Bacteria have established strategies for infecting organisms and utilize them as a source of nutrients. Many bacteria use their secreted toxins to simply pierce the outer shell of the cell to destroy the cell membrane. Human pathogens such as Yersinia pestis or other bacteria from Salmonella produce a more subtle mechanism: injecting their toxic substances by using a special toxin complex.

 

Bacterial toxins are one of the most effective natural poisons. The strongest bacterial toxins include tetanus toxin and botox, which are still toxic when taken in one-thousandth of a gram. Photohhabdus luminescens, Yersinia pestis, and Salmonella use the so-called Tc toxin. The Tc toxin consists of several subunits (TcA, TcB, and TcC). Until then, it was not clear how these components work together.

 

 

In a recent study, researchers from the Max Planck Institute for Molecular Physiology in Germany used cryo-electron microscopy (cryo-EM) to first resolve the three-dimensional structure of the photobacterium Tc toxin at near-atomic resolution. The relevant research results were published on the issue of Nature, entitled “Tc toxin activation requires unfolding and refolding of a β-propeller”.

 

This structure indicates that as the largest subunit of this toxin, TcA is a bell-like structure composed of a channel surrounded by a shell. This channel is similar to a propeller with six blades. The upper-end portion of this bell-like structure is bonded to a toxin capsule formed of subunits TcB and TcC. The receptor on the surface of the cell membrane recognizes the lower end portion of the bell-like structure such that the Tc toxin binds to the cell membrane.

 

Once the pH of the surrounding medium changes, the outer shell of the Tc toxin opens, exposing its passage. A protein chain protected by this toxin capsule will rapidly bounce and push this channel through the cell membrane, just like syringe injects a toxin. This protein chain is an enzyme that catalyzes the condensation of the cytoskeleton, leading to cell death.

 

To fully understand how bacteria inject this toxin, these researchers still lack the last detail. They need to understand how this Fc toxin is controlled. They worked with the Manajit Hayer-Hartl research team from the Max Planck Institute of Biochemistry to solve this problem. They focus on a small hairpin structure, also known as a “gatekeeper.” This controls the toxic substances coming out of the channels of the TcA subunit. When this toxin capsule is combined with the channel of TcA, this boundary region undergoes structural reorganization: this molecular guard will unscrew itself from the center of the propeller, which exposes the central opening of the propeller, thus the central opening is accurately connected to the channel of the TcA subunit. They were also able to confirm that the presence of this toxic enzyme in the toxin capsule is essential to the formation of this intact toxin complex. This points to a possible control mechanism to ensure that the TcA subunit binds to the toxin capsule loaded with toxic substances.

 

Revealing this bacterial infection mechanism helps to better understand how human pathogens work. This newly acquired insight into the specific mechanisms of Tc toxin injection may serve as a starting point for the development of innovative treatments.

 

 

Reference

Christos Gatsogiannis, Felipe Merino, Daniel Roderer et al. Tc toxin activation requires unfolding and refolding of a β-propeller. Nature, 8 November 2018, 563(7730):209–213, doi:10.1016/j.cell.2018.08.033.