Faculty

John J. G. Tesmer

Professor of Pharmacology; Professor of Biological Chemistry; Research Professor of the Life Sciences Institute

Ph.D., Purdue University
Postdoctoral Fellow, UTSW Medical Center

Research Focus: Molecular mechanisms of heterotrimeric G protein signaling. X-ray crystallography, protein structure and function.

Phone: 734.615.9544
E-mail: tesmerjj@umich.edu
Fax: 734.763.6492

The primary goal of the Tesmer laboratory is to understand molecular mechanisms of signal transduction. The primary tool is X-ray crystallography, which enables the structure determination of macromolecules 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 drugs.

Current studies span two signal transduction systems thought to be important in human physiology and disease. Each system involves the activation of G protein-coupled receptors (GPCRs), which constitute the largest receptor family in the humane genome and are involved in nearly all known physiological processes. The first signaling system involves the structure and function of GPCR 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 β-adrenergic receptor kinase 1 and rhodopsin kinase. The second signaling system is that of the heterotrimeric G protein known as G-alphaq, whose activity regulates cardiac hypertrophy, blood pressure and platelet activation. GPCRs that couple to G-alphaq regulate the activity of several downstream targets, including the Rho nucleotide exchange factor p63RhoGEF, which in turn regulates the actin cytoskeleton, and phospholipase-Cbeta, which in turn regulates intracellular calcium levels.

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 spanning a diverse range of disciplines, including molecular biology, protein chemistry, pharmacology, molecular biophysics and bioinformatics.

Tesmer Research Group

 

Awards

2010
ASBMB Young Investigator Award
2009 John H. Abel Award, American Society for Pharmacology and Experimental Therapeutics
2008 University of Michigan Medical School Basic Science Research Award
2004 American Cancer Society Research Scholar
2002 Cottrell Scholar Award
2000
American Heart Association Texas Affiliate LBJ Research Award

 

Representative Publications

  1. Boughton AP, Yang P, Tesmer VM, Ding B, Tesmer JJG, Chen Z: Heterotrimeric G protein b1g2 subunits change orientation upon complex formation with G protein-coupled receptor kinase 2 (GRK2) on a model membrane. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:E667-73.

  2. Lyon AM, Tesmer VM, Dhamsania VD, Thal DM, Gutierrez J, Chowdhury S, Suddala KC, Northup JK, Tesmer JJG: An autoinhibitory helix in the C-terminal region of phospholipase Cβ mediates Gαq activation. Nature Struct. Mol. Biol. 2011, 18:999-1005. PMCID: 3168981

  3. Thal DM, Yeow RY, Schoenau C, Huber J, Tesmer JJG: Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol. Pharm. 2011, 80: 294-303. PMCID: 3141885

  4. Boguth CA, Singh P, Huang C, Tesmer JJG: Molecular basis for activation of G protein-coupled receptor kinases. EMBO J, 2010, 29: 3249-59. PMCID: 2957210

  5. Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJG: Structure of Gaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs. Science 2007, 318:1923-7. PMID: 18096806

  6. Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJG: Snapshot of activated G proteins at the membrane: the Gaq-GRK2-Gbg complex. Science 2005, 310: 1686-1690. PMID: 16339447

 

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