Effects of jasplakinolide on the kinetics of actin polymerization - An explanation for certain in vivo observations

Jasplakinolide paradoxically stabilizes actin filaments in vitro, but in vi vo it can disrupt actin filaments and induce polymerization of monomeric ac tin into amorphous masses. A detailed analysis of the effects of jasplakino lide on the kinetics of actin polymerization suggests a resolution to this paradox. Jasplakinolide markedly enhances the rate of actin filament nuclea tion. This increase corresponds to a change in the size of actin oligomer c apable of nucleating filament growth from four to approximately three subun its, which is mechanistically consistent with the localization of the jaspl akinolide-binding site at an interface of three actin subunits, Because jas plakinolide both decreases the amount of sequestered actin (by lowering the critical concentration of actin) and augments nucleation, the enhancement of polymerization by jasplakinolide is amplified in the presence of actin-m onomer sequestering proteins such as thymosin beta(4). Overall, the kinetic parameters in vitro define the mechanism by which jasplakinolide induces p olymerization of monomeric actin in vivo, Expected consequences of jasplaki nolide function are consistent with the experimental observations and inclu de de novo nucleation resulting in disordered polymeric actin and in insuff icient monomeric actin to allow for remodeling of stress fibers.