Actin Mechanics and Fragmentation
2015; Elsevier BV; Volume: 290; Issue: 28 Linguagem: Inglês
10.1074/jbc.r115.636472
ISSN1083-351X
AutoresEnrique M. De La Cruz, Margaret L. Gardel,
Tópico(s)Biocrusts and Microbial Ecology
ResumoCell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent advances in understanding the mechanical properties and stability of actin filaments and how these properties are manifested at larger (network) length scales. We discuss how forces can influence local biochemical interactions, resulting in the formation of mechanically sensitive dynamic steady states. Understanding the regulation of such force-activated chemistries and dynamic steady states reflects an important challenge for future work that will provide valuable insights as to how the actin cytoskeleton engenders mechanoresponsiveness of living cells. Cell physiological processes require the regulation and coordination of both mechanical and dynamical properties of the actin cytoskeleton. Here we review recent advances in understanding the mechanical properties and stability of actin filaments and how these properties are manifested at larger (network) length scales. We discuss how forces can influence local biochemical interactions, resulting in the formation of mechanically sensitive dynamic steady states. Understanding the regulation of such force-activated chemistries and dynamic steady states reflects an important challenge for future work that will provide valuable insights as to how the actin cytoskeleton engenders mechanoresponsiveness of living cells. The non-covalent polymerization of the cytoskeleton protein actin (Fig. 1) into linear filaments powers a variety of non-muscle cell movements underlying their migration, division, and assembly into multicellular tissue (1Blanchoin L. Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (860) Google Scholar). Cross-linking proteins arrange filaments into higher-order assemblies such as parallel bundles of filopodia and microvilli, isotropic networks of the cortex, and contractile bundles in the lamella that provide cells with mechanical integrity, sensing, and shape (2Gardel M.L. Schneider I.C. Aratyn-Schaus Y. Waterman C.M. Mechanical integration of actin and adhesion dynamics in cell migration.Annu. Rev. Cell Dev. Biol. 2010; 26: 315-333Crossref PubMed Scopus (686) Google Scholar, 3Parsons J.T. Horwitz A.R. Schwartz M.A. Cell adhesion: integrating cytoskeletal dynamics and cellular tension.Nat. Rev. Mol. Cell Biol. 2010; 11: 633-643Crossref PubMed Scopus (1446) Google Scholar4Schwarz U.S. Gardel M.L. United we stand: integrating the actin cytoskeleton and cell-matrix adhesions in cellular mechanotransduction.J. Cell Sci. 2012; 125: 3051-3060Crossref PubMed Scopus (270) Google Scholar). 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Boujemaa-Paterski R. Sykes C. Plastino J. Actin dynamics, architecture, and mechanics in cell motility.Physiol. Rev. 2014; 94: 235-263Crossref PubMed Scopus (860) Google Scholar). Severing and contractile proteins fragment actin filaments and accelerate actin turnover in cells and in reconstituted biomimetic systems (6Abu Shah E. Keren K. Symmetry breaking in reconstituted actin cortices.eLife. 2014; 3: e01433Crossref PubMed Google Scholar7Haviv 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 (136) Google Scholar, 8Medeiros N.A. Burnette D.T. Forscher P. Myosin II functions in actin-bundle turnover in neuronal growth cones.Nat. Cell Biol. 2006; 8: 215-226Crossref PubMed Scopus (386) Google Scholar, 9Murrell M.P. Gardel M.L. F-actin buckling coordinates contractility and severing in a biomimetic actomyosin cortex.Proc. Natl. Acad. Sci. 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Actins are single polypeptide chain proteins (∼375 amino acids with an ∼42-kDa molecular mass) folded into a U-shaped structure containing four subdomains (SD1–4) with a bound adenine nucleotide, either ATP, ADP-Pi, or ADP, and an associated divalent cation, Mg2+ in cells, bound within the cleft separating subdomains 1–2 and 3–4 (Fig. 2A). Actin filaments are commonly described as either a one-start, left-handed helix of subunits with a 2.77-nm rise per subunit (13Moore P.B. Huxley H.E. DeRosier D.J. Three-dimensional reconstruction of F-actin, thin filaments and decorated thin filaments.J. Mol. Biol. 1970; 50: 279-295Crossref PubMed Scopus (407) Google Scholar) or a two-start, right-handed helix with half-staggered filament strands displaying an ∼72-nm repeat (14Pollard T.D. Earnshaw W.C. Lippincott-Schwartz J. Cell Biology. Elsevier Health Sciences, 2007Google Scholar). However, filaments in solution adopt multiple distinct