Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases.

Escherichia coli cytotoxic necrotizing factors (CNFs) and Bordetella dermonecrotic toxin (DNT) have been recently found to comprise a novel family of dermonecrosis-inducing toxins which activate the small GTPases of the Rho family. They are single chain polypeptides consisting of an N-terminal domain responsible for binding to target cells and a C-terminal catalytic domain. CNFs (CNF1 and 2) and DNT share in the catalytic domain about 30% identical residues and a consensus sequence where the catalytically active center Cys resides. Both toxins deamidate Rho and other members of the Rho family, Rac and Cdc42, at Gln in the switch II region, which plays an important role in their GTPase activity. DNT, in addition, catalyzes a cross-link of the Gln of the GTPases with ubiquitous polyamines such as putrescine, spermidine, and spermine. The deamidation and the polyamination result in abrogation of the GTPase activity, and in addition, the polyamination endows Rho with the ability to interact with a downstream effector, ROCK, in a GTP-independent manner. These effects render the GTPases constitutively active, which underlies the toxicities of CNFs and DNT.