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
JournalNature
Date Published2019 Jul 05
ISSN1476-4687
Abstract

The high-conductance intracellular calcium (Ca2+) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca2+-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 Ca2+-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 Ca2+ binding to CaM, rather than to RyR2. Ca2+-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca2+-activated channel. By contrast, the pore of the ATP, caffeine and Ca2+-activated channel remains open in the presence of Ca2+-CaM, which suggests that Ca2+-CaM is one of the many competing modulators of RyR2 gating.

DOI10.1038/s41586-019-1377-y
Alternate JournalNature
PubMed ID31278385