SWINHOLIDE-A IS A MICROFILAMENT DISRUPTING MARINE TOXIN THAT STABILIZES ACTIN DIMERS AND SEVERS ACTIN-FILAMENTS

Swinholide A, isolated from the marine sponge Theonella swinhoei, is a 44-carbon ring dimeric dilactone macrolide with a 2-fold axis of symm etry. Recent studies have elucidated its unusual structure and shown t hat it has potent cytotoxic activity, We now report that swinholide A disrupts the actin cytoskeleton of cells grown in culture, sequesters actin dimers in vitro in both polymerizing and non-polymerizing buffer s with a binding stoichiometry of one swinholide A molecule per actin dimer, and rapidly severs F-actin in vitro with high cooperativity, Th ese unique properties are sufficient to explain the cytotoxicity of sw inholide A. They also suggest that swinholide A might be a model for s tudies of the mechanism of action of F-actin severing proteins and be therapeutically useful in conditions where filamentous actin contribut es to pathologically high viscosities.