The calcium release activated calcium channel is activated by the endoplasmic reticulum-resident calcium sensor protein STIM1. On activation, STIM1 C terminus changes from an inactive, tight to an active, extended conformation. A coiled-coil clamp involving the CC1 and CC3 domains is essential in controlling STIM1 activation, with CC1 as the key entity. The nuclear magnetic resonance-derived solution structure of the CC1 domain represents a three-helix bundle stabilized by interhelical contacts, which are absent in the Stormorken disease-related STIM1 R304W mutant. Two interhelical sites between the CC1α₁ and CC1α₂ helices are key in controlling STIM1 activation, affecting the balance between tight and extended conformations. Nuclear magnetic resonance-directed mutations within these interhelical interactions restore the physiological, store-dependent activation behavior of the gain-of-function STIM1 R304W mutant. This study reveals the functional impact of interhelical interactions within the CC1 domain for modifying the CC1–CC3 clamp strength to control the activation of STIM1.

钙释放激活的钙通道由内质网驻留钙传感器蛋白 STIM1 激活。激活后，STIM1 C 末端从不活跃的紧密构象变为活跃的延伸构象。涉及 CC1 和 CC3 结构域的卷曲螺旋钳对于控制 STIM1 激活至关重要，其中 CC1 是关键实体。核磁共振衍生的 CC1 结构域溶液结构代表由螺旋间接触稳定的三螺旋束，这在 Stormorken 疾病相关的 STIM1 R304W 突变体中不存在。 CC1α ₁和 CC1α ₂螺旋之间的两个螺旋间位点是控制 STIM1 激活的关键，影响紧密构象和延伸构象之间的平衡。这些螺旋间相互作用中的核磁共振定向突变恢复了功能获得性 STIM1 R304W 突变体的生理学、存储依赖性激活行为。这项研究揭示了 CC1 结构域内螺旋间相互作用对修改 CC1-CC3 钳强度以控制 STIM1 激活的功能影响。