CT belongs to the larger family of AB toxins [13
]. These toxins are characterized by having an enzymatically active A-domain, responsible for inducing toxicity, and a cell binding B-domain, responsible for cell entry. The AB toxins often consist of a single polypeptide chain that are cleaved into individual A and B components (e.g., ricin and diphtheria toxin), while others are comprised of individual A and B polypeptides that self assemble during the process of intoxication (e.g., anthrax toxin.) A subset of the AB family, the AB5
family of toxins, are comprised of six polypeptides, a single A-subunit and a homopentameric B-subunit that self assemble to form the holotoxin prior to secretion from the microbe. CT typifies this AB5
family of toxins. Other members include the closely related heat labile enterotoxins, as well as shiga toxin, the shiga-like toxins, and pertussis toxin.
The 27 kDa A-subunit of CT is comprised of an A2- and enzymatically active A1-chain, which is linked non-covalently to the B-subunit via
the A2-chain (). The A-subunit contains a serine-protease cleavage site located between residues 192 and 195 that allows for cleavage of the A-subunit into two polypeptides: the A2-chain and A1-chain. A disulfide bond between residues 187 and 199 bridges these chains together. Both the peptide and disulfide bonds must be broken before the A1-chain can enter the cytosol of host cells. The B-subunit consists of five 11.5 kDa peptides assembled non-covalently into a stable homopentamer that binds to the ganglioside GM1 on the PM. The B-subunit-GM1 complex carries the A-subunit into the ER [4
Figure 2 Three-dimensional structure of CT [14,15]. The A-subunit non-covalently associates with the pentameric B-subunit. The A-subunit is further subdivided into A1- and A2-chains, which are separated by a protease cleavage site and are joined by a disulfide (more ...)
Following retro-translocation, the A1-chain enters the cytosol as an active ADP-ribosyltransferase that modifies the heterotrimeric G protein, Gsα. Modification of this G protein leads to the constitutive activation of adenylate cyclase and the rapid production of cAMP. In intestinal cells, this induces intestinal chloride secretion, which is accompanied by a massive movement of water and the diarrhea that is the hallmark of cholera.