PEP-19 and neurogranin (Ng or RC3) are small IQ-motif proteins that bind to the ubiquitous Ca2+-dependent regulator, calmodulin (CaM). Although they have no known intrinsic activity, PEP-19 and RC3 have broad-based effects on CaM signaling. PEP-19 is proposed to have general cytoprotective activity, and experimental data show that expression of PEP-19 inhibits apoptosis and Ca2+ cytotoxicity. These observations suggest that PEP-19 regulates, or attenuates, CaM activity to enhance survival when cells are faced with challenging Ca2+ dynamics due to normal or pathologic conditions. This highlights the significance of understanding the structural basis for the mechanism of action of PEP-19 and homologous proteins. Work presented during this talk show that PEP-19 and RC3 have novel effects on rate limiting kinetics of Ca2+ binding to the C-domain of CaM. We show that PEP-19 is intrinsically disordered, that it binds to CaM in the presence or absence of Ca2+ via a novel 30-residue acidic/IQ motif, and that binding confers novel dynamical properties to CaM.

Biography of John Putkey:
Dr. Putkey’s lab 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 structural basis behind why mutations in the extracelluar matix protein COMP lead to skeletal dysplasias and dwarfing syndromes.