Structural determinants of specific lipid binding to potassium channels.
Structural determinants of specific lipid binding to potassium channels.
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DOI：
10.1021/ja3119114
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发表时间：
2013-03
影响因子：
15
通讯作者：
M. Weingarth;A. Prokofyev;Elwin A. W. van der Cruijsen;D. Nand;A. Bonvin;O. Pongs;M. Baldus
中科院分区：
文献类型：
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作者：
M. Weingarth;A. Prokofyev;Elwin A. W. van der Cruijsen;D. Nand;A. Bonvin;O. Pongs;M. Baldus
我们使用广泛的粗粒和原子分子动力学模拟、固体核磁共振和单通道测量，在结构和功能水平上研究了钾通道KCSA和嵌合体KCSA-Kv1.3的孔域与特定脂质的结合。我们表明，虽然KCSA活性受到靠近通道选择性过滤器的阴离子非环状脂类的特异性和协同结合的关键调控，但非环状脂类结合对KCSA-Kv1.3的影响要小得多。特异性脂质结合对KCSA-Kv1.3的影响减弱是由于相应的非环状脂质结合位点的点突变导致相邻KCSA-Kv1.3亚基之间的盐桥，该盐桥在许多电压门控钾通道中保守，阻止了强烈的非环状脂质与孔区的结合。我们的发现阐明了蛋白质-脂质和蛋白质-蛋白质相互作用是如何调节K(+)通道活性的。MD、核磁共振和功能研究的结合可能有助于剖析对较大的膜蛋白功能至关重要的结构和动态过程，包括膜环境中的Kv通道。
We have investigated specific lipid binding to the pore domain of potassium channels KcsA and chimeric KcsA-Kv1.3 on the structural and functional level using extensive coarse-grained and atomistic molecular dynamics simulations, solid-state NMR, and single channel measurements. We show that, while KcsA activity is critically modulated by the specific and cooperative binding of anionic nonannular lipids close to the channel's selectivity filter, the influence of nonannular lipid binding on KcsA-Kv1.3 is much reduced. The diminished impact of specific lipid binding on KcsA-Kv1.3 results from a point-mutation at the corresponding nonannular lipid binding site leading to a salt-bridge between adjacent KcsA-Kv1.3 subunits, which is conserved in many voltage-gated potassium channels and prevents strong nonannular lipid binding to the pore domain. Our findings elucidate how protein-lipid and protein-protein interactions modulate K(+) channel activity. The combination of MD, NMR, and functional studies as shown here may help to dissect the structural and dynamical processes that are critical for the functioning of larger membrane proteins, including Kv channels in a membrane setting.