Energetics of the open - closed transition in the RYR N-terminal region: importance for the CPVT phenotype

The central helix of the N-terminal region (NTR) of human cardiac ryanodine receptor (RyR) was shown to be crucial for NTR stability (1). Mutations in this helix were shown to cause the hereditary arrhythmia CPVT (http://triad.fsm.it/cardmoc/), characteristic by increased open probability of the RyR. Using structural modelling, we compared energetics of the NTR in the open and closed conformation for wild-type NTR, for each of the seven known CPVT mutants, and for a putative complex of NTR with a domain peptide that was found to increase RyR open probability. In both conformations, peptide binding induced a decrease of NTR energy due to formation of new H-bonds, while all mutations induced an increase of NTR energy due to loss of H-bonds. However, the energetic difference between the closed and open conformation was lower in the complex as well as in six of the seven mutations, because H-bonds were preferentially formed in the open conformation of the complex, while they were preferentially lost in the closed conformation of the mutated NTR. We hypothesize that impairment of ryanodine receptor function in CPVT arrhythmias may be caused at least in part by the decrease of the energetic difference between the closed and the open conformation of the NTR. Supported by APVV-15-0302. (1) Borko L, Bauerová-Hlinková V, Hostinová E, Gašperík J, Beck K, Lai FA, Zahradníková A, Sevčík J. Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias. Acta Crystallogr D Biol Crystallogr. 2014;70(11): 2897-912. Available from: doi: 10.1107/S1399004714020343. Financing: Agentúra na podporu výskumu a vývoja