University of British Columbia, Department of Biochemistry and Molecular Biology, Life Sciences Centre, Vancouver, BC, Canada.
Nat Commun. 2021 Feb 5;12(1):807. doi: 10.1038/s41467-021-21141-3.
Ryanodine Receptors (RyRs) are massive channels that release Ca from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological 'intermediate' conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions.
兰尼碱受体（RyRs）是从内质网和肌浆网释放 Ca 的巨大通道。数百种突变与恶性高热（MH）、肌病和心律失常有关。在这里，我们通过提供猪同源物 R615C 的冷冻电镜快照来探索人类首次发现的 MH 突变，表明它影响三个螺线管区域之间的界面。我们还展示了无钙调蛋白（apoCaM）的影响，以及它如何通过其 N 端结构域介导的桥接螺线管的弯曲来诱导开放。对于 R615C RyR1，apoCaM 结合会消除病理性“中间”构象，将群体分布到开放和关闭通道的混合物中，这两种构象都与没有 apoCaM 的结构不同。比较表明，该突变主要影响关闭状态，诱导与通道激活相关的部分运动。这表明疾病突变可以导致 RyR 的不同病理构象，并通过破坏不同螺线管区域之间的相互作用促进通道开放。
