Swinholide A is a microfilament disrupting marine toxin that stabilizes actin dimers and severs actin filaments.
Swinholide A, isolated from the marien sponge Theonella swinhoei, is a 44-carbon ring dimeric dilactone macrolide with a 2-fold axis of symmetry. Recent studies have elucidated its unusual structure and shown that 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 buffers with a binding stoichiometry of one swinholide A molecule per actin dimer, and rapidly severs F-actin in vitro with high cooperativity. These unique properties are sufficient to explain the cytotoxicity of swinholide A. They also suggest that swinholide A might be a model for studies of the mechanism of action of F-actin severing proteins and be therapeutically useful in conditions where filamentous actin contributes to pathologically high viscosities.
Bubb
M R
MR
Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
Spector
I
I
Bershadsky
A D
AD
Korn
E D
ED
D016475:3T3 Cells; D000199:Actins / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects; D006868:Hydrolysis; D008387:Marine Toxins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C
D000199:Actins; D000970:Antineoplastic Agents; D008387:Marine Toxins; C086235:swinholide A