Dr.John Putkey

Department of Biochemistry and Molecular Biology
Program in Biochemistry and Molecular Biology

University of Texas-Houston Medical School
P.O. Box 20708 - Houston, Texas 77225
(713) 500-6061: fax (713) 500-0652
email: John.Putkey@uth.tmc.edu

Ph.D., University of California, Riverside
Damon Runyon-Walter Winchell Olive V. Levin
Postdoctoral Fellow, Baylor College of Medicine
NIH Career Research Development Award

Molecular Mechanisms of Calcium-Dependent Cell Regulation

Calcium plays an essential role as a structural element and as a second messenger in the regulation of an array of cellular processes. However, the calcium ion itself encodes no intrinsic information. The cellular signal represented by fluctuations in calcium ion concentrations must be interpreted by specific calcium-binding proteins which act to regulate the activity of other enzymes or proteins. The importance of proteins that bind calcium is underscored by the lethality of disrupting these genes in transgenic mice, and genetic diseases which result from mutations in genes that encode calcium binding proteins. Thus, an understanding of structure/function relationships in calcium binding proteins would provide unique insights into the structural basis of diseases, and provide a data base of information for the development of drugs that can alter the properties of regulatory calcium binding proteins.

My laboratory applies a synergistic blend of molecular and structural biology to study the molecular anatomy of calcium binding proteins. Current projects focus on cardiac troponin C, calmodulin, and cartilage oligomeric matrix protein (COMP). Areas of interest include: The mechanisms of regulation of calmodulin activity by post-translational modification and modulation of calmodulin binding to target proteins; Exploring the molecular mechanism of regulation of cardiac muscle contraction by calcium binding to cardiac troponin C, and how cardiotonic drugs lead to an increased efficiency of cardiac muscle contraction; Using NMR to reveal the strucutral basis behind why mutations in the extracelluar matix protein COMP lead to skeletal dysplasias and dwarfing syndromes.

Contraction and relaxation of the human heart depends on the binding and release of calcium from cardiac troponin C.

The figure to the left shows the NMR solution structure of this critical regulatory protein

Selected References

Kleerekoper, Q. and Putkey, J.A. (1999): Drug binding to cardiac troponin C. J. Biol. Chem. 274: 23932-23939.

Li, Y., Love, M.L., Putkey, J.A., and Carolyn Cohen, C (2000): Bepridil opens the regulatory N-terminal lobe of cardiac troponin C. Proc. Natl. Acad. Sci. USA 87:

Kleerekoper, Q and Putkey, J.A. (2002): Disease-causing mutations in COMP cause and unstructured calcium binding domain. J. Biol. Chem. 277: 10581-10589.

Putkey, J.A., Kleerekoper, Q. Gaertner, T.A. and Waxham, M.N. A new role for IQ motif proteins in regulating calmodulin function (2003). J. Biol. Chem. (Accelerated Communication) 278: 49667-49670. (See commentary: PEPping Up the Calmodulin Response Science. STKE 2003 (213), tw484. [DOI: 10.1126/stke.2132003tw484]).

Gaertner, T.R., Putkey, J.A., and Waxham, M.N. RC3/Neurogranin and Ca2+/calmodulin-dependent protein kinase II produce opposing effects on the affinity of calmodulin for calcium. J. Biol. Chem. 279: 9374-82, 2004.

Xiong, L., Quinn K. Kleerekoper, Q.K., He, R., Putkey, J.A., and Hamilton, H. L. Sites on Calmodulin that Interact with the Carboxyterminal Tail of CaV1.2 Channel. J. Biol. Chem. in press 2005.