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以狼蛛毒素为载体的电压传感器激活

Voltage-sensor activation with a tarantula toxin as cargo.

作者信息

Phillips L Revell, Milescu Mirela, Li-Smerin Yingying, Mindell Joseph A, Kim Jae Il, Swartz Kenton J

机构信息

Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, MSC 3701 Bethesda, Maryland 20892-3701, USA.

出版信息

Nature. 2005 Aug 11;436(7052):857-60. doi: 10.1038/nature03873.

Abstract

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, crucial helix-turn-helix motifs within the voltage-sensing domains that are composed of S3b and S4 helices. The active surface of the toxin is amphipathic, and related toxins have been shown to partition into membranes, 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 A 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.

摘要

电压激活的钠离子、钙离子和钾离子(Kv)通道的开闭是整个生物学中电信号和化学信号的基础,然而电压感应的结构基础尚不清楚。哈那毒素是一种狼蛛毒素,它通过与电压感应桨结合来抑制Kv通道,电压感应桨是电压感应域内由S3b和S4螺旋组成的关键螺旋-转角-螺旋基序。该毒素的活性表面具有两亲性,并且已证明相关毒素可分配到膜中,这增加了毒素集中在膜中且仅与电压传感器弱且短暂相互作用的可能性。在这里,我们研究了毒素-通道相互作用的动力学和状态依赖性以及毒素在膜中的物理位置。我们发现哈那毒素与电压传感器形成了一种强而稳定的复合物,其持续时间远远超过电压传感器在负电压下的静息(关闭)构象和正电压下的激活(开放)构象之间的波动。电压传感器激活会降低毒素亲和力,这解释了毒素为何能稳定静息构象。我们还发现,当哈那毒素分配到膜中时,它定位于界面区域,色氨酸30距离双层中心约8.5埃。这些结果表明,电压感应桨作为货物与毒素一起激活,并表明在激活过程中,桨穿越的距离不超过双层的外半部分。

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