Biophysical Characteristics of Cholera Toxin and Escherichia coli Heat-Labile Enterotoxin Structure and Chemistry Lead to Differential Toxicity

• Published in: The journal of physical chemistry. B Vol. 119; no. 3; pp. 1048 - 1061
• Main Authors: Craft, John W, Shen, Tsai-wei, Brier, Lindsey M, Briggs, James M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.01.2015
• Subjects: Amino acids; Aspartic acid; Backbone; Biophysical Phenomena; Cholera Toxin - chemistry; Cholera Toxin - metabolism; Cholera Toxin - toxicity; Escherichia coli; Hot Temperature; Hydrogen Bonding; Molecular Dynamics Simulation; Porosity; Protein Conformation; Similarity; Solvents - chemistry; Structure-Activity Relationship; Surface Properties; Toxicity; Toxins; Vibrio cholerae; Water - chemistry
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp506509c

The biophysical chemistry of macromolecular complexes confer their functional characteristics. We investigate the mechanisms that make the AB5 holotoxin of Vibrio cholerae (CT) a significantly more pathogenic molecule than the enterotoxin of Escherichia coli (LT) with which it shares 88% similarity and whose structure is homologous with a backbone RMSD of 0.84 Å and imposes its deleterious effects though the same process to constitutively ADP-ribosylate adenylate cyclase. We present computational data that characterizes the impact of amino acid variations in the A2 tail, which helps to explain experimental data that demonstrate CT’s higher toxicity. A hydrophobic patch on the B pentamer interface and its interactions with the A subdomain are partially disrupted by the substitution of an aspartic acid (LT) for glycine in CT. CT’s holotoxin has less solvent accessible surface area (94 Å2 vs 54 Å2) and higher contact area (280 Å2 vs 241 Å2) with S228, which is a gatekeeper, partially controlling the diffusion of water into the pore. CT excludes water from the top of the central pore whereas LT allows much more water to interact. These biophysical properties of the toxins lead to their differential toxicity and resulting impact to human health.