Models of Thin-Filament Regulation

  • David Aitchison Smith


While the strength of contraction in our muscles is activated by the frequency of action potentials in its efferent nerves, this chapter is concerned with the way in which calcium ions released by the transverse-tubule system regulate contraction via the thin filament. Each strand of the actin double helix is regulated by overlapping tropomyosin-troponin units, and theories of thin-filament Ca2+-regulation have evolved from seven-site regulation by independent Tm-Tn units switching between two states (the original steric blocking model) or three states (blocked, closed and open), to models with end-to-end Tm interactions. Recent structural studies point to an alternative model in which Tm-Tn protomers join to form a continuous flexible chain (CFC). This chapter presents a quantitative version of the chain model, in which myosin binding in the absence of calcium is blocked by TnI bound to actin. Calcium binding to TnC releases TnI, which allows the chain to make angular Brownian fluctuations about the closed state, from which myosin binding pushes the chain out to a local open state. These models have been tested by solution experiments.


Regulated actin Tropomyosin Troponin Blocking Chain model 


  1. Bacchiocchi C, Graceffa P, Lehrer SS (2004) Myosin-induced movement of αα, αβ, and ββ smooth muscle tropomyosin on actin observed by multisite FRET. Biophys J 86:2295–2307CrossRefGoogle Scholar
  2. Bremel RD, Weber A (1972) Cooperation within actin filament in vertebrate skeletal muscle. Nat New Biol 238:97–101CrossRefGoogle Scholar
  3. Bremel RD, Murray JM, Weber A (1972) Manifestations of cooperative behaviour in the regulated actin filament during actin-activated ATP hydrolysis in the presence of calcium. Cold Spring Harb Symp Quant Biol 37:267–275CrossRefGoogle Scholar
  4. Brenner B, Schoenberg M, Chalovich JM, Greene LE, Eisenberg E (1982) Evidence for cross-bridge attachment in relaxed muscle at low ionic strength. Proc Natl Acad Sci USA 79:7288–7291CrossRefGoogle Scholar
  5. Chalovich JM, Eisenberg E (1982) Inhibition of actomyosin ATPase activity by troponin-tropomyosin without blocking the binding of myosin to actin. J Biol Chem 257:2432–2437PubMedPubMedCentralGoogle Scholar
  6. Chen Y, Yan B, Chalovich JM, Brenner B (2001) Theoretical kinetic studies of models for binding myosin subfragment-1 to regulated actin: hill model versus Geeves model. Biophys J 80:2338–2349CrossRefGoogle Scholar
  7. Doi M, Edwards SF (1988) The theory of polymer dynamics. Oxford University Press, OxfordGoogle Scholar
  8. Dominguez R (2011) Tropomyosin; the gatekeeper’s view of the actin filament revealed. Biophys J 100:797–798CrossRefGoogle Scholar
  9. Dong W-J, Rosenfeld SS, Wang C-K, Gordon AM, Cheung HC (1996) Kinetic studies of calcium binding to the regulatory site of troponin C from cardiac muscle. J Biol Chem 271:688–694CrossRefGoogle Scholar
  10. Ebashi S (1963) Third component participating in the superprecipitation of ‘natural actomyosin’. Nature 200:1010CrossRefGoogle Scholar
  11. Feynman RP, Hibbs AR (1965) Quantum mechanics and path integrals. McGraw Hill, New York/London, reprinted Dover Inc. (2005)Google Scholar
  12. Frye J, Klenchin VA, Rayment I (2010) Stucture of the tropomyosin overlap complex from chicken smooth muscle: insight into the diversity of N-terminal recognition. Biochemistry 48:1272–1283Google Scholar
