Mechanism of Tc toxin action revealed in molecular detail

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. High-resolution structures of the Photorhabdus luminescens TcA toxin subunit and the entire Tc toxin complex reveal important new insights into Tc complex structure and function. Tc bacterial virulence factor The human plague pathogen Yersinia pestis , the insect pathogen Photorhabdus luminescens and other bacteria target host cells through the action of a range of virulence factors including the large tripartite ABC-type toxin complex (Tc) that acts through a syringe-like mechanism to deliver toxin to the target cell. However, little is known about the force that drives this mechanism. Here Stefan Raunser and colleagues report the first high-resolution structures of the P. luminescens TcA subunit and also of the entire 1.7 megadalton Tc complex. Key features identified include receptor-binding sites and a neuraminidase-like region important for host specificity, a pH-induced 'entropic spring' that drives injection of the TcA channel into the membrane, and a translocation channel that continuously holds an unfolded toxin poised for insertion into the target cell membrane.