Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel.
Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel.
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DOI：
10.1021/bi800875q
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发表时间：
2008-08-05
期刊：
影响因子：
2.9
通讯作者：
Sanders, Charles R.
中科院分区：
文献类型：
--
作者：
Kang, Congbao;Tian, Changlin;Soennichsen, Frank D.;Smith, Jarrod A.;Meiler, Jens;George, Alfred L., Jr.;Vanoye, Carlos G.;Kim, Hak Jun;Sanders, Charles R.
KCNE1 是一种单跨膜蛋白，通过减缓激活和增强通道电导来调节电压门控钾通道 KCNQ1 (KV7.1)，以产生对心脏动作电位复极阶段至关重要的缓慢延迟整流电流 (IK)。 KCNE1 或 KCNQ1 遗传突变对通道功能的干扰会导致心律失常和猝死（伴或不伴耳聋）的易感性增加。在这里，我们展示了 KCNE1 的三维结构。 KCNE1 的跨膜结构域 (TMD) 是一个弯曲的 α 螺旋，两侧是由通过柔性接头连接的 α 螺旋组成的胞内和胞外结构域。 KCNE1 TMD 与 KCNQ1 闭合状态模型的实验限制对接表明，KCNE1 通过坐在并限制将电压传感器连接到孔域的 S4-S5 连接器的运动来减缓通道激活。我们假设这是一种粘附相互作用，在响应膜去极化而打开通道之前必须破坏这种相互作用。对接打开 KCNQ1 表明 KCNE1 TMD 的细胞外末端与通道中的亚基间裂口形成界面，该通道与大多数已知的功能获得性疾病突变相关。 KCNE1 与这种“功能获得性裂缝”的结合可以解释它如何增加电导并稳定开放状态。 KCNE1/KCNQ1 复合物的这些工作模型可用于为与 KCNE1 和 KCNQ1 中数十种已知遗传突变相关的疾病表型的分子基础制定可检验的假设。
KCNE1 is a single span membrane protein that modulates the voltage-gated potassium channel KCNQ1 (KV7.1) by slowing activation and enhancing channel conductance to generate the slow delayed rectifier current (IKs) that is critical for the repolarization phase of the cardiac action potential. Perturbation of channel function by inherited mutations in KCNE1 or KCNQ1 results in increased susceptibility to cardiac arrhythmias and sudden death with or without accompanying deafness. Here, we present the three-dimensional structure of KCNE1. The transmembrane domain (TMD) of KCNE1 is a curved α-helix and is flanked by intra- and extracellular domains comprised of α-helices joined by flexible linkers. Experimentally-restrained docking of the KCNE1 TMD to a closed state model of KCNQ1 suggests that KCNE1 slows channel activation by sitting on and restricting the movement of the S4-S5 linker that connects the voltage sensor to the pore domain. We postulate that this is an adhesive interaction that must be disrupted before the channel can be opened in response to membrane depolarization. Docking to open KCNQ1 indicates that the extracellular end of the KCNE1 TMD forms an interface with an intersubunit cleft in the channel that is associated with most known gain-of-function disease mutations. Binding of KCNE1 to this “gain-of-function cleft” may explain how it increases conductance and stabilizes the open state. These working models for the KCNE1/KCNQ1 complexes may be used to formulate testable hypotheses for the molecular bases of disease phenotypes associated with the dozens of known inherited mutations in KCNE1 and KCNQ1.
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影响因子：
16.2
作者：
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通讯作者：
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