Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An open model of actin dendritic nucleation.

ABSTRACT: The availability of quantitative experimental data on the kinetics of actin assembly has enabled the construction of many mathematical models focused on explaining specific behaviors of this complex system. However these ad hoc models are generally not reusable or accessible by the large community of actin biologists. In this work, we present a comprehensive model that integrates and unifies much of the in vitro data on the components of the dendritic nucleation mechanism for actin dynamics. More than 300 simulations have been run based on compartmental and three-dimensional spatial versions of this model. Several key findings are highlighted, including an explanation for the sharp boundary between actin assembly and disassembly in the lamellipodia of migrating cells. Because this model, with the simulation results, is "open source", in the sense that it is publicly available and editable through the Virtual Cell database (http://vcell.org), it can be accessed, analyzed, modified, and extended.

SUBMITTER: Ditlev JA

PROVIDER: S-EPMC2711424 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

An open model of actin dendritic nucleation.

Ditlev Jonathon A JA Vacanti Nathaniel M NM Novak Igor L IL Loew Leslie M LM

Biophysical journal 20090501 9

The availability of quantitative experimental data on the kinetics of actin assembly has enabled the construction of many mathematical models focused on explaining specific behaviors of this complex system. However these ad hoc models are generally not reusable or accessible by the large community of actin biologists. In this work, we present a comprehensive model that integrates and unifies much of the in vitro data on the components of the dendritic nucleation mechanism for actin dynamics. Mor ...[more]

PMID: 19413959

Similar Datasets

Self-organization of actin filament orientation in the dendritic-nucleation/array-treadmilling model.

Project description:The dendritic-nucleation/array-treadmilling model provides a conceptual framework for the generation of the actin network driving motile cells. We have incorporated it into a 2D, stochastic computer model to study lamellipodia via the self-organization of filament orientation patterns. Essential dendritic-nucleation submodels were incorporated, including discretized actin monomer diffusion, Monte-Carlo filament kinetics, and flexible filament and plasma membrane mechanics. Model parameters were estimated from the literature and simulation, providing values for the extent of the leading edge-branching/capping-protective zone (5.4 nm) and the autocatalytic branch rate (0.43/sec). For a given set of parameters, the system evolved to a steady-state filament count and velocity, at which total branching and capping rates were equal only for specific orientations; net capping eliminated others. The standard parameter set evoked a sharp preference for the +/-35 degree filaments seen in lamellipodial electron micrographs, requiring approximately 12 generations of successive branching to adapt to a 15 degree change in protrusion direction. This pattern was robust with respect to membrane surface and bending energies and to actin concentrations but required protection from capping at the leading edge and branching angles >60 degrees. A +70/0/-70 degree pattern was formed with flexible filaments approximately 100 nm or longer and with velocities < approximately 20% of free polymerization rates.

| S-EPMC1855413 | biostudies-literature

Integration of linear and dendritic actin nucleation in Nck-induced actin comets.

Project description:The Nck adaptor protein recruits cytosolic effectors such as N-WASP that induce localized actin polymerization. Experimental aggregation of Nck SH3 domains at the membrane induces actin comet tails--dynamic, elongated filamentous actin structures similar to those that drive the movement of microbial pathogens such as vaccinia virus. Here we show that experimental manipulation of the balance between unbranched/branched nucleation altered the morphology and dynamics of Nck-induced actin comets. Inhibition of linear, formin-based nucleation with the small-molecule inhibitor SMIFH2 or overexpression of the formin FH1 domain resulted in formation of predominantly circular-shaped actin structures with low mobility (actin blobs). These results indicate that formin-based linear actin polymerization is critical for the formation and maintenance of Nck-dependent actin comet tails. Consistent with this, aggregation of an exclusively branched nucleation-promoting factor (the VCA domain of N-WASP), with density and turnover similar to those of N-WASP in Nck comets, did not reconstitute dynamic, elongated actin comets. Furthermore, enhancement of branched Arp2/3-mediated nucleation by N-WASP overexpression caused loss of the typical actin comet tail shape induced by Nck aggregation. Thus the ratio of linear to dendritic nucleation activity may serve to distinguish the properties of actin structures induced by various viral and bacterial pathogens.

| S-EPMC4713129 | biostudies-literature

Dendritic actin filament nucleation causes traveling waves and patches.