  13. Geeves MA (1991) The dynamics of actin and myosin association and the crossbridge model of muscle contraction. Biochem J 274:1–14CrossRefGoogle Scholar
  14. Geeves MA (2016) Thin filament regulation. Comprehensive biophys. In: Goldman YE, Ostap EM (eds) Molecular motors and motility, vol 4. Elsevier Press, Amsterdam, pp 251–267Google Scholar
  15. Geeves MA, Halsall DJ (1987) Two-step ligand binding and cooperativity: a model to describe the cooperative binding of myosin subfragment 1 to regulated actin. Biophys J 52:215–220CrossRefGoogle Scholar
  16. Geeves MA, Lehrer SS (1994) Dynamics of the muscle thin filament regulatory switch: the size of the regulatory unit. Biophys J 67:272–282CrossRefGoogle Scholar
  17. Geeves MA, Lehrer SS (2002) In: Solaro RJ, Moss RL (eds) Molecular control mechanisms in striated muscle contraction. Kluwer, Dordrecht, pp 247–269CrossRefGoogle Scholar
  18. Geeves MA, Griffiths H, Mijailovich S, Smith D (2011) Cooperative [Ca2+]- dependent regulation of the rate of myosin binding to actin: solution data and the tropomyosin chain model. Biophys J 100:1–9CrossRefGoogle Scholar
  19. Gordon AM, Homsher E, Regnier M (2000) Regulation of contraction in striated muscle. Physiol Rev 80:853–924CrossRefGoogle Scholar
  20. Grabarek Z, Grabarek J, Leavis PC, Gergely J (1982) Calcium binding to the Ca2+- specific sites of troponin C in regulated actin and actomyosin. J Biol Chem 258:14098–14102Google Scholar
  21. Greenfield NJ, Kotlyanskaya L, Hitchcock-DeGregori S (2009) Structure of the N terminus of a nonmuscle α-tropomyosin in complex with the C terminus: implications for actin binding. Biochemistry 48:1272–1283CrossRefGoogle Scholar
  22. Haselgrove JC (1972) X-ray evidence for a conformational change in the actin- containing filaments of vertebrate striated muscle. Cold Spring Harb Symp Quant Biol 37:341–352CrossRefGoogle Scholar
  23. Heeley DH, Belknap B, White HD (2006) Maximal activation of skeletal muscle thin filaments requires both rigor myosin S1 and calcium. J Biol Chem 281:668–676CrossRefGoogle Scholar
  24. Herzberg O, James MNG (1985) Structure of the calcium regulatory protein troponin- C at 2.8Å resolution. Nature 313:653–659CrossRefGoogle Scholar
  25. Hill AV (1913) The combinations of haemoglobin with oxygen and with carbon monoxide. I. Biochem J 7:471–480CrossRefGoogle Scholar
  26. Hill TL (1960) Introduction to statistical mechanics. Addison-Wesley, ReadingGoogle Scholar
  27. Hill TL, Eisenberg E, Greene LE (1980) Theoretical model for the cooperative equilibrium binding of myosin subfragment 1 to the actin-troponin-tropomyosin complex. Proc Natl Acad Sci USA 77:3186–3190CrossRefGoogle Scholar
  28. Hitchcock-DeGregori SY, Moraczewska J (2001) Importance of internal regions and the overall length of tropomyosin for actin binding and regulatory function. Biochemistry 40:2104–2112CrossRefGoogle Scholar
  29. Holmes KC, Lehman W (2008) Gestalt binding of tropomyosin to actin filaments. J Muscle Res Cell Motil 29:213–219CrossRefGoogle Scholar
  30. Howard J (2001) Mechanics of motor proteins and the cytoskeleton. Sinauer Assoc. Inc., SunderlandGoogle Scholar
  31. Huxley HE (1972) Structural changes in the actin- and myosin-containing filaments during contraction. Cold Spring Harbor Sympos. Quant Biol 37:361–376CrossRefGoogle Scholar
