Modulation of cardiac ryanodine receptor 2 by calmodulin
Modulation of cardiac ryanodine receptor 2 by calmodulin
复制标题
DOI：
10.1038/s41586-019-1377-y
复制
发表时间：
2019-08-15
期刊：
影响因子：
64.8
通讯作者：
Yan, Nieng
中科院分区：
文献类型：
--
作者：
Gong, Deshun;Chi, Ximin;Yan, Nieng
高电导细胞内钙离子通道RyR2对于心肌兴奋和收缩的耦合是必不可少的。在各种调节剂中，钙调蛋白（CaM）以Ca2+依赖的方式调节RyR2。本研究通过对猪RyR2在8种条件下的结构测定，揭示了人CaM对猪RyR2的调控机制。Apo-CaM和Ca2+-CaM结合在由柄状、螺旋状和中心结构域形成的细长裂缝中不同但重叠的位点上。在RyR2上CaM结合位点的转移是由Ca2+结合到CaM而不是RyR2控制的。Ca2+-CaM诱导单个中心结构域的旋转和结构域内移动，导致PCB95和Ca2+激活通道的孔关闭。相比之下，在Ca2+-CaM存在的情况下，ATP、咖啡因和Ca2+激活通道的孔保持开放，这表明Ca2+-CaM是RyR2门控的众多竞争调节剂之一。
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.