Project description:The polymerization of actin via branching at a cell membrane containing nucleation-promoting factors is simulated using a stochastic-growth methodology. The polymerized-actin distribution displays three types of behavior: (a) traveling waves, (b) moving patches, and (c) random fluctuations. Increasing actin concentration causes a transition from patches to waves. The waves and patches move by a treadmilling mechanism not involving myosin II. The effects of downregulation of key proteins on actin wave behavior are evaluated.

| S-EPMC2947330 | biostudies-literature

Quantifying a pathway: kinetic analysis of actin dendritic nucleation.

Project description:Progress in uncovering the reaction networks that underlie important cell functions is laying the groundwork for quantitative identification of protein-interaction pathways. Since direct measurement of rate constants is not always feasible, the parameters are often inferred from multiple pieces of data using kinetic analyses based on appropriate mathematical models. The success of this approach relies on the sufficiency of available experimental data for a unique parameterization of the network. The concept of a rate-limiting step is applied to the analysis of experimental data that are usually used to quantify a pathway of actin dendritic nucleation, the Arp2/3-mediated mechanism that enables rapid changes of cell shape in response to external cues. The method yields analytical descriptions of the dynamics of polymerized actin and provides insights into how the experimental curves should be analyzed. It is shown that dynamics measured by pyrene-labeled actin assays with varying Arp2/3 concentrations are equally well described by two different rate-limiting steps: 1), binding of a nucleating complex to the side of a preexisting filament; or 2), its subsequent activation. To distinguish between the alternatives, we propose experiments with varying concentrations of actin monomers, taking advantage of the fact that the number of branches in the two cases depends differently on the initial monomer concentration. The idea is tested by simulating the proposed experiments with the use of spatial stochastic modeling.

| S-EPMC2913184 | biostudies-literature

Nanoscale segregation of actin nucleation and elongation factors determines dendritic spine protrusion.

Project description:Actin dynamics drive morphological remodeling of neuronal dendritic spines and changes in synaptic transmission. Yet, the spatiotemporal coordination of actin regulators in spines is unknown. Using single protein tracking and super-resolution imaging, we revealed the nanoscale organization and dynamics of branched F-actin regulators in spines. Branched F-actin nucleation occurs at the PSD vicinity, while elongation occurs at the tip of finger-like protrusions. This spatial segregation differs from lamellipodia where both branched F-actin nucleation and elongation occur at protrusion tips. The PSD is a persistent confinement zone for IRSp53 and the WAVE complex, an activator of the Arp2/3 complex. In contrast, filament elongators like VASP and formin-like protein-2 move outwards from the PSD with protrusion tips. Accordingly, Arp2/3 complexes associated with F-actin are immobile and surround the PSD. Arp2/3 and Rac1 GTPase converge to the PSD, respectively, by cytosolic and free-diffusion on the membrane. Enhanced Rac1 activation and Shank3 over-expression, both associated with spine enlargement, induce delocalization of the WAVE complex from the PSD. Thus, the specific localization of branched F-actin regulators in spines might be reorganized during spine morphological remodeling often associated with synaptic plasticity.

| S-EPMC4282554 | biostudies-literature

Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells.

Project description:Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA-mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42-Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4-MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDia1-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function.

| S-EPMC5885286 | biostudies-literature

Actin turnover-dependent fast dissociation of capping protein in the dendritic nucleation actin network: evidence of frequent filament severing.

Project description:Actin forms the dendritic nucleation network and undergoes rapid polymerization-depolymerization cycles in lamellipodia. To elucidate the mechanism of actin disassembly, we characterized molecular kinetics of the major filament end-binding proteins Arp2/3 complex and capping protein (CP) using single-molecule speckle microscopy. We have determined the dissociation rates of Arp2/3 and CP as 0.048 and 0.58 s(-1), respectively, in lamellipodia of live XTC fibroblasts. This CP dissociation rate is three orders of magnitude faster than in vitro. CP dissociates slower from actin stress fibers than from the lamellipodial actin network, suggesting that CP dissociation correlates with actin filament dynamics. We found that jasplakinolide, an actin depolymerization inhibitor, rapidly blocked the fast CP dissociation in cells. Consistently, the coexpression of LIM kinase prolonged CP speckle lifetime in lamellipodia. These results suggest that cofilin-mediated actin disassembly triggers CP dissociation from actin filaments. We predict that filament severing and end-to-end annealing might take place fairly frequently in the dendritic nucleation actin arrays.

| S-EPMC2064704 | biostudies-literature

Insights into Actin Polymerization and Nucleation Using a Coarse-Grained Model.

