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• W2283643310 abstract "•We generated actin architectures that span the diversity of contractile structures•These different actin organizations respond differently to myosin-induced contraction•Actin filament organization and connectivity determine the contractile response•Network contraction is dominated by either sarcomeric-like or buckling mechanisms Actomyosin contractility plays a central role in a wide range of cellular processes, including the establishment of cell polarity, cell migration, tissue integrity, and morphogenesis during development. The contractile response is variable and depends on actomyosin network architecture and biochemical composition. To determine how this coupling regulates actomyosin-driven contraction, we used a micropatterning method that enables the spatial control of actin assembly. We generated a variety of actin templates and measured how defined actin structures respond to myosin-induced forces. We found that the same actin filament crosslinkers either enhance or inhibit the contractility of a network, depending on the organization of actin within the network. Numerical simulations unified the roles of actin filament branching and crosslinking during actomyosin contraction. Specifically, we introduce the concept of “network connectivity” and show that the contractions of distinct actin architectures are described by the same master curve when considering their degree of connectivity. This makes it possible to predict the dynamic response of defined actin structures to transient changes in connectivity. We propose that, depending on the connectivity and the architecture, network contraction is dominated by either sarcomeric-like or buckling mechanisms. More generally, this study reveals how actin network contractility depends on its architecture under a defined set of biochemical conditions. Actomyosin contractility plays a central role in a wide range of cellular processes, including the establishment of cell polarity, cell migration, tissue integrity, and morphogenesis during development. The contractile response is variable and depends on actomyosin network architecture and biochemical composition. To determine how this coupling regulates actomyosin-driven contraction, we used a micropatterning method that enables the spatial control of actin assembly. We generated a variety of actin templates and measured how defined actin structures respond to myosin-induced forces. We found that the same actin filament crosslinkers either enhance or inhibit the contractility of a network, depending on the organization of actin within the network. Numerical simulations unified the roles of actin filament branching and crosslinking during actomyosin contraction. Specifically, we introduce the concept of “network connectivity” and show that the contractions of distinct actin architectures are described by the same master curve when considering their degree of connectivity. This makes it possible to predict the dynamic response of defined actin structures to transient changes in connectivity. We propose that, depending on the connectivity and the architecture, network contraction is dominated by either sarcomeric-like or buckling mechanisms. More generally, this study reveals how actin network contractility depends on its architecture under a defined set of biochemical conditions. Actomyosin contractility plays a central role in a wide range of cellular processes including the establishment of cell polarity, cell migration, tissue integrity, or morphogenesis during development [1Levayer R. Lecuit T. Biomechanical regulation of contractility: spatial control and dynamics.Trends Cell Biol. 2012; 22: 61-81Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 2Heisenberg C.P. Bellaïche Y. Forces in tissue morphogenesis and patterning.Cell. 2013; 153: 948-962Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar]. Contraction is generated by myosin molecular motors that exert forces on actin filaments [3Thoresen T. Lenz M. Gardel M.L. Reconstitution of contractile actomyosin bundles.Biophys. J. 2011; 100: 2698-2705Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 4Alvarado J. Sheinman M. Sharma A. MacKintosh F.C. Koenderink G.H. Molecular motors robustly drive active gels to a critically connected state.Nat. Phys. 2013; 9: 591-597Crossref Scopus (154) Google Scholar, 5Köhler S. Bausch A.R. Contraction mechanisms in composite active actin networks.PLoS ONE. 2012; 7: e39869Crossref PubMed Scopus (41) Google Scholar, 6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar]. This active process is complex, in part because actin filaments in contractile networks are assembled in a variety of dynamic organized structures that undergo continuous assembly, disassembly, and overall reorganization [7Letort G. Ennomani H. Gressin L. Théry M. Blanchoin L. Dynamic reorganization of the actin cytoskeleton.F1000Research. 