Molecular noise of capping protein binding induces macroscopic instability in filopodial dynamics

Abstract

Capping proteins are among the most important regulatory proteins involved in controlling complicated stochastic dynamics of filopodia, which are dynamic finger-like protrusions used by eukaryotic motile cells to probe their environment and help guide cell motility. They attach to the barbed end of a filament and prevent polymerization, leading to effective filament retraction due to retrograde flow. When we simulated filopodial growth in the presence of capping proteins, qualitatively different dynamics emerged, compared with actin-only system. We discovered that molecular noise due to capping protein binding and unbinding leads to macroscopic filopodial length fluctuations, compared with minuscule fluctuations in the actin-only system. Thus, our work shows that molecular noise of signaling proteins may induce micrometer-scale growth-retraction cycles in filopodia. When capped, some filaments eventually retract all the way down to the filopodial base and disappear. This process endows filopodium with a finite lifetime. Additionally, the filopodia transiently grow several times longer than in actin-only system, since less actin transport is required because of bundle thinning. We have also developed an accurate mean-field model that provides qualitative explanations of our numerical simulation results. Our results are broadly consistent with experiments, in terms of predicting filopodial growth retraction cycles and the average filopodial lifetimes. Eukaryotic motile cells project finger-like protrusions, called filopodia, to probe their environment and help guide cell motility (1). They play important roles in neuronal growth (2), wound healing (3), and cancer metastasis (4). The filopodial structure consists of parallel actin filaments, cross-linked into bundles by actin-binding proteins, all of which is enclosed by the cell's plasma membrane (1, 5). Despite their importance in eukaryotic biology and human health, the physical mechanisms behind filopodial regulation and dynamics are poorly understood, including what drives ubiquitous growth-retraction cycles and eventual filopodial disappearance (1-7). Using stochastic simulations of filopodial dynamics, we have discovered that molecular noise due to binding/unbinding of a capping protein results in macroscopic growth-retraction fluctuations, compared with minuscule fluctuations in the actin-only system. Because of rare fluctuations some filaments eventually retract all the way down to the filopodial base and disappear. In contrast to prior computational models that predicted stable filopodia at steady state, our simulations show that filopodial lifetimes are finite. We have also developed an accurate mean-field model that provides insights into filament disappearance kinetics.A comprehensive computational model of a filopodium should contain the following features: mechanical interactions including membrane dynamics, protrusion force, and retrograde flow; chemical interactions, including actin polymerization and depolymerization; and biological signaling int...

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