The aim of this project for Foteini Karapanagioti is to investigate the structural changes of arrhythmic calmodulin mutations and the effects on the binding to and regulation of the Plasma Membrane Ca2+ ATPase (PMCA) pump. The acquired data will give an insight on the involvement of PMCA dysregulation in the mechanism of calmodulin mutation induced heart arrhythmia.

Calmodulin (CaM) is an abundant intracellular and multifunctional Ca2+ binding protein, which exists only in eukaryotic organisms. It is one of the most conserved mammalian genes and in humans the family consists of three independent genes encoding the exact protein. CaM interacts with a variety of different targets, such as short peptides, enzymes, and pumps, and this interaction as well as the regulation of its targets are quite diverse. Mutations in calmodulin have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long-QT syndrome (LQTS). One of its targets, which has also been associated with cardiac contractility, is the Plasma Membrane Ca2+ ATPase (PMCA). PMCAs are key regulators of intracellular Ca2+and their activation is being regulated by the binding of calcium loaded calmodulin on the amino- or carboxy-terminal regulatory domain responsible for the autoinhibition of the pump. Although there has been given an insight on the structural basis for the activation mechanism in plants, the physiological consequences of the calmodulin-mediated PMCA regulation in the heart remain unknown. Biophysical and structural analysis of the PMCA-CaM interaction would evaluate the effect of point CaM mutations causing arrhythmia.