Structural Insight into KCNQ (Kv7) Channel Assembly and Channelopathy
Structural Insight into KCNQ (Kv7) Channel Assembly and Channelopathy
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DOI：
10.1016/j.neuron.2007.02.010
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发表时间：
2007-03-01
期刊：
影响因子：
16.2
通讯作者：
Minor, Daniel L., Jr.
中科院分区：
文献类型：
--
作者：
Howard, Rebecca J.;Clark, Kimberly A.;Minor, Daniel L., Jr.
Kv7.x（KCNQ）电压门控钾通道形成心脏和听觉I（Ks）电流和神经元M电流。五种Kv 7亚型具有由C-末端胞质组装结构域（A-结构域尾）编码的不同组装偏好。在这里，我们提出了Kv7.4 Adomain Tail的高分辨率结构以及生化实验，这些实验表明该结构域是一个自组装的，平行的，四链卷曲螺旋。结构分析和生化研究表明，在所有Kv 7亚型的卷曲螺旋的保护和有限的一组相互作用编码组装特异性决定簇。Kv 7突变在心律失常、耳聋和癫痫中具有突出作用。结构连同生化数据表明，A-结构域尾部心律失常突变簇在调节蛋白的可能作用位点处的亚基界面的溶剂可及表面上。总之，这些数据为理解Kv 7组装特异性和一组不同的Kv 7通道病的分子基础提供了一个框架。
Kv7.x (KCNQ) voltage-gated potassium channels form the cardiac and auditory l(Ks) current and the neuronal M-current. The five Kv7 subtypes have distinct assembly preferences encoded by a C-terminal cytoplasmic assembly domain, the A-domain Tail. Here, we present the high-resolution structure of the Kv7.4 Adomain Tail together with biochemical experiments that show that the domain is a selfassembling, parallel, four-stranded coiled coil. Structural analysis and biochemical studies indicate conservation of the coiled coil in all Kv7 subtypes and that a limited set of interactions encode assembly specificity determinants. Kv7 mutations have prominent roles in arrhythmias, deafness, and epilepsy. The structure together with biochemical data indicate that A-domain Tail arrhythmia mutations cluster on the solvent-accessible surface of the subunit interface at a likely site of action for modulatory proteins. Together, the data provide a framework for understanding Kv7 assembly specificity and the molecular basis of a distinct set of Kv7 channelopathies.