Jasplakinolide, a cytotoxic natural product, induces actin polymerization and competitively inhibits the binding of phalloidin to F-actin.
Year: 1994
Type: article
Abstract: Jasplakinolide, a naturally occurring cyclic peptide from the marine sponge, Jaspis johnstoni, has both fungicidal and antiproliferative activity.We now report that this peptide is a potent inducer of actin polymerization in vitro.The peptide has a much greater effect on Me-actin than on Ca2+-actin.Competitive binding studies using rhodamine-phalloidin suggest that jasplakinolide binds to F-actin competitively with phalloidin with a dissociation constant of approximately 15 MI.This compares favorably to the previously reported IC, of 35 MI for the antiproliferative effect of jasplakinolide on PC3 prostate carcinoma cells.The binding curve suggests that nearest neighbor positive cooperativity influences the binding of jasplakinolide (and perhaps also phalloidin) to F-actin.These results imply that jasplakinolide may exert its cytotoxic effect in vivo by inducing actin polymerization and/or stabilizing pre-existing actin filaments.Jasplakinolide is a cyclic peptide with a 15-carbon macrocyclic ring containing three amino acid residues: L-alanine, N-methyl-2-bromotryptophan, and 0-tyrosine (1, 2).The function of the native molecule in the organism from which it is isolated, the marine sponge, Jaspis johnstoni, is unknown, but recent studies using purified jasplakinolide have demonstrated both fungicidal and antiproliferative activity (3, 4).In the current work, we show that jasplakinolide dramatically decreases the critical concentration of rabbit skeletal muscle actin and competes with rhodamine-phalloidin for F-actin.We suggest that jasplakinolide and phalloidin bind to F-actin by similar mechanisms.The pharmacologic and biochemical implications of these findings are discussed.EXPERIMENTAL PROCEDURES Materials-Rabbit skeletal muscle actin was prepared from frozen muscle (Pel-Freez, Rogers, A R ) as previously described and stored in a * The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
Source: Journal of Biological Chemistry
Institution: National Institutes of Health
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1560179018