TY - JOUR
T1 - Modulation of cardiac ryanodine receptor 2 by calmodulin
AU - Gong, Deshun
AU - Chi, Ximin
AU - Wei, Jinhong
AU - Zhou, Gewei
AU - Huang, Gaoxingyu
AU - Zhang, Lin
AU - Wang, Ruiwu
AU - Lei, Jianlin
AU - Chen, S. R.Wayne
AU - Yan, Nieng
N1 - Funding Information:
Acknowledgements We thank X. Li for technical support for electron microscopy image acquisition; the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support; the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of China National Center for Protein Sciences Beijing) and the ‘Explorer 100’ cluster system of Tsinghua National Laboratory for Information Science and Technology; M. T. Overgaard for providing the CaM protein for single channel studies. This work was funded by the National Key R&D Program (2016YFA0500402) and the National Key Basic Research (973) Program (2015CB910101) from Ministry of Science and Technology of China and the National Natural Science Foundation of China (projects 31621092, 31630017 and 81861138009). N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. This work was also supported by research grants from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research and the Heart and Stroke Foundation Chair in Cardiovascular Research (S.R.W.C.).
PY - 2019/8/15
Y1 - 2019/8/15
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-1377-y
DO - 10.1038/s41586-019-1377-y
M3 - Article
C2 - 31278385
AN - SCOPUS:85068573119
SN - 0028-0836
VL - 572
SP - 347
EP - 351
JO - Nature
JF - Nature
IS - 7769
ER -