2015; 4: 940Google Scholar, 8Murrell M. Oakes P.W. Lenz M. Gardel M.L. Forcing cells into shape: the mechanics of actomyosin contractility.Nat. Rev. Mol. Cell Biol. 2015; 16: 486-498Crossref PubMed Scopus (326) Google Scholar]. Actomyosin contractility can be reproduced using cell extracts [9Pollard T.D. Ito S. Cytoplasmic filaments of Amoeba proteus. I. The role of filaments in consistency changes and movement.J. Cell Biol. 1970; 46: 267-289Crossref PubMed Scopus (120) Google Scholar, 10Janson L.W. Kolega J. Taylor D.L. Modulation of contraction by gelation/solation in a reconstituted motile model.J. Cell Biol. 1991; 114: 1005-1015Crossref PubMed Scopus (88) Google Scholar] or reconstituted systems [4Alvarado J. Sheinman M. Sharma A. MacKintosh F.C. Koenderink G.H. Molecular motors robustly drive active gels to a critically connected state.Nat. Phys. 2013; 9: 591-597Crossref Scopus (154) Google Scholar, 5Köhler S. Bausch A.R. Contraction mechanisms in composite active actin networks.PLoS ONE. 2012; 7: e39869Crossref PubMed Scopus (41) Google Scholar, 11Bendix P.M. Koenderink G.H. Cuvelier D. Dogic Z. Koeleman B.N. Brieher W.M. Field C.M. Mahadevan L. Weitz D.A. A quantitative analysis of contractility in active cytoskeletal protein networks.Biophys. J. 2008; 94: 3126-3136Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 12Murrell M.P. Gardel M.L. F-actin buckling coordinates contractility and severing in a biomimetic actomyosin cortex.Proc. Natl. Acad. Sci. USA. 2012; 109: 20820-20825Crossref PubMed Scopus (257) Google Scholar, 13Carvalho K. Lemière J. Faqir F. Manzi J. Blanchoin L. Plastino J. Betz T. Sykes C. Actin polymerization or myosin contraction: two ways to build up cortical tension for symmetry breaking.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013; 368: 20130005Crossref PubMed Scopus (57) Google Scholar, 14Abu Shah E. Keren K. Symmetry breaking in reconstituted actin cortices.eLife. 2014; 3: e01433Crossref Scopus (28) Google Scholar]. In parallel, the molecular mechanism of single myosin motors has been studied extensively over the last decades [15Houdusse A. Sweeney H.L. Myosin motors: missing structures and hidden springs.Curr. Opin. Struct. Biol. 2001; 11: 182-194Crossref PubMed Scopus (152) Google Scholar]. Three principal mechanisms of contractility have been proposed for actin filament networks: (1) a sarcomeric-like model, where filaments slide because of structural asymmetry that originates from motor processivity, crosslinker distribution [16Kruse K. Jülicher F. Actively contracting bundles of polar filaments.Phys. Rev. Lett. 2000; 85: 1778-1781Crossref PubMed Scopus (156) Google Scholar, 17Zemel A. Mogilner A. Motor-induced sliding of microtubule and actin bundles.Phys. Chem. Chem. Phys. 2009; 11: 4821-4833Crossref PubMed Scopus (36) Google Scholar] or from contractile versus expansile state stability [18Dasanayake N.L. Michalski P.J. Carlsson A.E. General mechanism of actomyosin contractility.Phys. Rev. Lett. 2011; 107: 118101Crossref PubMed Scopus (50) Google Scholar]; (2) an actin filament treadmilling model, where contractility depends on actin filament turnover [19Oelz D.B. Rubinstein B.Y. Mogilner A. A Combination of Actin Treadmilling and Cross-Linking Drives Contraction of Random Actomyosin Arrays.Biophys. J. 2015; 109: 1818-1829Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]; and (3) a buckling model, where contractility depends on the mechanical deformation of actin filament under the force exerted by the myosin [20Lenz M. Thoresen T. Gardel M.L. Dinner A.R. Contractile units in disordered actomyosin bundles arise from F-actin buckling.Phys. Rev. Lett. 2012; 108: 238107Crossref PubMed Scopus (105) Google Scholar]. However, little is known about how the architecture of the actin structure influences contraction, the molecular mechanism of contraction in complex actin structures, or how network dynamic reorganization affects its deformation. In a cellular context, actin filaments can be roughly assembled into three categories of dynamical structures, each of them performing specific functions: (1) a nearly orthogonal network at the leading edge of motile cells; (2) parallel bundles in filipodia type of membrane protrusions or at adhesion sites; and (3) anti-parallel contractile actin fibers in the cell cytoplasm [21Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (795) Google Scholar]. Lamellipodia and filipodia types of actin organization have been extensively studied using a combination of biochemical and cell-biological approaches [21Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (795) Google Scholar, 22Pollard T.D. Blanchoin L. Mullins R.D. Molecular mechanisms controlling actin filament dynamics in nonmuscle cells.Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 545-576Crossref PubMed Scopus (1176) Google Scholar, 23Fletcher D.A. Mullins R.D. Cell mechanics and the cytoskeleton.Nature. 2010; 463: 485-492Crossref PubMed Scopus (1763) Google Scholar]. Although a general consensus emerges from these studies on the mechanism of force generation by actin polymerization and how this can deform or protrude the plasma membrane [21Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (795) Google Scholar, 24Pollard T.D. Borisy G.G. Cellular motility driven by assembly and disassembly of actin filaments.Cell. 2003; 112: 453-465Abstract Full Text Full Text PDF PubMed Scopus (3267) Google Scholar, 25Mogilner A. Oster G. Cell motility driven by actin polymerization.Biophys. J. 1996; 71: 3030-3045Abstract Full Text PDF PubMed Scopus (705) Google Scholar], the role of actomyosin interaction in the remodeling of these structures is far less characterized. Moreover, the mechanism of contraction, which depends on the organization of actin filaments, is largely unknown. Here, we used our ability to generate well-defined actin organization using surface micropatterning of actin Nucleating Promoting Factor (NPF) [26Reymann A.-C. Martiel J.-L. Cambier T. Blanchoin L. Boujemaa-Paterski R. Théry M. Nucleation geometry governs ordered actin networks structures.Nat. Mater. 2010; 9: 827-832Crossref PubMed Scopus (102) Google Scholar, 27Vignaud T. Ennomani H. Théry M. Polyacrylamide hydrogel micropatterning.Methods Cell Biol. 2014; 120: 93-116Crossref PubMed Scopus (55) Google Scholar], to challenge the actin-geometrical principles ruling contractility. We found that the rate of the macroscopic actin deformation due to myosin-contraction depends on network architecture (disordered branched networks, ordered or disordered bundles). Using numerical simulations, we established that in addition of filaments organization, network connectivity modulates the contractile response. We determined the mechanism of contraction leading to macroscopic deformation for the different actin architectures and how it depends on the degree of network connectivity. Finally, using our model, we predicted how dynamic transition upon actin organization can modulate the actomyosin contractile response and validated these predictions using a new experimental system allowing the dynamic and reversible modulation of actin organization during contraction. Cellular actin filaments assemble into a variety of structures that are distinct with respect to the orientation of the filaments, as well as their connectivity (ability of one filament to be linked to another filament) [21Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (795) Google Scholar, 23Fletcher D.A. Mullins R.D. Cell mechanics and the cytoskeleton.Nature. 2010; 463: 485-492Crossref PubMed Scopus (1763) Google Scholar, 28Tojkander S. Gateva G. Lappalainen P. Actin stress fibers--assembly, dynamics and biological roles.J. Cell Sci. 2012; 125: 1855-1864Crossref PubMed Scopus (568) Google Scholar]. The organization of actin filaments modulates the contractile response of a network. For example, branched networks are less contractile than bundles of anti-parallel filaments [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar]. Here, we investigate the factors that govern the coupling between filament spatial arrangement and the degree of crosslinking in the regulation of actomyosin contraction. We evaluated the contractile response of various in vitro reconstituted actin structures, that are branched or not, and in which filaments are either of mixed polarity, or prominently antiparallel (Figure 1). To obtain such diversity in actin architecture, we used surface micropatterning to initiate geometrically controlled actin assembly over 70-μm-wide rings [26Reymann A.-C. Martiel J.-L. Cambier T. Blanchoin L. Boujemaa-Paterski R. Théry M. Nucleation geometry governs ordered actin networks structures.Nat. Mater. 