Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels
Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels
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DOI：
10.1074/jbc.m112.431650
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发表时间：
2013-06-28
影响因子：
4.8
通讯作者：
Efremov, Roman G.
中科院分区：
文献类型：
--
作者：
Chugunov, Anton O.;Koromyslova, Anna D.;Efremov, Roman G.
为了在进化的“军备竞赛”中取得成功，蝎子等有毒动物会产生各种神经毒素，以攻击猎物的神经系统。蝎α毒素影响昆虫和/或哺乳动物的电压门控钠通道（Na（v）s），从而改变肌肉和神经细胞的兴奋性。虽然已知有100多种α毒素，并且其中一些已经被详细研究，但它们与Na（v）s相互作用的分子机制仍然知之甚少。在这里，我们采用广泛的分子动力学模拟和空间映射的疏水/亲水特性分布在分子表面的α-毒素。据透露，尽管小尺寸和相对刚性的结构，这些毒素具有模块化的组织从结构，功能和进化的角度来看。更保守和刚性的“核心模块”补充有“特异性模块”（SM），其相对灵活和可变，并确定α-毒素活性的分类单元（哺乳动物与昆虫）特异性。我们进一步表明，哺乳动物毒素中的SM比昆虫毒素中的SM更灵活和亲水。伴随的基于序列的分析的细胞外环的Na（V）S表明，α-毒素识别的通道使用这两个模块。我们建议，核心模块结合到电压敏感域IV，而更通用的SM与孔域的Na（V）的重复I相互作用。这些发现证实并扩展了先前报道的关于毒素的不同功能表位的假设。实际上，我们提出毒素的模块结构进化为与Na（v）s的结构域结构相匹配。
To gain success in the evolutionary "arms race," venomous animals such as scorpions produce diverse neurotoxins selected to hit targets in the nervous system of prey. Scorpion alpha-toxins affect insect and/or mammalian voltage-gated sodium channels (Na(v)s) and thereby modify the excitability of muscle and nerve cells. Although more than 100 alpha-toxins are known and a number of them have been studied into detail, the molecular mechanism of their interaction with Na(v)s is still poorly understood. Here, we employ extensive molecular dynamics simulations and spatial mapping of hydrophobic/hydrophilic properties distributed over the molecular surface of alpha-toxins. It is revealed that despite the small size and relatively rigid structure, these toxins possess modular organization from structural, functional, and evolutionary perspectives. The more conserved and rigid " core module" is supplemented with the " specificity module" (SM) that is comparatively flexible and variable and determines the taxon (mammal versus insect) specificity of alpha-toxin activity. We further show that SMs in mammal toxins are more flexible and hydrophilic than in insect toxins. Concomitant sequence-based analysis of the extracellular loops of Na(v)s suggests that alpha-toxins recognize the channels using both modules. We propose that the core module binds to the voltage-sensing domain IV, whereas the more versatile SM interacts with the pore domain in repeat I of Na(v)s. These findings corroborate and expand the hypothesis on different functional epitopes of toxins that has been reported previously. In effect, we propose that the modular structure in toxins evolved to match the domain architecture of Na(v)s.