Cholera Toxin (CT): Structure

This chapter presents our current knowledge of the primary, secondary, tertiary, and quaternary structures of the cholera toxin (CT) molecule, as derived using various physicochemical techniques and particularly X-ray crystallography. The holotoxin molecule contains six subunits: one A and five B subunits. The A subunit can be separated into two fragments—A1, containing 192 (positions 1–192 in the sequence) amino acids; and A2, containing 48 (positions 193–240 in the sequence) amino acids—by proteolytic cleavage at the site between residues Arg (192) and Ser (193) and reduction of the disulfide bond between the residues Cys (187) and Cys (199). Holotoxin contains a symmetrical pentamer of five identical B subunits surrounding a cylindrical central pore. While the A1 fragment of the A subunit sits on the top of the B pentamer as a wedge-shaped structure, the elongated A2 fragment consists of an alpha helix plus a “tail” that extends through the pore formed by the B pentamer, and it is mainly responsible for the interaction between the A and B subunits. Structural studies have beautifully revealed the nature of binding between the B subunits and the GM1 pentasaccharides of the epithelial cells as a “two-fingered grip,” and how the A1 fragment in the cytosol of the epithelial cell is activated by binding with the ARF-GTP complex. Structural studies further provide valuable insights into possible approaches to the design of drugs aimed at inhibiting the action of CT.