Modulation of cardiac ryanodine receptor 2 by calmodulin

Deshun Gong, Ximin Chi, Jinhong Wei, Gewei Zhou, Gaoxingyu Huang, Lin Zhang, Ruiwu Wang, Jianlin Lei, S. R.Wayne Chen, Nieng Yan

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17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)347-351
Number of pages5
JournalNature
Volume572
Issue number7769
DOIs
StatePublished - Aug 15 2019

All Science Journal Classification (ASJC) codes

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    Gong, D., Chi, X., Wei, J., Zhou, G., Huang, G., Zhang, L., Wang, R., Lei, J., Chen, S. R. W., & Yan, N. (2019). Modulation of cardiac ryanodine receptor 2 by calmodulin. Nature, 572(7769), 347-351. https://doi.org/10.1038/s41586-019-1377-y