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J Biol Chem, Vol. 275, Issue 7, 5163-5170, February 18, 2000
From the Department of Medicine, University of Florida,
Gainesville, Florida 32610 and the § Department of
Physiology and Biophysics, State University of New York,
Stony Brook, New York 11794
Jasplakinolide paradoxically stabilizes actin
filaments in vitro, but in vivo it can disrupt
actin filaments and induce polymerization of monomeric actin into
amorphous masses. A detailed analysis of the effects of jasplakinolide
on the kinetics of actin polymerization suggests a resolution to this
paradox. Jasplakinolide markedly enhances the rate of actin filament
nucleation. This increase corresponds to a change in the size of actin
oligomer capable of nucleating filament growth from four to
approximately three subunits, which is mechanistically consistent with
the localization of the jasplakinolide-binding site at an interface of
three actin subunits. Because jasplakinolide 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-monomer
sequestering proteins such as thymosin
Effects of Jasplakinolide on the Kinetics of Actin
Polymerization
AN EXPLANATION FOR CERTAIN IN VIVO OBSERVATIONS*
,
4. Overall, the
kinetic parameters in vitro define the mechanism by which
jasplakinolide induces polymerization of monomeric actin in
vivo. Expected consequences of jasplakinolide function are
consistent with the experimental observations and include de
novo nucleation resulting in disordered polymeric actin and in
insufficient monomeric actin to allow for remodeling of stress fibers.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by the Medical Research Service of the Department of
Veteran Affairs. To whom correspondence should be addressed: Box
100277, Dept. of Medicine, University of Florida, Gainesville, FL
32610. Tel.: 352-392-4059; Fax: 352-392-6481.
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