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Modulation of cardiac ryanodine receptor 2 by calmodulin

机译:钙调蛋白的心脏ryanodine受体2的调节

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摘要

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.
机译:高导率细胞内钙(CA2 +)通道Ryr2对于心肌激发和收缩的偶联至关重要。在各种调节剂中,钙调蛋白(CAM)以Ca2 +依赖性的方式调节Ryr2。在这里,我们揭示了通过人凸轮通过八条条件下的Ryr2的结构测定来调节猪Ryr2的调节机制。 apo-cam和ca2 + -cam与由手柄,螺旋和中心域形成的细长裂缝中的不同但重叠的位点。 Ryr2上的凸轮结合位点的偏移由Ca2 +与凸轮的结合控制,而不是Ryr2。 CA2 + -CAM诱导各个中央畴的旋转和纳内型偏移,导致PCB95和CA2 + -Activated通道的孔闭合。相比之下,在Ca2 + -CAM存在下,ATP,咖啡因和CA2 + -Activated通道的孔保持开放,这表明CA2 + -CAM是RYR2门控的许多竞争调制器之一。

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  • 来源
    《Nature》 |2019年第7769期|347-351|共5页
  • 作者单位

    Tsinghua Univ Sch Life Sci Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Beijing Peoples R China;

    Tsinghua Univ Sch Life Sci Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Beijing Peoples R China;

    Univ Calgary Libin Cardiovasc Inst Alberta Dept Physiol & Pharmacol Calgary AB Canada;

    Tsinghua Univ Sch Life Sci Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Beijing Peoples R China;

    Tsinghua Univ Sch Life Sci Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Beijing Peoples R China;

    Univ Calgary Libin Cardiovasc Inst Alberta Dept Physiol & Pharmacol Calgary AB Canada;

    Univ Calgary Libin Cardiovasc Inst Alberta Dept Physiol & Pharmacol Calgary AB Canada;

    Tsinghua Univ Sch Life Sci Technol Ctr Prot Sci Minist Educ Key Lab Prot Sci Beijing Peoples R China;

    Univ Calgary Libin Cardiovasc Inst Alberta Dept Physiol & Pharmacol Calgary AB Canada;

    Tsinghua Univ Sch Life Sci Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Beijing Peoples R China|Princeton Univ Dept Mol Biol Princeton NJ 08540 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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