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Voltage-sensor activation with a tarantula toxin as cargo

机译：以狼蛛毒素为货物激活电压传感器

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The opening and closing of voltage-activated Na+, Ca2+ and K+ (Kv) channels underlies electrical and chemical signalling throughout biology, yet the structural basis of voltage sensing is unknown. Hanatoxin is a tarantula toxin that inhibits Kv channels by binding to voltage-sensor paddles(1-5), crucial helix-turn-helix motifs within the voltage-sensing domains that are composed of S3b and S4 helices(6). The active surface of the toxin is amphipathic(7,8), and related toxins have been shown to partition into membranes(9-12), raising the possibility that the toxin is concentrated in the membrane and interacts only weakly and transiently with the voltage sensors. Here we examine the kinetics and state dependence of the toxin - channel interaction and the physical location of the toxin in the membrane. We find that hanatoxin forms a strong and stable complex with the voltage sensors, far outlasting fluctuations of the voltage sensors between resting ( closed) conformations at negative voltages and activated ( open) conformations at positive voltages. Toxin affinity is reduced by voltage-sensor activation, explaining why the toxin stabilizes the resting conformation. We also find that when hanatoxin partitions into membranes it is localized to an interfacial region, with Trp 30 positioned about 8.5 angstrom from the centre of the bilayer. These results demonstrate that voltage-sensor paddles activate with a toxin as cargo, and suggest that the paddles traverse no more than the outer half of the bilayer during activation.
机译：电压激活的Na +，Ca2 +和K +（Kv）通道的打开和关闭是整个生物学中电信号和化学信号的基础，但电压传感的结构基础尚不清楚。 Hanatoxin是一种狼蛛毒素，它通过结合电压感应器桨叶（1-5）来抑制Kv通道，这些电压感应器桨叶是由S3b和S4螺旋组成的电压感应域中的关键螺旋-转-螺旋基序（6）。毒素的活性表面是两亲性的（7,8），并且相关毒素已显示进入膜中（9-12），增加了毒素集中在膜中且仅与电压微弱和短暂相互作用的可能性。传感器。在这里，我们检查了毒素的动力学和状态依赖性-通道相互作用以及毒素在膜中的物理位置。我们发现，hanatoxin与电压传感器形成一个强大而稳定的复合体，在负电压下的静止（闭合）构型与正电压下的激活（开放）构型之间，电压传感器的波动范围非常持久。电压传感器激活会降低毒素亲和力，这说明了毒素为何能稳定静止构象的原因。我们还发现，当hanatoxin分配到膜中时，它被定位在一个界面区域，Trp 30位于距双层中心约8.5埃的位置。这些结果表明，电压传感器的桨叶被毒素作为货物激活，并表明在激活过程中，桨叶横穿的层数不超过双层的外半部。

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