Calmodulin and the ryanodine receptors: a challenging model system for the interplay of structural plasticity and protein-protein interactions

 

Research Project supported by the Danish Council for Independent Research | Natural Sciences

(Grant ID DFF-1323-00344)

 

Project leaders: Professor mso Reinhard Wimmer and Professor mso Michael T. Overgaard

Dept. of Biotechnology, Chemistry and Environmental Engineering

Aalborg University, Denmark

 

Calmodulin (CaM) is the universal intracellular calcium sensor and mediator of calcium signaling. Among many other processes, CaM is also involved in the contraction of muscles through interaction with the ryanodine receptors 1 (skeletal muscle) and 2 (cardiac muscle). Recently, mutations of CaM having a specific impact on heart rhythm were identified 1.  Their impact is similar to that of mutations in the cardiac ryanodine receptor 2 (RyR2) 2, but not in the skeletal ryanodine receptor (RyR1). With this project, we want to investigate the structural details of the interaction between CaM and RyR1&2. Differences in those interactions between wild-type and mutants will give valuable clues to the mechanism, by which the mutations cause CPVT.

 

 

References

1. Nyegaard M, Overgaard MT, Søndergaard MT, Vranas M, Behr ER, Hildebrandt LL, Lund J, Hedley PL, Camm AJ, Wettrell G, et al. (2012) Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death. Am. J. Hum. Genet. 91:703–712.

2. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2001) Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200.