Tropomyosin: Regulator of Actin Filaments

  • Sarah E. Hitchcock-DeGregori
  • Norma J. Greenfield
  • Abhishek Singh
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 592)


Cellular movement and function have long been known to depend on the actin cytoskeleton and its regulation. The actin cytoskeleton is the ultimate target of numerous cellular signaling pathways. The first signaling system understood in any detail was that of vertebrate skeletal muscle. Setsuro Ebashi, celebrated by this volume, was a pioneer through his role in showing that the calcium ion is the physiological regulator of muscle contraction followed by his landmark discovery and naming of troponin as the calcium ion receptor that regulates contraction through its interaction with tropomyosin and actin. Early work in the field is summarized in his remarkable 1968 review with M. Endo (Ebashi and Endo, 1968). There they put forth the evidence for a pathway by which activation of the muscle by an action potential would ultimately result in a contractile response consequent to the binding of calcium ion released from the sarcoplasmic reticulum to troponin bound to tropomyosin on the actin filament. The concept of a signaling cascade is now central to any thinking about signaling pathways as we attempt to understand such mechanisms at the molecular level. Whereas troponin is found only in striated muscles, tropomyosin is expressed in virtually all eucaryotic cells and is recognized to be a universal actin filament regulator, versatile in its function despite its deceptively simple coiled coil structure. In this chapter we give an overview of tropomyosin’s multiple regulatory roles and insights into aspects of the structural basis for its functions, focusing on vertebrate forms. As such, this is a personal view rather than a comprehensive review that can be found elsewhere (Perry, 2001; Gunning et al., 2005).


Actin Filament Myosin Head Coiled Coil Actin Binding Nonmuscle Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

