BiophysicalCharacteristics of Cholera Toxin and Escherichia coliHeat-Labile Enterotoxin Structure and Chemistry Lead to DifferentialToxicity.

Thebiophysical chemistry of macromolecular complexes confer their functionalcharacteristics. We investigate the mechanisms that make the AB5 holotoxinof Vibrio cholerae(CT) a significantlymore pathogenic molecule than the enterotoxin of Escherichiacoli(LT) with which it shares 88% similarity andwhose structure is homologous with a backbone RMSD of 0.84 Åand imposes its deleterious effects though the same process to constitutivelyADP-ribosylate adenylate cyclase. We present computational data thatcharacterizes the impact of amino acid variations in the A2 tail,which helps to explain experimental data that demonstrate CT’shigher toxicity. A hydrophobic patch on the B pentamer interface andits interactions with the A subdomain are partially disrupted by thesubstitution of an aspartic acid (LT) for glycine in CT. CT’sholotoxin has less solvent accessible surface area (94 Å2vs 54 Å2) and higher contact area (280 Å2vs 241 Å2) with S228, which is a gatekeeper,partially controlling the diffusion of water into the pore. CT excludeswater from the top of the central pore whereas LT allows much morewater to interact. These biophysical properties of the toxins leadto their differential toxicity and resulting impact to human health. [ABSTRACT FROM AUTHOR]