structural states (referred to as "structural polymorphism"(15Galkin V.E. Orlova A. Schröder G.F. Egelman E.H. Structural polymorphism in F-actin.Nat. Struct. Mol. Biol. 2010; 17: 1318-1323Crossref PubMed Scopus (150) Google Scholar)) with variable twist and subunit tilt distributions that are influenced by regulatory protein occupancy and external forces. Thus, one actually refers to a subset of populated states when describing actin structure. Polymerization is associated with a conformational change in actin, such that incorporated filament subunits appear "flattened" when compared with free monomers (16Fujii T. Iwane A.H. Yanagida T. Namba K. Direct visualization of secondary structures of F-actin by electron cryomicroscopy.Nature. 2010; 467: 724-728Crossref PubMed Scopus (290) Google Scholar, 17Oda T. Iwasa M. Aihara T. Maéda Y. Narita A. The nature of the globular- to fibrous-actin transition.Nature. 2009; 457: 441-445Crossref PubMed Scopus (475) Google Scholar). Extensive intersubunit contacts stabilize filaments (16Fujii T. Iwane A.H. Yanagida T. Namba K. Direct visualization of secondary structures of F-actin by electron cryomicroscopy.Nature. 2010; 467: 724-728Crossref PubMed Scopus (290) Google Scholar, 17Oda T. Iwasa M. Aihara T. Maéda Y. Narita A. The nature of the globular- to fibrous-actin transition.Nature. 2009; 457: 441-445Crossref PubMed Scopus (475) Google Scholar18Kang H. Bradley M.J. Elam W.A. De La Cruz E.M. Regulation of actin by ion-linked equilibria.Biophys. J. 2013; 105: 2621-2628Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), and an individual subunit contacts four neighboring actin molecules (Fig. 2A). Longitudinal contacts within a strand are thought to be stronger than lateral contacts across the strands (19Sept D. McCammon J.A. Thermodynamics and kinetics of actin filament nucleation.Biophys. J. 2001; 81: 667-674Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The DNase I binding loop (residues 36–52 of SD2; Fig. 2A) adopts a variety of conformations (20Orlova A. Egelman E. A conformational change in the actin subunit can change the flexibility of the actin filament.J. Mol. Biol. 1993; 232: 334-341Crossref PubMed Scopus (175) Google Scholar), some of which make important long-axis, intersubunit contacts, and plays a central role in regulating actin filament structure and mechanical properties (21Chu J.-W. Voth G.A. Coarse-grained modeling of the actin filament derived from atomistic-scale simulations.Biophys. J. 2006; 90: 1572-1582Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 22Pfaendtner J. Lyman E. Pollard T.D. Voth G.A. Structure and dynamics of the actin filament.J. Mol. Biol. 2010; 396: 252-263Crossref PubMed Scopus (73) Google Scholar). Actin filaments are polymers with lengths ranging up to >10 μm in solution (23Howard J. Mechanics of Motor Proteins and the Cytoskeleton. Sinauer Associates, Sunderland, Massachusetts2001Google Scholar) (Fig. 2B). The local asymmetry arising from the ribbon structure averages out to a diameter of ∼6 nm on the length scales associated with analysis of individual filament and network mechanics. How filaments deform in response to force is governed by their mechanical elastic properties. Recent biochemical, biophysical, and computational studies have revealed the molecular and geometric origins of actin filament mechanical properties and how solution conditions, particularly cations, influence them. Bending, torsional, and twist-bend coupling elasticities dominate individual actin filament mechanical properties. The flexural, or bending, rigidity as well as the extent of deformation determine the energy required to bend a filament segment of a certain length. Likewise, the energy require to twist a filament is determined by the twisting rigidity and the torsional angle that overwinds or unwinds the filament. Twist-bend coupling represents an obligatory coupling between bending and twisting motions, such that filament bending introduces twist and vice versa (24De La Cruz E.M. Roland J. McCullough B.R. Blanchoin L. Martiel J.-L. Origin of twist-bend coupling in actin filaments.Biophys. J. 2010; 99: 1852-1860Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 25Yogurtcu O.N. Kim J.S. Sun S.X. A mechanochemical model of actin filaments.Biophys. J. 2012; 103: 719-727Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar) (Fig. 2C). Actin filaments are rather resistant to stretching (26Higuchi H. Yanagida T. Goldman Y.E. Compliance of thin filaments in skinned fibers of rabbit skeletal muscle.Biophys. J. 1995; 69: 1000-1010Abstract Full Text PDF PubMed Scopus (199) Google Scholar). 