2010; 9: 827-832Crossref PubMed Scopus (102) Google Scholar]. In this assay, well-defined surfaces coated with Actin Promoting Factor (NPF) trigger actin assembly in a reaction chamber containing a mixture of proteins including the Arp2/3 complex, actin, and profilin. Throughout this study, we varied the architecture and biochemical composition of the overall ring-like network. The perimeter was used as a simple and global readout of contractility (Figure 1). We generated rings made of three different architectures (Figure 1A) that span the diversity of cellular contractile structures: (1) disordered branched networks (named: disordered networks) mimicking lamella-like structures were assembled from a full ring coated with NPF (Figure 1A, left panel); (2) a series of interconnected, ordered, antiparallel actin bundles (named: ordered bundles), mimicking sarcomeric-like bundles, were generated by a dotted ring where only the dots were coated with NPF (Figure 1A, middle panel); and (3) disordered, mixed polarity actin bundles (named: disordered bundles), mimicking cytokinesis ring-like bundles, were generated by debranching the disordered branched meshwork described above by addition of ADF/cofilin (Figures 1A, right panel, and S1; Movie S1 [for the illustration of ADF/cofilin debranching activity]). The deformation of these actin networks was triggered by the presence of double-headed (heavy-meromyosin (HMM)-like) myosin VI in the reaction mixture. Myosin VI-HMM [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar] is a pointed-end directed processive molecular motor [29Wells A.L. Lin A.W. Chen L.Q. Safer D. Cain S.M. Hasson T. Carragher B.O. Milligan R.A. Sweeney H.L. Myosin VI is an actin-based motor that moves backwards.Nature. 1999; 401: 505-508Crossref PubMed Scopus (554) Google Scholar]. Unlike myosin II, it can trigger continuous contraction and/or filament sliding (Movie S2) without the need to assemble into minifilaments. To generate significant force, myosin VI-HMM must tether two neighboring filaments and slide them with respect to one another (Movie S2). Of course, myosin VI-HMM could stay on a single actin filament for most of the time and act on separate filaments for a small fraction of total stepping events. Thus, using myosin VI-HMM has the advantage that it yields in unprecedented reproducibility of the contractile response, unlike myosin II-based minifilaments, which often vary in length when reconstituted in vitro [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar]. The contraction of actin rings by myosins follows three phases [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar]: an initial phase corresponding to actin assembly and reorganization by myosins, a second phase characterized by a constant and often fast rate of contraction, and a final phase where actin is slowly compacted at the center of the ring. We measured the contraction rate during the second phase, to quantify the contractile behavior of all systems. This readout was highly reproducible across experiments. Two types of rings contracted: the rings made of disordered branched networks and the rings made of ordered antiparallel bundles (Figure 1B, top and middle rows). Consistent with previous observations [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar], the rings made of ordered antiparallel bundles contract faster than the ones made of branched networks (Figure 1C, cf. green and red curves; Movie S3, cf. top row, left and middle rings). In contrast, the third type of rings, corresponding to disordered bundles, deforms very little over time (Figures 1B, bottom row, and 1C, blue curve; Movie S3, top row, right ring). To understand how different actin architectures respond to myosin-induced contraction, we performed detailed simulations of the different types of actin rings—disordered network, disordered and ordered bundles using Cytosim (Figures 2A and S2A; Movie S4; [30Nedelec F. Foethke D. Collective Langevin dynamics of flexible cytoskeletal fibers.New J. Phys. 2007; 9: 427Crossref Scopus (148) Google Scholar, 31Letort G. Politi A.Z. Ennomani H. Théry M. Nedelec F. Blanchoin L. Geometrical and mechanical properties control actin filament organization.PLoS Comput. Biol. 2015; 11: e1004245Crossref PubMed Scopus (23) Google Scholar]). We implemented our simulation with entities mimicking molecular motors with properties similar to myosin VI (Figures 2A and S2B). Thereby, we could reproduce in silico the diversity of contractile response for various actin architectures (Figures 2A and S2A; Movie S4, left panel, top row) and track individual actin filaments during ring evolution (Movie S4, left panel, bottom row). Disordered bundles do not contract but are nevertheless dynamic. Filaments in them slide with respect to one another (Figure 2A; Movie S4, left panel, bottom row, right ring), leading to local polarity sorting (see Movie S5 for an illustration of this mechanism), suggesting that myosin-produced forces are not transduced into contractile dipoles in this structure. In contrast, inter-connected filaments in disordered network and ordered bundles directly lead to whole-ring contraction (Movie S4, left panel, left and middle rings). The variation of the ring perimeter over time in our simulation was