S100A1, a small homodimeric EF-hand Ca 2+ -binding protein (~21 kDa), plays an important regulatory role in Ca 2+ signaling pathways involved in various biological functions including Ca 2+ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca 2+ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca 2+ . Ca 2+ -free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca 2+ -binding, S100A1 undergoes a conformational change resulting in the exposure of the hydrophobic pocket known to serve as a major interaction site of S100A1. Through interactions of the hydrophobic pocket with RyR1, Ca 2+ -bound S100A1 intrudes deeper into the RyR1 structure beneath BSol than the apo-form and induces sideways motions of the C-terminal BSol region toward the adjacent RyR1 protomer resulting in tighter interprotomer contacts. Interestingly, the second hydrophobic pocket of the S100A1-dimer is largely exposed at the hydrophilic surface making it prone to interactions with the local environment, suggesting that S100A1 could be involved in forming larger heterocomplexes of RyRs with other protein partners. Since S100A1 interactions stabilizing BSol are implicated in the regulation of RyR-mediated Ca 2+ release, the characterization of the S100A1 binding site conserved between RyR isoforms may provide the structural basis for the development of therapeutic strategies regarding treatments of RyR-related disorders.

中文翻译：

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S100A1 对 RyR1 调节的结构见解


S100A1 是一种小型同源二聚体 EF-hand Ca 2+ 结合蛋白 (~21 kDa)，在参与各种生物功能（包括骨骼肌细胞和心肌细胞的 Ca 2+ 循环和收缩性能）的 Ca 2+ 信号通路中发挥重要的调节作用。 S100A1 相互作用组的一个关键靶标是兰尼碱受体 (RyR)，它是肌质网的一个巨大的同源四聚体 Ca 2+ 释放通道 (~2.3 MDa)。在这里，我们报告了在存在和不存在 Ca 2+ 的情况下，S100A1 与骨骼肌亚型 RyR1 结合的冷冻电子显微镜结构。不含 Ca 2+ 的 apo-S100A1 在桥接螺线管 (BSol) 下方结合，并与连接螺线管和 RyR1 的壳核连接体形成接触。 Ca 2+ 结合后，S100A1 发生构象变化，导致已知作为 S100A1 主要相互作用位点的疏水袋暴露。通过疏水口袋与 RyR1 的相互作用，Ca 2+ 结合的 S100A1 比 apo 形式更深地侵入 BSol 下方的 RyR1 结构，并诱导 C 端 BSol 区域向邻近的 RyR1 原聚体侧向运动，从而导致原聚体间接触更紧密。有趣的是，S100A1-二聚体的第二个疏水口袋大部分暴露在亲水表面，使其易于与局部环境相互作用，这表明S100A1可能参与与其他蛋白质伙伴形成更大的RyR杂复合物。由于稳定 BSol 的 S100A1 相互作用涉及 RyR 介导的 Ca 2+ 释放的调节，因此 RyR 同工型之间保守的 S100A1 结合位点的表征可能为开发有关 RyR 相关疾病的治疗策略提供结构基础。