How pore forming toxins act on membranes?

How pore forming toxins act on membranes?

Pore-forming toxins (PFT) are common bacterial poisons. They attack organisms by introducing holes in cell membranes. A team of scientists has now unraveled the mechanism of action for one of these toxins.

Many bacterial pathogens produce such toxins, including, for example, some strains of the intestinal bacterium Escherichia coli as well as Yersinia enterolitica, a pathogen related to the plague. The Yersinia YaxAB system represents a family of binary α-PFTs with orthologues in human, insect, and plant pathogens, with unknown structures. YaxAB was shown to be cytotoxic and likely involved in pathogenesis, though the molecular basis for its two-component lytic mechanism remains elusive.

Scientists all over the world are trying to understand how these toxins produce the fatal openings in cell membranes in hope of one day inhibiting the pathogenic, pore-forming poisons.

After several years of research, an interdisciplinary team managed to elucidate the mode of action of a toxin subspecies in which two components interact to develop the deadly effect. Authors in the journal Nature Communications present crystal structures of YaxA and YaxB, together with a cryo-electron microscopy map of the YaxAB complex.

The structures reveal a pore predominantly composed of decamers of YaxA–YaxB heterodimers. Both subunits bear membrane-active moieties, but only YaxA is capable of binding to membranes by itself. YaxB can subsequently be recruited to membrane-associated YaxA and induced to present its lytic transmembrane helices. Pore formation can progress by further oligomerization of YaxA–YaxB dimers.

"We determined that only one of the two components is able to bind to the membrane. In a second step it recruits the other component and the base domains of two proteins together form the basic pore unit," explains the author. "This is a new kind of mechanism from which we can obtain much useful insight."

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