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
Wang, X., Kleerekoper, Q.K, and Putkey, J.A. Structural dynamics of calcium-CaM bound to PEP-19. Biochemistry (submitted).
Xiong, L., Kleerekoper, Q. K. and Putkey, J.A. Intra and inter domain effects due to mutation of calcium binding sites in calmodulin. Biochemistry (submitted).
Kleerekoper, Q. K. and Putkey, J.A. PEP-19: An intrinsically disordered regulator of calmodulin signaling. J. Biol. Chem. 284: 7455-7464, 2009.
Putkey, J.A., Waxham, M.N., Gaertner, T.A., Brewer, K.J., Goldsmith, M., Kubota, Y., and Kleerekoper, Q.R. Acidic/IQ Motif Regulators of Calmodulin J. Biol. Chem. 283: 1401-1410, 2008
Maximiciuc, A.A., Putkey, J.A., Shamoo, Y., and MacKenzie, K.R. Complex of Calmodulin with a Ryanodine Receptor Target Reveals a Novel, Flexible Binding Mode. Structure 14: 1547-1556, 2006.
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. 280: 7070-7079, 2005.
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: 39374-39382, 2004.
Putkey, J.A., Kleerekoper, Q. Gaertner, T.A. and Waxham, M.N. A new role for IQ motif proteins in regulating calmodulin function. J. Biol. Chem. (Accelerated Communication) 278: 49667-49670. 2003 (See commentary: PEPping Up the Calmodulin Response Science. STKE 2003 (213), tw484. [DOI: 10.1126/stke.2132003tw484]).
Search PubMed for a complete list of Dr. Putkey's publications.