Unusual quaternary structure of a homodimeric synergistic-type toxin from mamba snake venom defines its molecular evolution
Unusual quaternary structure of a homodimeric synergistic-type toxin from mamba snake venom defines its molecular evolution
复制标题
曼巴蛇毒液中同型二聚体协同型毒素的不寻常四级结构定义了其分子进化
DOI：
10.1042/bcj20200529
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发表时间：
2020
影响因子：
4.1
通讯作者：
Kini R. Manjunatha
中科院分区：
文献类型：
--
作者：
Aoki-Shioi Narumi;Jobichen Chacko;Sivaraman J.;Kini R. Manjunatha
蛇毒是酶和非酶蛋白质的复杂混合物，已经进化到杀死猎物或阻止捕食者。其中，三指毒素（3FTxs）属于最大的非酶蛋白超家族。它们共有一个共同的结构，即从含有所有四个保守二硫键的中心核心像手指一样延伸的三个β-链环。大多数3FTx是单体，通过其氨基酸序列的微妙变化，它们与不同的受体、离子通道和酶相互作用，表现出多种生物学效应。3FTx通过共价或非共价二聚化进一步扩展了其药理学空间。从致命的曼巴毒液中分离出的协同型毒素（SynTxs）虽然无毒，但已知会增强其他毒液蛋白的毒性。然而，这种不寻常的3FTx的三维结构和分子活性机制的细节尚不清楚。我们确定了第一个三维结构的SynTx分离Dendroaspis jamesoni jamesoni（詹姆森的曼巴）毒液。SynTx形成独特的同二聚体，其通过链间二硫键保持在一起。二聚体界面是精细的并且包括环II和III。除了亚基间二硫键之外，单体之间的氢键和疏水相互作用也有助于二聚体的形成。此外，两个硫酸根离子介导单体之间的相互作用。这种独特的四级结构是通过非共价同源二聚体如κ-银环蛇毒素进化而来的。这种新的二聚化进一步增强了3FTx结构和功能的多样性。
Snake venoms are complex mixtures of enzymes and nonenzymatic proteins that have evolved to immobilize and kill prey animals or deter predators. Among them, three-finger toxins (3FTxs) belong to the largest superfamily of nonenzymatic proteins. They share a common structure of three β-stranded loops extending like fingers from a central core containing all four conserved disulfide bonds. Most 3FTxs are monomers and through subtle changes in their amino acid sequences, they interact with different receptors, ion channels and enzymes to exhibit a wide variety of biological effects. The 3FTxs have further expanded their pharmacological space through covalent or noncovalent dimerization. Synergistic-type toxins (SynTxs) isolated from the deadly mamba venoms, although nontoxic, have been known to enhance the toxicity of other venom proteins. However, the details of three-dimensional structure and molecular mechanism of activity of this unusual class of 3FTxs are unclear. We determined the first three-dimensional structure of a SynTx isolated fromDendroaspis jamesoni jamesoni(Jameson's mamba) venom. The SynTx forms a unique homodimer that is held together by an interchain disulfide bond. The dimeric interface is elaborate and encompasses loops II and III. In addition to the inter-subunit disulfide bond, the hydrogen bonds and hydrophobic interactions between the monomers contribute to the dimer formation. Besides, two sulfate ions that mediate interactions between the monomers. This unique quaternary structure is evolved through noncovalent homodimers such as κ-bungarotoxins. This novel dimerization further enhances the diversity in structure and function of 3FTxs.