Project description:We studied actin filament polymerization and nucleation with molecular dynamics simulations and a previously established coarse-grained model having each residue represented by a single interaction site located at the Cα atom. We approximate each actin protein as a fully or partially rigid unit to identify the equilibrium structural ensemble of interprotein complexes. Monomers in the F-actin configuration bound to both barbed and pointed ends of a short F-actin filament at the anticipated locations for polymerization. Binding at both ends occurred with similar affinity. Contacts between residues of the incoming subunit and the short filament were consistent with expectation from models based on crystallography, x-ray diffraction, and cryo-electron microscopy. Binding at the barbed and pointed end also occurred at an angle with respect to the polymerizable bound structure, and the angle range depended on the flexibility of the D-loop. Additional barbed end bound states were seen when the incoming subunit was in the G-actin form. Consistent with an activation barrier for pointed end polymerization, G-actin did not bind at an F-actin pointed end. In all cases, binding at the barbed end also occurred in a configuration similar to the antiparallel (lower) dimer. Individual monomers bound each other in a short-pitch helix complex in addition to other configurations, with several of them apparently nonproductive for polymerization. Simulations with multiple monomers in the F-actin form show assembly into filaments as well as transient aggregates at the barbed end. We discuss the implications of these observations on the kinetic pathway of actin filament nucleation and polymerization and possibilities for future improvements of the coarse-grained model.

| S-EPMC7399502 | biostudies-literature

Local actin nucleation tunes centrosomal microtubule nucleation during passage through mitosis.

Project description:Cells going through mitosis undergo precisely timed changes in cell shape and organisation, which serve to ensure the fair partitioning of cellular components into the two daughter cells. These structural changes are driven by changes in actin filament and microtubule dynamics and organisation. While most evidence suggests that the two cytoskeletal systems are remodelled in parallel during mitosis, recent work in interphase cells has implicated the centrosome in both microtubule and actin nucleation, suggesting the potential for regulatory crosstalk between the two systems. Here, by using both in vitro and in vivo assays to study centrosomal actin nucleation as cells pass through mitosis, we show that mitotic exit is accompanied by a burst in cytoplasmic actin filament formation that depends on WASH and the Arp2/3 complex. This leads to the accumulation of actin around centrosomes as cells enter anaphase and to a corresponding reduction in the density of centrosomal microtubules. Taken together, these data suggest that the mitotic regulation of centrosomal WASH and the Arp2/3 complex controls local actin nucleation, which may function to tune the levels of centrosomal microtubules during passage through mitosis.

| S-EPMC6545563 | biostudies-literature

Apicomplexan actin polymerization depends on nucleation.

Project description:Filamentous actin is critical for apicomplexan motility and host cell invasion. Yet, parasite actin filaments are short and unstable. Their kinetic characterization has been hampered by the lack of robust quantitative methods. Using a modified labeling method, we carried out thorough biochemical characterization of malaria parasite actin. In contrast to the isodesmic polymerization mechanism suggested for Toxoplasma gondii actin, Plasmodium falciparum actin I polymerizes via the classical nucleation-elongation pathway, with kinetics similar to canonical actins. A high fragmentation rate, governed by weak lateral contacts within the filament, is likely the main reason for the short filament length. At steady state, Plasmodium actin is present in equal amounts of short filaments and dimers, with a small proportion of monomers, representing the apparent critical concentration of ~0.1?µM. The dimers polymerize but do not serve as nuclei. Our work enhances understanding of actin evolution and the mechanistic details of parasite motility, serving as a basis for exploring parasite actin and actin nucleators as drug targets against malaria and other apicomplexan parasitic diseases.

| S-EPMC5610305 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data