Cartoon representation of the hypothetical synergistic mechanism involved in the membrane-damaging activity of Asp49 and Lys49 myotoxins.

<p>Toxins bind to the muscle cell membrane (A), although acceptor moieties for this event are unknown. Each toxin type by its own has the ability to induce cytotoxicity <i>in vitro</i> or myonecrosis <i>in vivo</i> through membrane damage. Asp49 myotoxins destabilize the membrane by the enzymatic hydrolysis of phospholipids (PL) and consequent production of lyso-PL and fatty acids (FA), whereas Lys49 myotoxins exert a direct permeabilization mechanism via their C-terminal region (B). When acting in combination, FA produced by the Asp49 myotoxin generate new anionic sites (red spheres) that facilitate the binding of Lys49 myotoxin through electrostatic interactions (C). The membrane becomes more unstable due to PL hydrolysis <i>per se</i>, and to the accumulation of the reaction products (lysoPL and FA). As a result of these combined actions of Asp49 and Lys49 myotoxins, membrane damage is enhanced and the cell becomes irreversibly damaged (D). Note that the toxin cartoons are represented as monomers for simplicity, although these toxins actually occur as homodimers. Cartoons are not drawn to scale, and the orientation of the toxins interacting with the membrane is only for illustrative purposes.