  32. Johnson JD, Robinson DE, Robertson SP, Schwartz A, Potter JD (1981) In: Grinnell A, Brazier MAB (eds) The regulation of muscle contraction: excitation-contraction coupling. Academic Press, Inc, New York, pp 241–259Google Scholar
  33. Lehman W, Hatch V, Korman M, Rosol M, Thomas L, Maytum R, Geeves MA, van Eyk JE, Tobacman LS, Craig R (2000) Tropomyosin and actin isoforms modulate the localization of tropomyosin strands on actin filaments. J Mol Biol 302:593–606CrossRefGoogle Scholar
  34. Lehman W, Rosol M, Tobacman LS, Craig R (2001) Troponin organization on relaxed and activated thin filaments revealed by electron microscopy and three-dimensional reconstruction. J Mol Biol 307:739–744CrossRefGoogle Scholar
  35. Lehman W, Orzechowksi M, Li XE, Fischer S, Raunser S (2013) Gestalt binding of tropomyosin on actin during thin filament activation. J Muscle Res Cell Motil 34:155–163CrossRefGoogle Scholar
  36. Lehrer SS, Morris EP (1982) Dual effects of tropomyosin and troponin-tropomyosin on actomyosin subfragment 1 ATPase. J Biol Chem 257:8073–8080PubMedGoogle Scholar
  37. Lehrer SS, Golitsina NL, Geeves MA (1997) Actin-tropomyosin activation of myosin subfragment 1 ATPase and thin filament cooperativity. The role of tropomyosin flexibility and end-to-end interaction. Biochemistry 36:13449–13,454CrossRefGoogle Scholar
  38. Li XE, Holmes KC, Lehman W, Jung HS, Fischer S (2010a) The shape and flexibility of tropomyosin coiled coils: implications for actin filament assembly. J Mol Biol 395:327–339CrossRefGoogle Scholar
  39. Li XE, Lehman W, Fischer S, Holmes KC (2010b) Curvature variation along the tropomyosin molecule. J Struct Biol 170:307–312CrossRefGoogle Scholar
  40. Li XE, Lehman W, Fischer S (2010c) The relationship between curvature, flexibility and persistence length in the tropomyosin coiled coil. J Struct Biol 170:313–318CrossRefGoogle Scholar
  41. Li XE, Tobacman LS, Mun JY, Craig R, Fischer S (2011) Tropomyosin position on F-actin revealed by EM reconstruction and computational chemistry. Biophys J 100:1005–1013CrossRefGoogle Scholar
  42. Marko JF, Siggia ED (1995) Stretching DNA. Macromolecules 28:8759–8770CrossRefGoogle Scholar
  43. Maytum R, Lehrer SS, Geeves MA (1999) Cooperativity and switching within the three-state model of muscle regulation. Biochemistry 38:1102–1110CrossRefGoogle Scholar
  44. McKay RT, Saltibus LF, Li X, Sykes BD (2000) Energetics of the induced structural change in a Ca2+ regulatory protein: Ca2+ and troponin I peptide binding to the E41A mutant of the N-domain of skeletal troponin C. Biochemistry 39:12731–12738CrossRefGoogle Scholar
  45. McKillop DFA, Geeves MA (1993) Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys J 65:693–701CrossRefGoogle Scholar
  46. Mijailovich SM, Li X, Griffiths RH, Geeves MA (2012) The Hill model for binding myosin S1 to regulated actin is not equivalent to the McKillop-Geeves model. J Mol Biol 417:112–128CrossRefGoogle Scholar
  47. Monod J, Wyman J, Changeux J-P (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118CrossRefGoogle Scholar
  48. Palm T, Greenfield NJ, Hitchcok-DeGregori SE (2003) Tropomyosin ends determine the stability and functionality of overlap and troponin T complexes. Biophys J 81:3181–3189CrossRefGoogle Scholar
  49. Palmiter KA, Solaro RJ (1997) Molecular mechanisms regulating the myofilament response to Ca2+: Implications of mutations causal for familial cardiac hypertrophy. Basic Res Cardiology 92:63–74CrossRefGoogle Scholar
