Stochastic Severing of Actin Filaments by Actin Depolymerizing Factor/Cofilin Controls the Emergence of a Steady Dynamical Regime

Université Joseph Fourier, TIMC-IMAG Laboratory, Grenoble, France.
Biophysical Journal (Impact Factor: 3.97). 04/2008; 94(6):2082-94. DOI: 10.1529/biophysj.107.121988
Source: PubMed


Actin dynamics (i.e., polymerization/depolymerization) powers a large number of cellular processes. However, a great deal remains to be learned to explain the rapid actin filament turnover observed in vivo. Here, we developed a minimal kinetic model that describes key details of actin filament dynamics in the presence of actin depolymerizing factor (ADF)/cofilin. We limited the molecular mechanism to 1), the spontaneous growth of filaments by polymerization of actin monomers, 2), the ageing of actin subunits in filaments, 3), the cooperative binding of ADF/cofilin to actin filament subunits, and 4), filament severing by ADF/cofilin. First, from numerical simulations and mathematical analysis, we found that the average filament length, L, is controlled by the concentration of actin monomers (power law: 5/6) and ADF/cofilin (power law: -2/3). We also showed that the average subunit residence time inside the filament, T, depends on the actin monomer (power law: -1/6) and ADF/cofilin (power law: -2/3) concentrations. In addition, filament length fluctuations are approximately 20% of the average filament length. Moreover, ADF/cofilin fragmentation while modulating filament length keeps filaments in a high molar ratio of ATP- or ADP-P(i) versus ADP-bound subunits. This latter property has a protective effect against a too high severing activity of ADF/cofilin. We propose that the activity of ADF/cofilin in vivo is under the control of an affinity gradient that builds up dynamically along growing actin filaments. Our analysis shows that ADF/cofilin regulation maintains actin filaments in a highly dynamical state compatible with the cytoskeleton dynamics observed in vivo.

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    • "While at high concentrations they can increase the polymerization by nucleating new actin filaments (Andrianantoandro and Pollard, 2006). ADF/cofilins can keep the actin filaments in a very dynamic state by inducing a steady regime in the filament length fluctuation (Roland et al., 2008). The ADF/cofilins can bind actin monomers as well (Paavilainen et al., 2004). "
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    • "Actin polymerization plays a key role in cell morphology and motility [59] [60]. Roland et al. [40] presented a dynamic model of actin polymerization featuring filament elongation by monomer addition, stabilization by ATP hydrolysis, and severing mediated by actin depolymerizing factor (ADF)/cofilin. Sneddon et al. [14] presented a rule-based formulation of the Roland et al. model and replicated their results using NFsim. The model features an excess of actin monomer and ADF molecules. "
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