Nature2014-06-19 3:39 PM

Tc 细菌毒性因子 Mechanism of Tc toxin action revealed in molecular detail

论文摘要 

人鼠疫病原体“鼠疫耶氏菌”、昆虫病原体“发光杆菌”和其他细菌通过一系列毒性因子的作用来定位宿主细胞,这些毒性因子包括大型的、由三部分组成的ABC型“毒素复合物”(Tc),它通过一个与注射器相似的机制来发挥作用,将毒素输送到目标细胞。然而,我们对驱动这一机制的力却知之甚少。在这篇论文中,Stefan Raunser及同事首次报告了“发光杆菌”TcA亚单元以及整个1.7兆道尔顿的Tc复合物的高分辨率结构。所识别出的关键特征包括对宿主特异性很重要的受体结合点和与神经氨酸苷酶相似的一个区域,一个由pH值诱导产生的、驱动TcA通道向细胞膜内的注射的“熵弹簧”(entropic spring),以及将已做好向目标细胞膜内插入准备的一个未折叠的毒素持续抓住的一个转位通道。

Abstract 

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 β-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.

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