Strutz-Seebohm Nathalie, Pusch Michael, Wolf Steffen, Stoll Raphael, Tapken Daniel, Gerwert Klaus, Attali Bernard, Seebohm Guiscard
Department of Biochemistry I--Cation Channel Group, Ruhr University, Bochum, Germany.
Cell Physiol Biochem. 2011;27(5):443-52. doi: 10.1159/000329965. Epub 2011 Jun 15.
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.
KCNE基因家族的辅助β亚基通过形成异源多聚体来调节各种阳离子通道α亚基的功能。KCNEs对电压门控通道生物物理特性最显著的改变之一是KCNE1对KCNQ1通道的影响。KCNQ1和KCNE1被认为形成了天然的I(Ks)通道。在此，我们通过扫描诱变、双突变循环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。我们的研究结果表明，KCNE1与KCNQ1通道孔结构域的外表面结合，改变电压感受器、S4-S5连接子与孔结构域之间的相互作用，导致选择性过滤器和电压感受器结构域的结构改变。分子动力学模拟表明，在假定的预开放通道状态下，KCNE1跨膜α螺旋与KCNQ1的孔结构域S5/S6和部分电压感受器结构域S4存在稳定的相互作用。这种状态的形成可能会诱导缓慢激活门控，这是天然心脏I(Ks)通道的关键特征。这个新的KCNQ1-KCNE1模型可能对与疾病相关的突变I(Ks)通道的动态建模有用。