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J. 1995; 68: 1231-1245Abstract Full Text PDF PubMed Scopus (59) Google Scholar) presumably play a role in overall filament mechanics. However, mathematical and computational models that treat filament subunits as incompressible entities capture the reported mechanical parameters with reasonable accuracy (24De La Cruz E.M. Roland J. McCullough B.R. Blanchoin L. Martiel J.-L. Origin of twist-bend coupling in actin filaments.Biophys. J. 2010; 99: 1852-1860Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 25Yogurtcu O.N. Kim J.S. Sun S.X. A mechanochemical model of actin filaments.Biophys. J. 2012; 103: 719-727Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Filaments twist more easily than they bend, which manifests itself as a larger bending than torsional rigidity. Solution cations bind and stiffen some, but not all (e.g. Saccharomyces cerevisiae), actin filaments (20Orlova A. Egelman E. A conformational change in the actin subunit can change the flexibility of the actin filament.J. Mol. Biol. 1993; 232: 334-341Crossref PubMed Scopus (175) Google Scholar, 30Kang H. Bradley M.J. McCullough B.R. Pierre A. Grintsevich E.E. Reisler E. De La Cruz E.M. Identification of cation-binding sites on actin that drive polymerization and modulate bending stiffness.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 16923-16927Crossref PubMed Scopus (71) Google Scholar). Substitution of a single amino acid residue positioned between adjacent, long-axis filament subunits confers S. cerevisiae actin filaments with salt-dependent bending stiffness (30Kang H. Bradley M.J. McCullough B.R. Pierre A. Grintsevich E.E. Reisler E. De La Cruz E.M. Identification of cation-binding sites on actin that drive polymerization and modulate bending stiffness.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 16923-16927Crossref PubMed Scopus (71) Google Scholar). The filament bending stiffness (i.e. flexural rigidity, κ) is equal to the product of the shape-independent stiffness of the protein material (i.e. apparent Young's modulus, Eapp; referred to as apparent because proteins are not homogenous isotropic materials) and the shape-dependent second moment of area (I), which is determined by the strength and distribution of intersubunit contacts. Filaments possessing this "stiffness cation site" display salt-dependent structure and intersubunit contacts, suggesting that stiffness cations may exert their effects on filament mechanics by binding to discrete sites at subunit interfaces and altering the radial distribution (I) and/or the strength (Eapp) of the intersubunit contacts (18Kang H. Bradley M.J. Elam W.A. De La Cruz E.M. Regulation of actin by ion-linked equilibria.Biophys. J. 2013; 105: 2621-2628Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). A mechanism in which cations bind at distal sites and allosterically alter intersubunit contacts is also plausible (31Kang H. Bradley M.J. Cao W. Zhou K. Grintsevich E.E. Michelot A. Sindelar C.V. Hochstrasser M. De La Cruz E.M. Site-specific cation release drives actin filament severing by vertebrate cofilin.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 17821-17826Crossref PubMed Scopus (35) Google Scholar). The DNase I binding loop of SD2 participates in longitudinal intersubunit contacts, plays a central role in modulating the filament bending stiffness and displays salt-dependent conformations, making it an attractive structural element for linking salt-dependent filament structure and mechanics. Changes in filament stiffness can also arise from side binding proteins. For example, tropomyosin stiffens actin filaments by increasing its geometric movement (32Kojima H. Ishijima A. Yanagida T. Direct measurement of stiffness of single actin filaments with and without tropomyosin by in vitro nanomanipulation.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 12962-12966Crossref PubMed Scopus (429) Google Scholar). Mechanically strained filaments (e.g. deformed in bending and/or twisting) store elastic free energy in their shape. The stored energy density depends on the deformation amplitude and the bending rigidity; larger deformations store more energy than small ones, and stiff filaments store more energy than compliant ones at identical deformations. Relaxation back to the straight conformation can potentially be used to generate work and/or force. Alternatively, the deformation amplitude and stored energy can reach the point of irreversibility, causing the filament to fragment. Thermal energy (kBT, where kB is Boltzmann's constant and T is temperature in Kelvin) can be sufficiently large to induce actin filament shape