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 () and Nieng Yan ()
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Deshun Gong: Tsinghua University
Ximin Chi: Tsinghua University
Jinhong Wei: University of Calgary
Gewei Zhou: Tsinghua University
Gaoxingyu Huang: Tsinghua University
Lin Zhang: University of Calgary
Ruiwu Wang: University of Calgary
Jianlin Lei: Tsinghua University
S. R. Wayne Chen: University of Calgary
Nieng Yan: Tsinghua University

Nature, 2019, vol. 572, issue 7769, 347-351

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1377-y

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