Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476, Potsdam, Germany.
Nat Commun. 2020 Jun 1;11(1):2694. doi: 10.1038/s41467-020-16536-7.
Toxin complex (Tc) toxins are virulence factors of pathogenic bacteria. Tcs are composed of three subunits: TcA, TcB and TcC. TcA facilitates receptor-toxin interaction and membrane permeation, TcB and TcC form a toxin-encapsulating cocoon. While the mechanisms of holotoxin assembly and pore formation have been described, little is known about receptor binding of TcAs. Here, we identify heparins/heparan sulfates and Lewis antigens as receptors for different TcAs from insect and human pathogens. Glycan array screening reveals that all tested TcAs bind negatively charged heparins. Cryo-EM structures of Morganella morganii TcdA4 and Xenorhabdus nematophila XptA1 reveal that heparins/heparan sulfates unexpectedly bind to different regions of the shell domain, including receptor-binding domains. In addition, Photorhabdus luminescens TcdA1 binds to Lewis antigens with micromolar affinity. Here, the glycan interacts with the receptor-binding domain D of the toxin. Our results suggest a glycan dependent association mechanism of Tc toxins on the host cell surface.
毒素复合物 (Tc) 毒素是病原菌的毒力因子。Tcs 由三个亚基组成：TcA、TcB 和 TcC。TcA 促进受体-毒素相互作用和膜渗透，TcB 和 TcC 形成毒素包裹的茧。虽然已经描述了全毒素的组装和孔形成机制，但对 TcA 的受体结合知之甚少。在这里，我们确定肝素/硫酸乙酰肝素和 Lewis 抗原是昆虫和人类病原体中不同 TcA 的受体。糖组阵列筛选表明，所有测试的 TcA 都与带负电荷的肝素结合。Morganella morganii TcdA4 和 Xenorhabdus nematophila XptA1 的冷冻电镜结构显示，肝素/硫酸乙酰肝素出人意料地结合到外壳域的不同区域，包括受体结合域。此外，Photorhabdus luminescens TcdA1 以微摩尔亲和力结合 Lewis 抗原。在这里，聚糖与毒素的受体结合域 D 相互作用。我们的结果表明 Tc 毒素在宿主细胞表面的糖依赖性结合机制。