fluctuations. The filament length at which the deformation energy compares to thermal energy defines the persistence length, which can be defined for bending (LB), twisting (LT), and twist-bend coupling (LTB) deformations (Fig. 2D). Filaments behave as rigid rods at lengths much shorter than the persistence length, as flexible polymers much larger than the persistence length, and as semi-flexible polymers at lengths comparable with the persistence length (33Graham J.S. McCullough B.R. Kang H. Elam W.A. Cao W. De La Cruz E.M. Multi-platform compatible software for analysis of polymer bending mechanics.PLoS One. 2014; 9: e94766Crossref PubMed Scopus (0) Google Scholar). The bending fluctuations reduce the filament end-to-end length, and the force required to extend and "straighten" the filament is determined by the energy required to reduce the bending fluctuation amplitude. This entropic spring constant is both highly sensitive to the length of filament segment and becomes highly nonlinear as the end-to-end length approaches the full polymer contour length (34Bustamante C. Marko J.F. Siggia E.D. Smith S. Entropic elasticity of lambda-phage DNA.Science. 1994; 265: 1599-1600Crossref PubMed Scopus (1859) Google Scholar) (Fig. 3). Compressive forces tend to excite the longest wavelength (softest) bending mode, which is comparable with kBT for micrometer length filaments. At a critical compressive force, referred to as critical or Euler force, buckling will occur. The critical force scales linearly with filament bending rigidity and inversely with the square of the filament length (e.g. it takes four times less force to buckle a 2-μm filament than a 1-μm one with identical bending rigidity) (35Phillips R. Kondev J. Theriot J.A. Physical Biology of the Cell. Garland Science, London2008Google Scholar). This different response to extension and compression gives filaments a highly asymmetric force extension curve (Fig. 3) that can be approximated in coarse-grained models as cables (36Bischofs I.B. Klein F. Lehnert D. Bastmeyer M. Schwarz U.S. Filamentous network mechanics and active contractility determine cell and tissue shape.Biophys. J. 2008; 95: 3488-3496Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar) and is a powerful mechanism by which actin networks can sense (and respond) to different types of stresses (9Murrell M.P. Gardel M.L. F-actin buckling coordinates contractility and severing in a biomimetic actomyosin cortex.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 20820-20825Crossref PubMed Scopus (272) Google Scholar). Cross-linking proteins organize filaments into parallel (or antiparallel) bundles. The mechanical parameters (twist, bend, and extension) of bundles depend on the width of the bundle and length of the filaments comprising them, as well as the density, mechanics, affinity, and exchange kinetics of the cross-links. For instance, filaments in bundles formed with a compliant cross-linker (e.g. plastin) can readily slide past each and are weakly coupled such that the bundle stiffness increases linearly with the number of actin filaments (37Bathe M. Heussinger C. Claessens M.M. Bausch A.R. Frey E. Cytoskeletal bundle mechanics.Biophys. J. 2008; 94: 2955-2964Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). By contrast, when filaments become tightly coupled to each other by use of crowding agents or high density of compact cross-linker (e.g. fascin), the bundles act as single unit that displays a bending persistence length that scales quadratically with the number of filaments in the bundle (23Howard J. Mechanics of Motor Proteins and the Cytoskeleton. 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Cytoskeletal bundle mechanics.Biophys. J. 2008; 94: 2955-2964Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 39Strehle D. Schnauss J. Heussinger C. Alvarado J. Bathe M. Käs J. Gentry B. Transiently crosslinked F-actin bundles.Eur. Biophys. J. 2011; 40: 93-101Crossref PubMed Scopus (46) Google Scholar). Fragmentation by severing and contractile motor proteins accelerates actin network turnover and assembly dynamics by increasing the concentration of filament ends where subunits can add and dissociate. As described above, compressive stresses buckle filaments. However, filaments under compressive loads do not deform indefinitely. Rather, they buckle and bend until they reach a deformation curvature where the stored elastic energy exceeds that holding the subunits together and it becomes energetically more favorable for the filament to fragment than remain intact (40De La Cruz E.M. Martiel J.