciplines, including molecular biology, protein chemistry, pharmacology, molecular biophysics and bioinformatics.

Awards

John H. Abel Award, American Society for Pharmacology and Experimental Therapeutics, 2009
University of Michigan Medical School Basic Science Research Award, 2008
American Cancer Society Research Scholar, 2004
Cottrell Scholar Award, 2002
American Heart Association Texas Affiliate LBJ Research Award, 2000

Representative Publications

1. Sing, P., Wang, B., Madea, T., Palczewski, K., and Tesmer, J.J.G., "Structures of rhodopsin kinase in different ligand states reveal key elements in G protein-coupled receptor kinase activation," J. Biol. Chem., 2008, 283, 14053-14062.

2. Luts, S. Shankaranarayanan, A., Coco, C., Nance, M., Vettel, C., Baltus, D., Evelyn, C., Neubig, R., Wieland, T., and Tesmer, J.J.G., "Structure of Gαq-p63RhoGEF-RhoA Complex reveals a pathway for the activation of Rho-A by GPCRs," Science, 2007, 318, 1923-1927.

3. Gu, S., He, J., Ho, W.T., Ramineni, S., Thal, D.M., Natesh, R., Tesmer, J.J.G., Hepler, J.R. and Heximer, S.P., "Unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other RGS R4/B subfamily members", J. Biol. Chem., 2007, Epub ahead of print.

4. Chen, X., Boughton, A.P., Tesmer, J.J.G. and Chen, X., "In situ investigation of heterotrimeric G protein betagamma subunit binding and orientation on membrane bilayers", J. Am. Chem. Soc., 2007, in press.

5. Williams, S.L., Lutz, S., Charlie, N.K., Vettel, C., Ailion, M., Coco, C., Tesmer, J.J.G., Jorgensen, E.M., Wieland, T. and Miller, K.G., "Trio's Rho-specific GEF domain is the missing Gαλπηα-Θ effector in C. elegans", Genes Dev., 2007, in press.

6. Lodowski, D.T., Tesmer, V.M., Benovic, J.L., and Tesmer, J.J.G., "The structure of G protein-coupled receptor kinase 6 defines a second lineage of GRKs", J. Biol. Chem., 2006, 281, 16785-16793.

7. Kreutz, B., Yau, D.M., Nance, M., Tanabe, S., Tesmer, J.J.G. and Kozasa, T., "A new approach to producing functional Gαλπηα subunits yields the activated and deactivated structures of Gα_12/13 proteins", Biochem., 2006, 45, 167.