Deadly Duo

Research team clarifies mechanism of action of a class of bacterial toxins

bacterial toxins
Individual components YaxA (blue) and YaxB (purple) as well as a pore made up of these. Image: Bastian Bräuning / TUM

Pore-forming toxins are among the most common bacterial toxins. They attack organisms by creating holes in the cell membrane. A team of scientists at the Technische Universität München (TUM) has now elucidated the mechanism of action of one of these poisons. The findings could help combat such diseases or protect plants from damage.

Pore-forming toxins are bacterial toxins that create holes in the cell membrane, destroying the cell. Many bacterial pathogens produce these, for example, some strains of the intestinal bacterium Escherichia coli and the pathogen related to the bacterium Yersinia enterolitica. With the help of their toxins, they attack very different organisms – from plants to insects to humans.

Scientists worldwide are trying to understand exactly how these toxins create the fatal holes in the cell membrane, so that one day they might be able to inhibit pore-forming toxins from pathogens.

Now, an interdisciplinary team at the Technical University of Munich has succeeded in elucidating the mode of action of a subspecies of these toxins, in which two components work together to develop the deadly effect.

Two Partners with Lethal Effects

By combining crystallographic and cryo-electron microscopic methods, Bastian Bräuning and Professor Michael Groll from the Department of Biochemistry together with Eva Bertosin and Professor Hendrik Dietz from the Department of Experimental Biophysics succeeded in elucidating the exact molecular structure of both the soluble individual components and the pore complex.

“We have found that only one of the two components can bind to the membrane. Only in a second step does she recruit the second component and the foot domains of both proteins together form the basic unit of the pore, “explains Bastian Bräuning. “This is a new kind of mechanism from which we can gain many useful insights.”

The structure of the resulting hole in the cell membrane resembles a crown, whose teeth consist of 40 subunits of the two cooperating partners.

One Mechanism – Many Possible Applications

Browning and resentment researchers investigated the interaction of the two partner proteins with the poisons of Yersinia enterolitica and Photorhabdus luminescens, a bacterium that lives in nematodes and attacks in symbiosis with these insects. The latter is therefore interesting as a remedy for insects.

The development of substances that block the interaction of the two components and thus prevent the formation of pores is generally imaginable with the help of the new findings.

“Our combination of crystallography and cryo-electron microscopy was essential to biochemically understand the necessity of the two-part construction of this toxin,” explains Professor Michael Groll. “This knowledge will help us in the future to understand even more complex variants, such as those in which three components interact.”

Source : Technische Universität München