Calcins are peptides from scorpion venom with the unique ability to cross cell membranes, gaining access to intracellular targets. Ryanodine Receptors (RyR) are intracellular ion channels that control release of Ca 2+ from the endoplasmic and sarcoplasmic reticulum. Calcins target RyRs and induce long-lived subconductance states, whereby single-channel currents are decreased. We used cryo–electron microscopy to reveal the binding and structural effects of imperacalcin, showing that it opens the channel pore and causes large asymmetry throughout the cytosolic assembly of the tetrameric RyR. This also creates multiple extended ion conduction pathways beyond the transmembrane region, resulting in subconductance. Phosphorylation of imperacalcin by protein kinase A prevents its binding to RyR through direct steric hindrance, showing how posttranslational modifications made by the host organism can determine the fate of a natural toxin. The structure provides a direct template for developing calcin analogs that result in full channel block, with potential to treat RyR-related disorders.

中文翻译：

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蝎毒素与 Ryanodine 受体结合的冷冻电镜分析揭示了 PKA 磷酸化消除的亚电导

钙素是来自蝎子毒液的肽，具有穿过细胞膜的独特能力，能够进入细胞内的靶标。Ryanodine 受体 (RyR) 是控制 Ca 释放的细胞内离子通道2+来自内质网和肌浆网。钙素以 RyR 为目标并诱导长寿命的亚电导状态，从而降低单通道电流。我们使用冷冻电子显微镜揭示了英普拉钙素的结合和结构效应，表明它打开了通道孔并在整个四聚体 RyR 的胞质组装中引起很大的不对称性。这还产生了跨膜区域之外的多个延伸的离子传导路径，从而导致亚电导。蛋白激酶 A 磷酸化英普拉钙素可通过直接空间位阻阻止其与 RyR 结合，这表明宿主生物体进行的翻译后修饰如何决定天然毒素的命运。该结构为开发钙蛋白类似物提供了直接模板，该类似物可导致完全通道阻断，并具有治疗 RyR 相关疾病的潜力。