@article{168046,
  keywords = {Animals, Models, Molecular, Humans, Adenosine Triphosphate, Binding Sites, Calcium, Reproducibility of Results, Cryoelectron Microscopy, Swine, Calmodulin, Apoproteins, Caffeine, Ryanodine Receptor Calcium Release Channel},
  author = {Deshun Gong and Ximin Chi and Jinhong Wei and Gewei Zhou and Gaoxingyu Huang and Lin Zhang and Ruiwu Wang and Jianlin Lei and Wayne Chen and Nieng Yan},
  title = {Modulation of cardiac ryanodine receptor 2 by calmodulin},
  abstract = {<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>
},
  year = {2019},
  journal = {Nature},
  volume = {572},
  pages = {347-351},
  month = {08/2019},
  issn = {1476-4687},
  doi = {10.1038/s41586-019-1377-y},
  language = {eng},
}