Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators
Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators
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DOI：
10.1073/pnas.1914451116
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发表时间：
2019-12-17
影响因子：
11.1
通讯作者：
Yan, Nieng
中科院分区：
文献类型：
--
作者：
Chi, Ximin;Gong, Deshun;Yan, Nieng
2型Ryanodine受体(RyR2)负责从心肌细胞的肌浆网释放钙离子，从而导致肌肉收缩。在这里，我们报告了4种猪RyR2与不同调节器结合的冷冻电子显微镜(Cryo-EM)结构，与我们发表的结构一起，提供了对RyR2调控的机械性洞察。Ca2+单独引起中央区域的收缩，这有助于S6束的扩张，但不足以打开毛孔。小分子激动剂PCB95帮助钙离子克服开放的障碍。FKBP12.6诱导中央结构域的松弛，使其与S6束解偶联，即使在钙离子和PCB95存在的情况下，也能稳定处于关闭状态的RyR2。尽管当PCB95被咖啡因和三磷酸腺苷(ATP)取代时，该通道是开放的，但这两种调节剂本身都不足以对抗这种拮抗作用，从而开放该通道。我们的研究标志着从机制上理解这一关键通道的复杂调控迈出了重要的一步，该通道的异常活动会导致危及生命的心脏疾病。
The type 2 ryanodine receptor (RyR2) is responsible for releasing Ca2+ from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report 4 cryoelectron microscopy (cryo-EM) structures of porcine RyR2 bound to distinct modulators that, together with our published structures, provide mechanistic insight into RyR2 regulation. Ca2+ alone induces a contraction of the central domain that facilitates the dilation of the S6 bundle but is insufficient to open the pore. The small-molecule agonist PCB95 helps Ca2+ to overcome the barrier for opening. FKBP12.6 induces a relaxation of the central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state even in the presence of Ca2+ and PCB95. Although the channel is open when PCB95 is replaced by caffeine and adenosine 5'-triphosphate (ATP), neither of the modulators alone can sufficiently counter the antagonistic effect to open the channel. Our study marks an important step toward mechanistic understanding of the sophisticated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.