9.8. References

  1. Bamburg, J. R., 1999, Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu. Rev. Cell Dev. Biol. 15:185–230.PubMedCrossRefGoogle Scholar
  2. Bharadwaj, S., Shah, V., Tariq, F., Damartoski, B., and Prasad, G. L., 2005, Amino terminal, but not the carboxy terminal, sequences of tropomyosin-1 are essential for the induction of stress fiber assembly in neoplastic cells. Cancer Lett. 229:253–260.PubMedCrossRefGoogle Scholar
  3. Blanchoin, L., Pollard, T. D., and Hitchcock-DeGregori, S. E., 2001, Inhibition of the Arp2/3 complex-nucleated actin polymerization and branch formation by tropomyosin. Curr. Biol. 11:1300–1304.PubMedCrossRefGoogle Scholar
  4. Braverman, R. H., Cooper, H. L., Lee, H. S., and Prasad, G. L., 1996, Anti-oncogenic effects of tropomyosin: isoform specificity and importance of protein coding sequences. Oncogene 13:537–545.PubMedGoogle Scholar
  5. Bremel, R. D., and Weber, A., 1972, Cooperation within actin filament in vertebrate skeletal muscle. Nat. New Biol. 238:97–101.PubMedGoogle Scholar
  6. Broschat, K. O., 1990, Tropomyosin prevents depolymerization of actin filaments from the pointed end. J. Biol. Chem. 265:21323–21329.PubMedGoogle Scholar
  7. Brown, J. H., Kim, K. H., Jun, G., Greenfield, N. J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S. E., and Cohen, C., 2001, Deciphering the design of the tropomyosin molecule. Proc. Natl. Acad. Sci. USA 98:8496–8501.PubMedCrossRefGoogle Scholar
  8. Bryce, N. S., Schevzov, G., Ferguson, V., Percival, J. M., Lin, J. J., Matsumura, F., Bamburg, J. R., Jeffrey, P. L., Hardeman, E. C., Gunning, P., and Weinberger, R. P., 2003, Specification of actin filament function and molecular composition by tropomyosin isoforms. Mol. Biol. Cell 14:1002–1016.PubMedCrossRefGoogle Scholar
  9. Butters, C. A., Willadsen, K. A., and Tobacman, L. S., 1993, Cooperative interactions between adjacent troponin-tropomyosin complexes may be transmitted through the actin filament. J. Biol. Chem. 268:15565–15570.PubMedGoogle Scholar
  10. Cassell, M., and Tobacman, L. S., 1996, Opposite effects of myosin subfragment 1 on binding of cardiac troponin and tropomyosin to the thin filament. J. Biol. Chem. 271:12867–12872.PubMedCrossRefGoogle Scholar
  11. Cho, Y. J., Liu, J., and Hitchcock-DeGregori, S. E., 1990, The amino terminus of muscle tropomyosin is a major determinant for function. J. Biol. Chem. 265:538–545.PubMedGoogle Scholar
  12. Cooper, H. L., Feuerstein, N., Noda, M., and Bassin, R. H., 1985, Suppression of tropomyosin synthesis, a common biochemical feature of oncogenesis by structurally diverse retroviral oncogenes. Mol. Cell. Biol. 5:972–983.PubMedGoogle Scholar
  13. DesMarais, V., Ichetovkin, I., Condeelis, J., and Hitchcock-DeGregori, S. E., 2002, Spatial regulation of actin dynamics: a tropomyosin-free, actin-rich compartment at the leading edge. J. Cell Sci. 115:4649–4660.PubMedCrossRefGoogle Scholar
  14. Eaton, B. L., 1976, Tropomyosin binding to F-actin induced by myosin heads. Science 192:1337–1339.PubMedCrossRefGoogle Scholar
  15. Ebashi, S., and Endo, M., 1968, Calcium Ion and Muscle Contraction. Prog. Biophys. Mol. Biol. 18:125–183.Google Scholar
  16. Flicker, P. F., Phillips, G. N., Jr., and Cohen, C., 1982, Troponin and its interactions with tropomyosin. An electron microscope study. J. Mol. Biol. 162:495–501.PubMedCrossRefGoogle Scholar
  17. Fujime, S., and Ishiwata, S., 1971, Dynamic study of F-actin by quasielastic scattering of laser light. J. Mol. Biol. 62:251–265.PubMedCrossRefGoogle Scholar
  18. Geeves, M. A., and Lehrer, S. S., 1994, Dynamics of the muscle thin filament regulatory switch: the size of the cooperative unit. Biophys. J. 67:273–282.PubMedGoogle Scholar
  19. Gimona, M., Kazzaz, J. A., and Helfman, D. M., 1996, Forced expression of tropomyosin 2 or 3 in v-Kiras-transformed fibroblasts results in distinct phenotypic effects. Proc. Natl. Acad. Sci. USA 93:9618–9623.PubMedCrossRefGoogle Scholar
  20. Gordon, A. M., Homsher, E., and Regnier, M., 2000, Regulation of contraction in striated muscle. Physiol. Rev. 80:853–924.PubMedGoogle Scholar
  21. Greenfield, N. J., Montelione, G. T., Farid, R. S., and Hitchcock-DeGregori, S. E., 1998, The structure of the N-terminus of striated muscle alpha-tropomyosin in a chimeric peptide: nuclear magnetic resonance structure and circular dichroism studies. Biochemistry 37:7834–7843.PubMedCrossRefGoogle Scholar
