Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage-dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT.

中文翻译：

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钙调素依赖于C-Lobe Ca2 +的开关控制Kv7通道功能。

Kv7（KCNQ）电压门控钾离子通道控制着大脑，心脏和耳朵的兴奋性。钙调蛋白（CaM）对于Kv7功能至关重要，但该钙传感器如何影响活性尚不清楚。在这里，我们介绍CaM：Kv7.4和CaM：Kv7.5 AB结构域复合物的X射线晶体分析，揭示了Apo / CaM钳位构象和钙结合偏好。这些结构与小角度X射线散射，生化和功能研究相结合，基于一种常见的结构建立了Kv7 CaM调节的调节机制，其中CaM C瓣钙依赖性开关释放了共享的Apo / CaM钳位构象。此C瓣开关可抑制Kv7.4和Kv7.5的电压依赖性激活，但有助于Kv7.1，证明尽管CaM调制的方向不同，但Kv7亚型共有该机制。我们的发现为了解CaM如何控制不同的Kv7亚型提供了一个统一的框架，并突出了膜近端域在控制电压门控通道功能中的作用。视频摘要。