title: Computational simulation of formin-mediated actin polymerization predicts homologue-dependent mechanosensitivity.
abstract: Many actin structures are nucleated and assembled by the barbed-end tracking polymerase formin family, including filopodia, focal adhesions, the cytokinetic ring and cell cortex. These structures respond to forces in distinct ways. Formins typically have profilin-actin binding sites embedded in highly flexible disordered FH1 domains, hypothesized to diffusively explore space to rapidly capture actin monomers for delivery to the barbed end. Recent experiments demonstrate that formin-mediated polymerization accelerates when under tension. The acceleration has been attributed to modifying the state of the FH2 domain of formin. Intriguingly, the same acceleration is reported when tension is applied to the FH1 domains, ostensibly pulling monomers away from the barbed end. Here we develop a mesoscale coarse-grain model of formin-mediated actin polymerization, including monomer capture and delivery by FH1, which sterically interacts with actin along its entire length. The binding of actin monomers to their specific sites on FH1 is entropically disfavored by the high disorder. We find that this penalty is attenuated when force is applied to the FH1 domain by revealing the binding site, increasing monomer capture efficiency. Overall polymerization rates can decrease or increase with increasing force, depending on the length of FH1 domain and location of binding site. Our results suggest that the widely varying FH1 lengths and binding site locations found in known formins could be used to differentially respond to force, depending on the actin structure being assembled. © 2016 Wiley Periodicals, Inc.
authors: Department of Physics and Astronomy, University of California, Irvine, California.
authors: Derek
authors: D
authors: Bryant
authors: Center for Complex Biological Systems, University of California, Irvine, California.
authors: Lara
authors: L
authors: Clemens
authors: Department of Physics and Astronomy, University of California, Irvine, California.|Center for Complex Biological Systems, University of California, Irvine, California.|Department of Mathematics, University of California, Irvine, California.
authors: Jun
authors: J
authors: Allard
mesh_terms: D000199:Actins / Q000378:metabolism*; D003198:Computer Simulation / Q000706:statistics & numerical data*; D008954:Models, Biological; D058105:Polymerization
chemical_list: D000199:Actins
keywords: actin; formin; freely-jointed chain; mechanosensitivity; simulation