Energy Coupling In Profilin-Dependent Actin Polymerization

Abstract

Profilin regulates actin polymerization in cells and is required for normal cell proliferation and differentiation. The molecular mechanism of profilin has been extensively studied and debated in the last 25 years, however no satisfactory explanation consistent with the laws of thermodynamics has yet been provided. In our recent article (Biophys. J. BioFAST: doi:10.1529/biophysj.108.134569) we demonstrate that the mechanism of profilin action could be based a general principle of indirect energy coupling which, as emerges from recent theoretical and experimental research, underlies many biologic processes.In presence of profilin, there are two possible pathways for actin filament elongation. First pathway (g) is direct elongation through binding of G-actin subunits to the barbed end to obtain a filament one subunit longer. The second pathway (pg) is elongation through binding of profilin to G-actin, formation of profilin-actin complex, then binding of the profilin-actin complex to the barbed end with subsequent dissociation of profilin. In the absence of profilin, there is only one pathway g0, which is the pathway g in the absence of profilin.Our analysis shows that the pathway g for filament elongation in presence of profilin is not energetically equivalent to the pathway g0 for the filament elongation in the absence of profilin due to the dependence of standard free energy change for both pathways g and pg on profilin concentration. Conventional calculations of energy imbalance have neglected the difference between the pathways g and g0. We found that profilin can lower actin critical concentration even when the pathways g and pg are energetically equivalent. In this case the existence of the pathway pg can drive the filament nucleotide profile toward ATP-bound F-actin, making both pathways g and pg more energetically favorable than the single pathway g0 available in the absence of profilin.