qualitatively similar than in the experiments, in that rings of ordered bundles contract faster than rings of disordered networks and rings made of disordered bundles did not contract (Figure 2B). Three major mechanisms have been proposed to explain the macroscopic network contraction from the microscopic details: (1) a “sarcomeric-like mechanisms” where the distribution of the crosslinkers and motors are polarized along the actin filaments (see Movie S5 for an illustration of this mechanism and [16Kruse K. Jülicher F. Actively contracting bundles of polar filaments.Phys. Rev. Lett. 2000; 85: 1778-1781Crossref PubMed Scopus (156) Google Scholar]); (2) a “buckling mechanisms” where contraction arises after actin filament mechanical deformation generated by motor contraction see Movie S5 for an illustration of this mechanism and [20Lenz M. Thoresen T. Gardel M.L. Dinner A.R. Contractile units in disordered actomyosin bundles arise from F-actin buckling.Phys. Rev. Lett. 2012; 108: 238107Crossref PubMed Scopus (105) Google Scholar]; and (3) a more recent “dynamic mechanism” where contraction emerge by the combined effect of actin turnover and crosslinking [19Oelz D.B. Rubinstein B.Y. Mogilner A. A Combination of Actin Treadmilling and Cross-Linking Drives Contraction of Random Actomyosin Arrays.Biophys. J. 2015; 109: 1818-1829Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. Since our simulations do not need to include actin turnover to obtain macroscopic deformation, we focused on the first two mechanisms. We do not expect major turnover in the experimental conditions, but, since high myosin concentration can induce actin disassembly [6Reymann A.-C. Boujemaa-Paterski R. Martiel J.-L. Guérin C. Cao W. Chin H.F. De La Cruz E.M. Théry M. Blanchoin L. Actin network architecture can determine myosin motor activity.Science. 2012; 336: 1310-1314Crossref PubMed Scopus (230) Google Scholar, 32Haviv L. Gillo D. Backouche F. Bernheim-Groswasser A. A cytoskeletal demolition worker: myosin II acts as an actin depolymerization agent.J. Mol. Biol. 2008; 375: 325-330Crossref PubMed Scopus (132) Google Scholar], it will be interesting to investigate in the future if in these conditions the dynamic model would contribute to global deformation. To discriminate between sarcomeric-like and buckling models during ring contraction, we tested the effect of the polymer rigidity (Figure 2C). Indeed, increasing polymer rigidity should have a minimum impact if ring contraction is dominated by a sarcomeric-like model, where a high polymer rigidity should inhibit contraction driven by buckling. Our simulation revealed that polymer with infinite rigidity (Lp = ∞) support similar ring contraction than polymer with a Lp = 15 μm (cf. Figures 2B and 2C). This suggests that in these conditions ring contraction for the disordered networks and ordered bundles is mainly driven by a sarcomeric-like mechanism. This was further confirmed by the low degree of filament buckling during ring contraction in our simulations (Figure 2D). Other parameters such as motor binding range, actin filament lengths, ring perimeters, and number of myosins can also affect the contractile response but not the qualitative behavior of the different architectures (Figure S3). Filament inter-connection in cells is achieved with the help of crosslinking proteins such as α-actinin, fascin, and filamin [33Ahmed W.W. Betz T. Dynamic cross-links tune the solid-fluid behavior of living cells.Proc. Natl. Acad. Sci. USA. 2015; 112: 6527-6528Crossref PubMed Scopus (12) Google Scholar]. Strikingly, non-deforming rings comprising disordered fibers become contractile when α-actinin is added (Figures 3A, bottom row, and 3B, blue curve; Movie S3, bottom row, right). In marked contrast, α-actinin impairs the contraction of the other types of rings (Figures 3A, top and middle rows, and 3B, green and red curves; Movie S3, bottom row, left and middle rings). Therefore, the effects of α-actinin on ring deformation depend on their architecture. Ring deformation also depends on the α-actinin concentration (Figure 3C). In our experimental condition with 2 μM actin monomers, the maximal rate of ring contraction of the disordered network (Figure 3C, green curve) was first increased by low concentration (3 nM) of α-actinin and then decreased progressively for higher α-actinin concentrations (ranging from 5 to 30 nM) displaying undetectable deformation at high α-actinin concentration (>30 nM) over the timescale of our measurements. Increasing the concentration of α-actinin (Figure 3C, red curve) progressively lowered the maximal deformation rate of ordered bundles. At high concentrations (>30 nM), α-actinin blocked the deformation of all types of actin