STAC3 is a soluble protein essential for skeletal muscle excitation-contraction (EC) coupling. Through its tandem SH3 domains, it interacts with the cytosolic II-III loop of the skeletal muscle voltage-gated calcium channel. STAC3 is the target for a mutation (W284S) that causes Native American myopathy, but multiple other sequence variants have been reported. Here, we report a crystal structure of the human STAC3 tandem SH3 domains. We analyzed the effect of five disease-associated variants, spread over both SH3 domains, on their ability to bind to the Ca_V1.1 II-III loop and on muscle EC coupling. In addition to W284S, we find the F295L and K329N variants to affect both binding and EC coupling. The ability of the K329N variant, located in the second SH3 domain, to affect the interaction highlights the importance of both SH3 domains in association with Ca_V1.1. Our results suggest that multiple STAC3 variants may cause myopathy.

STAC3 是骨骼肌兴奋-收缩 (EC) 耦合所必需的可溶性蛋白质。通过其串联的 SH3 结构域，它与骨骼肌电压门控钙通道的胞质 II-III 环相互作用。STAC3 是导致美洲原住民肌病的突变 (W284S) 的靶标，但已报道了多种其他序列变体。在这里，我们报告了人类 STAC3 串联 SH3 域的晶体结构。_{我们分析了分布在两个 SH3 结构域上的五种疾病相关变体对它们与 Ca V}结合能力的影响1.1 II-III 环和肌肉 EC 耦合。除了 W284S，我们发现 F295L 和 K329N 变体影响结合和 EC 耦合。位于第二个 SH3 结构域的 K329N 变体影响相互作用的能力突出了两个 SH3 结构域与 Ca _V 1.1 相关的重要性。我们的结果表明多种 STAC3 变体可能导致肌病。