How profilin/barbed-end synergy controls actin polymerization: a kinetic model of the ATP hydrolysis circuit.
The role of ATP hydrolysis in the regulation of the actin cytoskeleton continues to be a subject of controversy. Since actin polymerization can occur in the absence of ATP, the energy of hydrolysis is not needed for filament assembly. Recent work has instead suggested a regulatory role for ATP in cytoskeletal remodeling. In particular, both profilin and free filament barbed ends have been shown to play major roles in the processing of ATP by actin. We have developed a new integrated kinetic model to examine how the maintenance of the pool of unpolymerized actin and the flux of actin subunits through filaments are controlled by profilin and free filament barbed ends through their interaction with ATP. An analysis of the model's steady states predicts how two novel regulatory pathways may regulate the cytoskeleton in vivo. Coordinated changes in the availability of both profilin and free barbed ends mediate the following regulatory effects: (1) both the nucleotide composition and the absolute amount of free G-actin can be changed separately or together to substantially alter the total amount of F-actin; and (2) uncapping the barbed ends of only a modest fraction of filaments causes all filaments to begin slowly depolymerizing from their pointed ends, resulting in the total depolymerization of the remaining capped filaments. We report that the phenomenon of treadmilling, wherein the barbed end growth of each filament is exactly balanced by pointed end loss at steady state, is only possible in the limiting case when all barbed ends are uncapped. The capping of any fraction of barbed ends increases the critical concentration of ATP-G-actin, causing the remaining free barbed ends to grow faster than their pointed ends can shrink. On the basis of these findings we propose a major revision to the treadmilling model for actin-based motility, in which the rapidly growing filaments with free barbed ends are continuously severed toward their rear followed by capping of the newly exposed barbed ends. This revised model, herein referred to as "treadsevering," allows sustained and rapid barbed end growth to occur indefinitely at a steady state provided a continuous input of ATP.
Dufort
P A
PA
Institute of Medical Science, University of Toronto, Canada.
Lumsden
C J
CJ
D000199:Actins / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D003285:Contractile Proteins / Q000378:metabolism*; D006868:Hydrolysis; D007091:Image Processing, Computer-Assisted; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D051304:Profilins; D013947:Thymosin / Q000378:metabolism; D000099201:Thymosin beta(4)
D000199:Actins; D000255:Adenosine Triphosphate; D003285:Contractile Proteins; D008840:Microfilament Proteins; D051304:Profilins; D013947:Thymosin; D000099201:Thymosin beta(4)