-L. Blanchoin L. Mechanical heterogeneity favors fragmentation of strained actin filaments.Biophys. J. 2015; 108: 2270-2281Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Estimating this stored energy and force requires that all elastic contributions be considered (e.g. bending, twisting, and coupling) because they all contribute to the local energy density that eventually causes filament subunit interface "bonds" to rupture (40De La Cruz E.M. Martiel J.-L. Blanchoin L. Mechanical heterogeneity favors fragmentation of strained actin filaments.Biophys. J. 2015; 108: 2270-2281Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Several classes of regulatory filament-severing proteins have been identified (14Pollard T.D. Earnshaw W.C. Lippincott-Schwartz J. Cell Biology. Elsevier Health Sciences, 2007Google Scholar). Gelsolin and ADF 3The abbreviations used are: ADFactin depolymerizing factorAip1actin-interacting protein 1pNpiconewtons. /cofilin family members have been characterized most extensively at the biochemical and biophysical level with purified components (14Pollard T.D. Earnshaw W.C. Lippincott-Schwartz J. Cell Biology. Elsevier Health Sciences, 2007Google Scholar). Gelsolin severs filaments by inserting one of its structural domains between long axis filament subunits, compromising stabilizing intersubunit interactions and promoting fragmentation. Formin INF2 may sever filaments by an analogous insertion, or "wedging," mechanism (41Gurel P.S. Ge P. Grintsevich E.E. Shu R. Blanchoin L. Zhou Z.H. Reisler E. Higgs H.N. INF2-mediated severing through actin filament encirclement and disruption.Curr. Biol. 2014; 24: 156-164Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). actin depolymerizing factor actin-interacting protein 1 piconewtons. The filament-severing mechanism of ADF/cofilin (heretofore referred to as cofilin) appears to be distinct from that of gelsolin and INF2. Cofilin isoforms within and across organisms and species are not identical, and often the observed biochemical activities depend on the isoform and conspecific nature of the actin (42Blanchoin L. Pollard T.D. Mechanism of interaction of Acanthamoeba actophorin (ADF/Cofilin) with actin filaments.J. Biol. Chem. 1999; 274: 15538-15546Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 43De La Cruz E.M. Cofilin binding to muscle and non-muscle actin filaments: isoform-dependent cooperative interactions.J. Mol. Biol. 2005; 346: 557-564Crossref PubMed Scopus (124) Google Scholar), indicating that the chemical and physical properties of actin itself can influence cofilin function. Cofilins bind weakly to "young" ATP- and ADP-Pi actin filaments and bind orders of magnitude more strongly to "old" ADP-actin filaments (42Blanchoin L. 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Guérin C. Martiel J.-L. De La Cruz E.M. Blanchoin L. Cofilin tunes the nucleotide state of actin filaments and severs at bare and decorated segment boundaries.Curr. Biol. 2011; 21: 862-868Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar), explaining why the severing activity peaks when filaments are partially decorated (31Kang H. Bradley M.J. Cao W. Zhou K. Grintsevich E.E. Michelot A. Sindelar C.V. Hochstrasser M. De La Cruz E.M. Site-specific cation release drives actin filament severing by vertebrate cofilin.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 17821-17826Crossref PubMed Scopus (35) Google Scholar, 43De La Cruz E.M. Cofilin binding to muscle and non-muscle actin filaments: isoform-dependent cooperative interactions.J. Mol. Biol. 2005; 346: 557-564Crossref PubMed Scopus (124) Google Scholar, 47Suarez C. Roland J. Boujemaa-Paterski R. Kang H. McCullough B.R. Reymann A.-C. Guérin C. Martiel J.-L. De La Cruz E.M. Blanchoin L. 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Determining the differences in actin binding by human ADF and cofilin.J. Mol. Biol. 2002; 315: 911-925Crossref PubMed Scopus (128) Google Scholar). Multiple factors likely influence the severing activity of ADF/cofilin, and the contributions of some have yet to be fully resolved. Cofilin alters filament twist (52McGough A. Pope B. Chiu W. Weeds A. Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function.J. Cell Biol. 1997; 138: 771-781Crossref PubMed Scopus (593) Google Scholar) and subunit tilt (53Galkin V.E. Orlova A. Kudryashov D.S. Solodukhin A. Reisler E. Schröder G.F. Egelman E.H. Remodeling of actin filaments by ADF/cofilin proteins.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 20568-20572Crossref PubMed Scopus (166) Google Scholar), renders filaments more compliant in bending (54McCullough B.R. Blanchoin L. Martiel J.-L. De La Cruz E.M. 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