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首页> 外文期刊>Cellular Physiology and Biochemistry >Structural basis of slow activation gating in the cardiac I_(Ks) channel complex
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Structural basis of slow activation gating in the cardiac I_(Ks) channel complex

机译：心脏I_（Ks）通道复合体中慢速激活门控的结构基础

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摘要

Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeI_(Ks) channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac I_(Ks) channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant I _(Ks) channels.
机译：KCNE基因家族的辅助β亚基通过异源多聚体的形成来调节各种阳离子通道α亚基的功能。 KCNE在电压门控通道的生物物理特性中最显着的变化之一是KCNE1对KCNQ1通道的影响。据信KCNQ1和KCNE1形成了nativeI_（Ks）通道。在这里，我们通过诱变，双突变周期分析和分子动力学模拟来表征KCNE1与KCNQ1通道相互作用的分子决定因素。我们的发现表明，KCNE1与KCNQ1通道孔结构域的外表面结合，修饰电压传感器，S4-S5接头与孔结构域之间的相互作用，从而导致选择性滤波器和电压传感器结构域的结构修饰。分子动力学模拟表明，KCNE1跨膜α-螺旋与KCNQ1的孔域S5 / S6和部分电压传感器域S4处于稳定的预开通道状态，具有稳定的相互作用。此状态的形成可能会导致慢速激活门控，这是天然心脏I_（Ks）通道的关键特征。这种新的KCNQ1-KCNE1模型可能对疾病相关突变I_（Ks）通道的动态建模有用。

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