The Effect of S616L, a CPVT1-Associated Mutation, on the Stability and Structure of Human Cardiac RyR2

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is a heritable genetic disease caused by mutations to hRyR2, the cardiac isoform of the human ryanodine receptor. One such mutation, S616L, is found in the α-helical part (NSol) of the hRyR2 N-terminal domain (NTD) close to a three-way junction between the NTD, junctional solenoid (JSol), and bridging solenoid (BSol) domains. In this study, we use molecular dynamics simulation to study the effect of S616L on the residues of this junction. We find that the mutation slightly weakens the interface between the N-terminal domain and the bridging solenoid by changing the preferred conformation of the residues at the interface, thereby promoting a slight opening between these domains. In addition, we determined the impact of this mutation on the biophysical and biochemical properties of a 655-residue fragment containing the entire hRyR2 N-terminal domain, finding that it slightly increases the thermal stability of the fragment.