Howard Rebecca J, Clark Kimberly A, Holton James M, Minor Daniel L
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA 94158-2330, USA.
Neuron. 2007 Mar 1;53(5):663-75. doi: 10.1016/j.neuron.2007.02.010.
Kv7.x (KCNQ) voltage-gated potassium channels form the cardiac and auditory I(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 A-domain Tail together with biochemical experiments that show that the domain is a self-assembling, 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.
Kv7.x（KCNQ）电压门控钾通道形成心脏和听觉I（Ks）电流以及神经元M电流。五种Kv7亚型具有由C末端胞质组装结构域（A结构域尾部）编码的不同组装偏好。在此，我们展示了Kv7.4 A结构域尾部的高分辨率结构，并通过生化实验表明该结构域是一种自组装的平行四链卷曲螺旋。结构分析和生化研究表明，所有Kv7亚型中卷曲螺旋都具有保守性，并且一组有限的相互作用编码了组装特异性决定因素。Kv7突变在心律失常、耳聋和癫痫中起重要作用。该结构与生化数据表明，A结构域尾部心律失常突变聚集在亚基界面的溶剂可及表面上，这可能是调节蛋白的作用位点。总之，这些数据为理解Kv7组装特异性以及一组独特的Kv7通道病的分子基础提供了一个框架。
