Mechanism of Tc toxin action revealed in molecular detail
Mechanism of Tc toxin action revealed in molecular detail
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DOI：
10.1038/nature13015
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发表时间：
2014-04-03
期刊：
影响因子：
64.8
通讯作者：
Raunser, Stefan
中科院分区：
文献类型：
--
作者：
Meusch, Dominic;Gatsogiannis, Christos;Raunser, Stefan
细菌病原体的三重Tc毒素复合物破坏宿主细胞膜并将有毒酶转运到宿主细胞中，包括在人类中。潜在的机制是复杂的，但知之甚少。在这里，我们报告的第一个，据我们所知，高分辨率的结构TCA亚基在其prepore和孔状态和一个完整的1.7兆道尔顿Tc复合物。结构表明，除了转运通道外，TcA还形成了四个受体结合位点和一个神经氨酸酶样区域，这对其宿主特异性很重要。pH诱导的壳的打开释放熵弹簧，其驱动TcA通道注射到膜中。TcB/TcC与TcA的结合打开了一个由六叶β螺旋桨形成的门，并导致一个连续的蛋白质转运通道，其结构和性质表明了一种新的蛋白质解折叠和转运模式。我们的研究结果使我们能够在分子水平上了解涉及Tc毒素的感染的关键步骤。
Tripartite Tc toxin complexes of bacterial pathogens perforate the host membrane and translocate toxic enzymes into the host cell, including in humans. The underlying mechanism is complex but poorly understood. Here we report the first, to our knowledge, high-resolution structures of a TcA subunit in its prepore and pore state and of a complete 1.7 megadalton Tc complex. The structures reveal that, in addition to a translocation channel, TcA forms four receptor-binding sites and a neuraminidase-like region, which are important for its host specificity. pH-induced opening of the shell releases an entropic spring that drives the injection of the TcA channel into the membrane. Binding of TcB/TcC to TcA opens a gate formed by a six-bladed beta-propeller and results in a continuous protein translocation channel, whose architecture and properties suggest a novel mode of protein unfolding and translocation. Our results allow us to understand key steps of infections involving Tc toxins at the molecular level.