Cholera Turn-On

AN IMPORTANT TOXIN behind cholera's lethality activates itself by clamping down on a signaling molecule found only in hosts susceptible to the disease, a new study shows. This newly discovered triggering process may be common to multiple bacteria that cause food- and waterborne illnesses.

The bacterium that causes cholera, a diarrheal illness that can be deadly, contains RTX, which stands for repeats in toxin, a protein that is thought to enhance the severity of the disease. RTX is nontoxic until its protease function is activated upon entering the host. Investigators have known that inositol hexakisphosphate (IP₆), a signaling molecule not found in bacteria but abundant in disease hosts, triggers RTX activation, but the activation mechanism has remained unclear. Now, a Stanford University team led by biochemist Matthew Bogyo and structural biologist K. Christopher Garcia suggests that IP₆ regulates RTX by triggering a structural rearrangement in its protease (Science 2008, 322, 265).

The team's X-ray crystal structure of the protease reveals that a protein flap rich in basic amino acid residues clamps down on IP₆'s phosphate groups. Biochemical experiments suggest that the action of that switch orients the active site on RTX and turns on its proteolysis function, activating the toxin.

Although many proteases are turned on by binding to activator molecules at sites other than the active site, "generally, these activators are other proteins," not signaling molecules like IP₆, comments protease expert Guy S. Salvesen of the Burnham Institute for Medical Research, in La Jolla, Calif.

The finding could corroborate suggestions that other protease families are activated similarly by small molecules, he adds. Bogyo agrees that this type of activation could be common, pointing out that several bacteria that cause gastrointestinal illnesses contain protease sequences similar to RTX's.

The team was unable to crystallize RTX in the absence of IP₆. They hope to obtain an NMR structure of the toxin to look for movement and nail down how activation happens.