Modulation of cardiac ryanodine receptor 2 by calmodulin.

TitleModulation of cardiac ryanodine receptor 2 by calmodulin.
Publication TypeJournal Article
Year of Publication2019
AuthorsGong, D, Chi, X, Wei, J, Zhou, G, Huang, G, Zhang, L, Wang, R, Lei, J, Chen, SRWayne, Yan, N
Date Published2019 Aug
KeywordsAdenosine Triphosphate, Animals, Apoproteins, Binding Sites, Caffeine, Calcium, Calmodulin, Cryoelectron Microscopy, Humans, Models, Molecular, Reproducibility of Results, Ryanodine Receptor Calcium Release Channel, Swine

<p>The high-conductance intracellular calcium (Ca) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca-dependent manner. Here we reveal the regulatory mechanism by which porcine RyR2 is modulated by human CaM through the structural determination of RyR2 under eight conditions. Apo-CaM and Ca-CaM bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical and central domains. The shift in CaM-binding sites on RyR2 is controlled by Ca binding to CaM, rather than to RyR2. Ca-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca-activated channel. By contrast, the pore of the ATP, caffeine and Ca-activated channel remains open in the presence of Ca-CaM, which suggests that Ca-CaM is one of the many competing modulators of RyR2 gating.</p>

Alternate JournalNature
PubMed ID31278385