architectures. The complex effect of α-actinin on the rate of myosin-induced contraction in different actin architectures suggests that both the filament organization and their physical interaction are key parameters governing the contractile response. Unfortunately, these parameters cannot be measured experimentally. We could, however, use numerical simulation to study how the amount of crosslinkers and branches affect actomyosin contraction. To the simulations containing myosin entities, we added structural elements connecting two actin filaments thereby representing the contribution of α-actinin to the system (Figures 4A and S2B, bottom panel). We then calculated the maximal contraction velocity as a function of the crosslinker number for the three types of ring architectures (Figure 4B). The number of crosslinkers in our simulations ranged from 0 to 6,000, corresponding at most to one crosslinker every 320 nm along filaments, on average. This range is similar to that in our experimental conditions. The contraction rate of the disordered networks, ordered bundles, and disordered bundles (respectively, green, red, and blue; Figure 4B) were qualitatively similar to those obtained experimentally (Figure 3C), indicating that our simulations had reliably modeled the role of filament crosslinkers on the various actin architectures. To establish the preferred ring contraction mechanism of α-actinin crosslinked networks, we evaluated how the maximal velocity depends on the filament rigidity and crosslinker density (Figure 4C). In contrast to the behavior observed in the absence of crosslinker, the filament rigidity has a major impact of the maximal velocity (cf. Figure 4C, curve Lp∼15 μm and Lp∼∞). Indeed, the maximal velocity of networks comprising filaments with infinite rigidity drop rapidly with the concentration of crosslinkers, for both disordered networks and ordered bundles (cf. to Lp∼15 μm). This shows that buckling is required to allow contraction and suggests that the buckling mechanism is at play under crosslinked conditions. The difference between the curves (Lp∼15 μm and Lp∼∞) of maximal velocity versus number of crosslinkers illustrated by the dotted curve readily illustrates the rigidity and buckling contributions to contraction (Figure 4C). Contraction of disordered networks and ordered bundles at low crosslinker density is dominated by the sarcomeric-like mechanism. The contribution of buckling to the contraction increased with the crosslinker density and became the main contraction mechanism at intermediate crosslinker concentrations. High concentrations of crosslinkers inhibit filament buckling and therefore reduce the maximal velocity of ring contraction (Figure 4C). For the disordered bundles configuration, the situation is different since its native architecture lacks connection. Therefore, the mechanism driven by myosin switches from polarity sorting at low crosslinker concentrations to buckling at a number of crosslinkers higher than 2,000. High numbers of crosslinkers also inhibit buckling of disordered bundles, and, as a result, ring contraction. To further validate the contribution of the buckling during ring contraction, we measured the maximal filament curvature as a function of the number of crosslinkers for the three different actin organization (Figure 4D). In agreement with our above statement, the maximum curvature of the filament increases for the three type of actin organization as a function of the number of crosslinkers to reach a maximum and then decreases at high number of crosslinkers. Both crosslinkers and branches act as filaments connectors [11Bendix P.M. Koenderink G.H. Cuvelier D. Dogic Z. Koeleman B.N. Brieher W.M. Field C.M. Mahadevan L. Weitz D.A. A quantitative analysis of contractility in active cytoskeletal protein networks.Biophys. J. 2008; 94: 3126-3136Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 34Wang S. Wolynes P.G. Tensegrity and motor-driven effective interactions in a model cytoskeleton.J. Chem. Phys. 2012; 136: 145102Crossref PubMed Scopus (29) Google Scholar]. We then estimated the global degree of “connectivity,” defined as the average number of connectors per actin filament (Figure 5A, generated by the Arp2/3 complex at branched point and by the bridge made by α-actinin between two filaments). By plotting the contraction velocity with respect to the connectivity for the different actin organizations (Figure 5B), we found that they all reach a maximum centered on an optimal connectivity comprised betw" @default.
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• W2283643310 title "Architecture and Connectivity Govern Actin Network Contractility" @default.
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