  50. Perry SV (2001) Vertebrate tropomyosin: distribution, properties and function. J Muscle Res Cell Motil 22:5–49CrossRefGoogle Scholar
  51. Pirani A, Xu C, Hatch V, Craig R, Tobacman LS, Lehman W (2005) Single particle analysis of relaxed and activated muscle thin filaments. J Mol Biol 346:761–772CrossRefGoogle Scholar
  52. Press WH, Teukolsky SA, Vetterling WT, Flannery BR (1992) Numerical Recipes in Fortran, 2nd edn. Cambridge University Press, Cambridge, pp 729–731Google Scholar
  53. Robinson JM, Wang Y, Kerrick GL, Kawai R, Cheung HC (2002) Activation of striated muscle: nearest-neighbour regulatory-unit and cross-bridge influence on myofilament kinetics. J Mol Biol 322:1065–1088CrossRefGoogle Scholar
  54. Ruegg JC (1988) Calcium in muscle activation. Springer, BerlinGoogle Scholar
  55. Singh A, Hitchcock-DeGregori S (2003) Local destabilization of the tropomyosin coiled coil gives the molecular flexibility required for actin binding. Biochemistry 42:14114–14121CrossRefGoogle Scholar
  56. Smith DA (2001) Path-integral theory of an axially confined worm-like chain. J Phys A Math Gen 34:4507–4523CrossRefGoogle Scholar
  57. Smith DA, Geeves MA (2003) Cooperative regulation of myosin-actin interactions by a continuous flexible chain II: actin-tropomyosin-troponin and regulation by calcium. Biophys J 84:3168–3180CrossRefGoogle Scholar
  58. Smith DA, Maytum R, Geeves MA (2003) Cooperative regulation of myosin- actin interactions by a continuous flexible chain I: Actin-tropomyosin systems. Biophys J 84:3155–3167CrossRefGoogle Scholar
  59. Steffen W, Smith D, Sleep J (2003) The working stroke upon myosin-nucleotide complexes binding to actin. Proc Nat Acad Sci USA 100:6434–6439CrossRefGoogle Scholar
  60. Sundaralingam M, Bergstrom R, Strasburg G, Rao ST, Rowchowdhury P, Greaser M, Wang BC (1985) Molecular structure of troponin C from chicken skeletal muscle at 3. angstrom resolution. Science 227:945–948CrossRefGoogle Scholar
  61. Takeda S, Yamashita A, Maeda K, Maeda Y (2003) Structure of the core domain of human cardiac troponin in the Ca2+-saturated form. Nature 424:35–41CrossRefGoogle Scholar
  62. Tobacman LS, Butters CA (2000) A new model of myosin-thin filament binding. J Biol Chem 275:27587–27,593PubMedGoogle Scholar
  63. Trybus KM, Taylor EW (1980) Kinetic studies of the cooperative binding of subfragment 1 to regulated actin. Proc Nat Acad Sci USA 77:7209–7213CrossRefGoogle Scholar
  64. Vassylyev DG, Takeda S, Wakatsuki S, Maeda K, Maeda Y (1998) Crystal structure of troponin C in complex with troponin I fragment at 2.3-Å resolution. Proc Nat Acad Sci USA 95:4847–4852CrossRefGoogle Scholar
  65. Vibert P, Craig R, Lehman W (1997) Steric model for activation of muscle thin filaments. J Mol Biol 266:8–14CrossRefGoogle Scholar
  66. Wegner A (1980) The interaction of α,α- and α,β-tropomyosin with actin filaments. FEBS Lett 119:245–248CrossRefGoogle Scholar
  67. Wiggins C, Riveline D, Ott A, Goldstein RE (1998) Trapping and wiggling: elastohydrodynamics of driven microfilaments. Biophys J 74:1043–1060CrossRefGoogle Scholar
  68. Zou G, Phillips JN Jnr (1994) A cellular automaton model for the regulatory behaviour of muscle thin filaments. Biophys J 67:11–28CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • David Aitchison Smith
    • 1
  1. 1.Department of Physiology, Anatomy and MicrobiologyLa Trobe UniversityMelbourneAustralia

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