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Molecular basis for gating of cardiac ryanodine receptor: underlying mechanisms for gain- and loss-of function mutations
bioRxiv - Biochemistry Pub Date : 2021-10-27 , DOI: 10.1101/2020.11.30.401026
Takuya Kobayashi , Akihisa Tsutsumi , Nagomi Kurebayashi , Kei Saito , Masami Kodama , Takashi Sakurai , Masahide Kikkawa , Takashi Murayama , Haruo Ogawa

Cardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations are implicated in severe arrhythmogenic diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remain unknown. Here, we addressed gating mechanism of RyR2 by combining high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated two fundamental mechanisms for channel gating: interactions close to the channel pore stabilize the channel to prevent hyperactivity and a series of interactions in the surrounding regions is necessary for channel opening upon Ca2+ binding. Mutations at the residues involved in the former and the latter mechanisms cause gain-of-function and loss-of-function, respectively. Our results reveal gating mechanisms of the RyR2 channel and alterations by pathogenic mutations at the atomic level.

中文翻译:

心脏兰尼碱受体门控的分子基础:获得和丧失功能突变的潜在机制

心脏兰尼碱受体 (RyR2) 是肌浆网中一个大的 Ca 2+释放通道,对于心脏中的兴奋-收缩耦合是必不可少的。RyR2 被 Ca 2+激活和 RyR2 突变与严重的致心律失常疾病有关。然而,通道开放的结构基础以及突变如何影响通道仍然未知。在这里,我们通过将冷冻电子显微镜确定的高分辨率结构与携带特定残基中各种突变的通道的定量功能分析相结合,解决了 RyR2 的门控机制。我们展示了通道门控的两种基本机制:靠近通道孔的相互作用稳定通道以防止过度活跃,并且周围区域的一系列相互作用对于 Ca 2+ 上的通道开放是必要的捆绑。前者和后者机制中涉及的残基突变分别导致功能获得和功能丧失。我们的结果揭示了 RyR2 通道的门控机制和原子水平的致病突变改变。
更新日期:2021-10-29
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