Filopodia: Complex models for simple rods

Faix, Jan; Breitsprecher, Dennis; Stradal, Theresia E. B.; Rottner, Klemens

doi:10.1016/j.biocel.2009.02.012

Cited by 153 publications

(158 citation statements)

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“…Extension and retraction of filopodia are regulated by dynamic balance between actin monomer added at the barbed end of filaments and continuous actin retrograde flow [4]. Formins promote the actin filament barbed end polymerization [5,6], which is profilin-dependent in vivo [7]. The characteristic Formin-Homology-2 (FH2) domain is a dimeric donut-shaped domain that persistently associates to the barbed end of actin filaments with de novo filament nucleation function [6,8,9].…”

Section: Introductionmentioning

confidence: 99%

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

et al. 2014

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a b s t r a c tFilopodia are essential for the development of neuronal growth cones, cell polarity and cell migration. Their protrusions are powered by the polymerization of actin filaments linked to the plasma membrane, catalyzed by formin proteins. The acceleration of polymerization depends on the number of profilin-actins binding with the formin-FH1 domain. Biophysical characterization of the disordered formin-FH1 domain remains a challenge. We analyzed the conformational distribution of the diaphanous-related formin mDia1-FH1 bound with one to six profilins. We found a coil-to-elongation transition in the FH1 domain. We propose a cooperative ''jack'' model for the Formin-Homology-1 (FH1) domain of formins stacked by profilin-actins.

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Section: Introductionmentioning

confidence: 99%

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

et al. 2014

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“…One current model for filopodia assembly is convergent elongation (5). Formin and/or Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) proteins gather and rapidly elongate subpopulations of lamellipodial actin-barbed ends, antagonizing inhibition by capping protein (CP), and the parallel actin-crosslinking protein Fascin aligns and bundles elongating filopodial filaments (6).Ena/VASP proteins are large, multidomain actin-assembly factors (7,8). The N-terminal Ena/VASP homology 1 (EVH1) domain binds FP4 motifs for proper localization (9).…”

mentioning

confidence: 99%

“…Ena/VASP proteins are large, multidomain actin-assembly factors (7,8). The N-terminal Ena/VASP homology 1 (EVH1) domain binds FP4 motifs for proper localization (9).…”

mentioning

confidence: 99%

Ena/VASP Enabled is a highly processive actin polymerase tailored to self-assemble parallel-bundled F-actin networks with Fascin

Winkelman¹,

Bilancia²,

Peifer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

140

172

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Filopodia are exploratory finger-like projections composed of multiple long, straight, parallel-bundled actin filaments that protrude from the leading edge of migrating cells. Drosophila melanogaster Enabled (Ena) is a member of the Ena/vasodilatorstimulated phosphoprotein protein family, which facilitates the assembly of filopodial actin filaments that are bundled by Fascin. However, the mechanism by which Ena and Fascin promote the assembly of uniformly thick F-actin bundles that are capable of producing coordinated protrusive forces without buckling is not well understood. We used multicolor evanescent wave fluorescence microscopy imaging to follow individual Ena molecules on both single and Fascinbundled F-actin in vitro. Individual Ena tetramers increase the elongation rate approximately two-to threefold and inhibit capping protein by remaining processively associated with the barbed end for an average of ∼10 s in solution, for ∼60 s when immobilized on a surface, and for ∼110 s when multiple Ena tetramers are clustered on a surface. Ena also can gather and simultaneously elongate multiple barbed ends. Collectively, these properties could facilitate the recruitment of Fascin and initiate filopodia formation. Remarkably, we found that Ena's actin-assembly properties are tunable on Fascinbundled filaments, facilitating the formation of filopodia-like F-actin networks without tapered barbed ends. Ena-associated trailing barbed ends in Fascin-bundled actin filaments have approximately twofold more frequent and approximately fivefold longer processive runs, allowing them to catch up with leading barbed ends efficiently. Therefore, Fascin and Ena cooperate to extend and maintain robust filopodia of uniform thickness with aligned barbed ends by a unique mechanistic cycle.profilin | formin | TIRF microscopy | self organization | single molecule T he actin cytoskeleton facilitates fundamental cellular processes including division, polarization, and motility. The organization and dynamics of particular F-actin networks are determined by the coordinated action of specific subsets of actinbinding proteins with complementary biochemical properties such as sequestering, nucleating, elongating, bundling/crosslinking, and severing (1-3).Cell motility is driven primarily by lamellipodia, protrusive structures at the cell's leading edge composed of a dendritic network of short-branched filaments produced by the rapid capping of filaments nucleated by the actin-related proteins 2 and 3 (Arp2/3) complex (4). Filopodia are exploratory finger-like projections composed of uniformly long, straight, parallel-bundled filaments that extend from lamellipodia. One current model for filopodia assembly is convergent elongation (5). Formin and/or Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) proteins gather and rapidly elongate subpopulations of lamellipodial actin-barbed ends, antagonizing inhibition by capping protein (CP), and the parallel actin-crosslinking protein Fascin aligns and bundles elongating filopodial filaments (...

