Disease-associated mutations alter the dynamic motion of the N-terminal domain of the human cardiac ryanodine receptor

• Published in: Journal of biomolecular structure & dynamics 2020-03, Vol.38 (4), p.1054-1070
• Main Authors: Bauer, Jacob A., Borko, Ľubomír, Pavlović, Jelena, Kutejová, Eva, Bauerová-Hlinková, Vladena
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Substitution; Genetic Predisposition to Disease; Human Ryanodine Receptor 2; Humans; molecular dynamics; Molecular Dynamics Simulation; Mutation; N-terminal domain; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs - genetics; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - genetics; SAXS; Structure-Activity Relationship
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2019.1600027

The human cardiac ryanodine receptor (hRyR2), the ion channel responsible for the release of Ca 2+ ions from the sarcoplasmic reticulum into the cytosol, plays an important role in cardiac muscle contraction. Mutations to this channel are associated with inherited cardiac arrhythmias. These mutations appear to cluster in distinct parts of the N-terminal, central and C-terminal areas of the channel. Here, we used molecular dynamics simulation to examine the effects three disease-associated mutations to the N-terminal region, R414L, I419F and R420W, have on the dynamics of a model of residues 1-655 of hRyR2. We find that the R414L and I419F mutations diminish the overall amplitude of motion without greatly changing the direction of motion of the individual domains, whereas R420W both enhances the amplitude and changes the direction of motion. Based on these results, we hypothesize that R414L and I419F hinder channel closing, whereas R420W may enhance channel opening. Overall, it appears that the wild-type protein possesses a moderate level of flexibility which allows the gate to close and not easily open without an opening signal. These mutations, however, disrupt this balance by making the gate either too rigid or too loose, causing closing to become difficult or less effective. Small-angle X-ray scattering studies of the same 1-655 residue fragment are in agreement with the molecular dynamics results and also suggest that the rest of the protein is needed to keep the entire domain properly folded. Communicated by Ramaswamy H. Sarma