Key result
The disease-causing A77V mutation in the cardiac Ryanodine receptor RyR2 disrupts the energy conduction pathway by causing a loss of energy responsiveness in certain residues.
The A77V mutation in the cardiac Ryanodine receptor RyR2 disrupts energy conduction pathways, providing structural insights into its disease-causing mechanism.
Energetically responsive residues of the 217 amino acid N-terminal domain of the cardiac Ryanodine receptor RyR2 are identified by a simple elastic net model. These residues lie along a hydrogen bonded path through the protein. The evolutionarily conserved residues of the protein are all located on this path or in its close proximity. All of the residues of the path are either located on the two Mir domains of the protein or are hydrogen bonded to them. Two calcium binding residues, E171 and E173, are proposed as potential binding residues, based on insights gained from the elastic net analysis of another calcium channel receptor, the inositol 1,4,5-triphosphate receptor, IP3R. Analysis of the disease causing A77V mutated RyR2 showed that the path is disrupted by the loss of energy responsiveness of certain residues.
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Erman et al. (2011) studied Arrhythmogenic right ventricular dysplasia type 2 (ARVD/C) / Catecholaminergic polymorphic ventricular tachycardia (CPVT). A77V mutation in RyR2 vs. Wild type RyR2 was evaluated on Energy conduction pathway disruption. The disease-causing A77V mutation in the cardiac Ryanodine receptor RyR2 disrupts the energy conduction pathway by causing a loss of energy responsiveness in certain residues.
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