Portability of paddle motif function and pharmacology in voltage sensors
Portability of paddle motif function and pharmacology in voltage sensors
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DOI：
10.1038/nature06266
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发表时间：
2007-11-15
期刊：
影响因子：
64.8
通讯作者：
Swartz, Kenton J.
中科院分区：
文献类型：
--
作者：
Alabi, AbdulRasheed A.;Bahamonde, Maria Isabel;Swartz, Kenton J.
电压感应结构域使膜蛋白能够感知并对膜电压的变化作出反应。尽管在一系列常规离子通道和其他缺乏孔结构域的膜蛋白中发现了可识别的S1-S4电压传感结构域，但其电压传感机制的保守程度尚不清楚。本研究表明，当从古细菌电压激活钾通道（KvAP）或电压传感结构域蛋白（Hv1和Ci-VSP）移植到真核生物电压激活钾通道时，由S3b和S4螺旋组成的电压传感器桨基可以驱动膜去极化打开通道。狼蛛毒素分裂到细胞膜上，可以在蛋白质-脂质界面与这些桨基相互作用，并类似地干扰离子通道和具有电压感应域的蛋白质中的电压传感器激活。我们的研究结果表明，桨基序是模块化的，它们的功能在电压传感器中是保守的，并且它们在脂质膜的相对不受约束的环境中移动。毒素广泛靶向电压传感器桨，表明这种模块化结构基序是一个重要的药理学靶点。
Voltage-sensing domains enable membrane proteins to sense and react to changes in membrane voltage. Although identifiable S1-S4 voltage-sensing domains are found in an array of conventional ion channels and in other membrane proteins that lack pore domains, the extent to which their voltage-sensing mechanisms are conserved is unknown. Here we show that the voltage-sensor paddle, a motif composed of S3b and S4 helices, can drive channel opening with membrane depolarization when transplanted from an archaebacterial voltage-activated potassium channel (KvAP) or voltage-sensing domain proteins (Hv1 and Ci-VSP) into eukaryotic voltage-activated potassium channels. Tarantula toxins that partition into membranes can interact with these paddle motifs at the protein-lipid interface and similarly perturb voltage-sensor activation in both ion channels and proteins with a voltage-sensing domain. Our results show that paddle motifs are modular, that their functions are conserved in voltage sensors, and that they move in the relatively unconstrained environment of the lipid membrane. The widespread targeting of voltage-sensor paddles by toxins demonstrates that this modular structural motif is an important pharmacological target.