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“…Filopodia are long, finger-like membrane protrusions with numerous roles in signaling and cell navigation (Fig. 2.2a) [19,22,31,33]. Unlike the enormous complexity of most cellular regions with dynamically interchanging actin networks, the comparatively simple organization of filopodia offers great advantages: (1) they contain only one form of prevailing actin network consisting of parallel F-actin bundles; (2) accordingly, the number of molecular players is limited; (3) filopodial dynamics are predominantly unidimensional, and (4) length changes of filopodial actin filament bundles directly translate into length changes of the entire filopodium, thus providing simple and efficient readouts for functional studies that can be carried out iteratively with modeling approaches (Fig.…”

Section: Filopodiamentioning

confidence: 99%

“…By adjusting the proportion of the polar assembly versus disassembly processes, filopodia can undergo regulated length changes. However, the high rate of polymerization at the very tip of filopodia requires uninterrupted delivery of large amounts of new building blocks which, at first sight, seems counterintuitive in these long and slender protrusions [19,22,31,33]. To explain this phenomenon, we propose the use of integrative models which consider catalyzed actin polymerization dynamics, diffusion as well as cytoplasmic flow dynamics.…”

mentioning

confidence: 99%

Mathematical-Computational Simulation of Cytoskeletal Dynamics

Moura

Kritz

Leal

et al. 2016

Mathematical Modeling and Computational Intelligence in Engineering Applications

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Actin and microtubules are components of the cytoskeleton, and are key mediators of neuron growth and maintenance. Knowing how they are regulated enhances our understanding of neural development, ageing, degeneration, and regeneration. However, biological investigation alone will not unravel the complex cytoskeletal machinery. We expect that inquiries about the cytoskeleton can be significantly enhanced if their physico-chemical behavior is concealed and summarized in mathematical and computational models that can be coupled to concepts of biological regulation. Our computational modeling concerns the mechanical aspects associated with the dynamics of relatively simple, finger-like membrane protrusions called filopodia. Here we propose an alternative approach for representing the displacement of molecules and cytoplasmic fluid in the extremely narrow and long filopodia and discuss strategies to couple the particle-in-cell method with algorithms for laminar flow to model the two phases of actin dynamics: polymerization into filaments which are pulled back into the cell and compensatory G-actin drift towards its tip to supply polymerization. We use nerve cells of the fruit fly Drosophila as an effective, genetically amenable biological system to generate experimental data as the basis for the abstract models and their validation.

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Filopodia: Complex models for simple rods

Cited by 153 publications

References 104 publications

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

Ena/VASP Enabled is a highly processive actin polymerase tailored to self-assemble parallel-bundled F-actin networks with Fascin

Mathematical-Computational Simulation of Cytoskeletal Dynamics

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