  22. Greenfield, N. J., Palm, T., and Hitchcock-DeGregori, S. E., 2002, Structure and interactions of the carboxyl terminus of striated muscle α-tropomyosin: It is important to be flexible. Biophys. J. 83:2754–2766.PubMedGoogle Scholar
  23. Greenfield, N. J., Swapna, G. V., Huang, Y., Palm, T., Graboski, S., Montelione, G. T., and Hitchcock-DeGregori, S. E., 2003, The structure of the carboxyl terminus of striated alpha-tropomyosin in solution reveals an unusual parallel arrangement of interacting alpha-helices. Biochemistry 42:614–619.PubMedCrossRefGoogle Scholar
  24. Gunning, P. W., Schevzov, G., Kee, A. J., and Hardeman, E. C., 2005, Tropomyosin isoforms: divining rods for actin cytoskeleton function. Trends Cell Biol. 15:333–341.PubMedCrossRefGoogle Scholar
  25. Gupton, S. L., Anderson, K. L., Kole, T. P., Fischer, R. S., Ponti, A., Hitchcock-DeGregori, S. E., Danuser, G., Fowler, V. M., Wirtz, D., Hanein, D., and Waterman-Storer, C. M., 2005, Cell migration without a lamellipodium: translation of actin dynamics into cell movement mediated by tropomyosin. J. Cell. Biol. 168:619–631.PubMedCrossRefGoogle Scholar
  26. Hammell, R. L., and Hitchcock-DeGregori, S. E., 1996, Mapping the functional domains within the carboxyl terminus of alpha-tropomyosin encoded by the alternatively spliced ninth exon. J. Biol. Chem. 271:4236–4242.PubMedCrossRefGoogle Scholar
  27. Hammell, R. L., and Hitchcock-DeGregori, S. E., 1997, The sequence of the alternatively spliced sixth exon of alpha-tropomyosin is critical for cooperative actin binding but not for interaction with troponin. J. Biol. Chem. 272:22409–22416.PubMedCrossRefGoogle Scholar
  28. Heald, R. W., and Hitchcock-DeGregori, S. E., 1988, The structure of the amino terminus of tropomyosin is critical for binding to actin in the absence and presence of troponin. J. Biol. Chem. 263:5254–5259.PubMedGoogle Scholar
  29. Heeley, D. H., Smillie, L. B., and Lohmeier-Vogel, E. M., 1989, Effects of deletion of tropomyosin overlap on regulated actomyosin subfragment 1 ATPase. Biochem. J. 258:831–836.PubMedGoogle Scholar
  30. Hendricks, M., and Weintraub, H., 1981, Tropomyosin is decreased in transformed cells. Proc. Natl. Acad. Sci. USA 78:5633–5637.PubMedCrossRefGoogle Scholar
  31. Hitchcock, S. E., Carisson, L., and Lindberg, U., 1976, Depolymerization of F-actin by deoxyribonuclease I. Cell 7:531–542.PubMedCrossRefGoogle Scholar
  32. Hitchcock-DeGregori, S. E., and An, Y., 1996, Integral repeats and a continuous coiled coil are required for binding of striated muscle tropomyosin to the regulated actin filament. J. Biol. Chem. 271:3600–3603.PubMedCrossRefGoogle Scholar
  33. Hitchcock-DeGregori, S. E., Lewis, S. F., and Mistrik, M., 1988, Lysine reactivities of tropomyosin complexed with troponin. Arch. Biochem. Biophys. 264:410–416.PubMedCrossRefGoogle Scholar
  34. Hitchcock-DeGregori, S. E., Song, Y., and Greenfield, N. J., 2002, Functions of tropomyosin’s periodic repeats. Biochemistry 41:15036–15044.PubMedCrossRefGoogle Scholar
  35. Hitchcock-DeGregori, S. E., Song, Y., and Moraczewska, J., 2001, Importance of internal regions and the overall length of tropomyosin for actin binding and regulatory function. Biochemistry 40:2104–2112.PubMedCrossRefGoogle Scholar
  36. Hitchcock-DeGregori, S. E., and Varnell, T. A., 1990, Tropomyosin has discrete actin-binding sites with sevenfold and fourteenfold periodicities. J. Mol. Biol. 214:885–896.PubMedCrossRefGoogle Scholar
  37. Ishii, Y., and Lehrer, S. S., 1990, Excimer fluorescence of pyrenyliodoacetamide-labeled tropomyosin: a probe of the state of tropomyosin in reconstituted muscle thin filaments. Biochemistry 29:1160–1166.PubMedCrossRefGoogle Scholar
  38. Ishikawa, R., Yamashiro, S., and Matsumura, F., 1989, Differential modulation of actin-severing activity of gelsolin by multiple isoforms of cultured rat cell tropomyosin. Potentiation of protective ability of tropomyosins by 83-kDa nonmuscle caldesmon. J. Biol. Chem. 264:7490–7497.PubMedGoogle Scholar
  39. Johnson, P., and Smillie, L. B., 1977, Polymerizability of rabbit skeletal tropomyosin: effects of enzymic and chemical modifications. Biochemistry 16:2264–2269.PubMedCrossRefGoogle Scholar
  40. Kostyukova, A. S., and Hitchcock-DeGregori, S. E., 2004, Effect of the structure of the N terminus of tropomyosin on tropomodulin function. J. Biol. Chem. 279:5066–5071.PubMedCrossRefGoogle Scholar
  41. Kwok, S. C., and Hodges, R. S., 2004, Stabilizing and destabilizing clusters in the hydrophobic core of long two-stranded alpha-helical coiled-coils. J. Biol. Chem. 279:21576–21588.PubMedCrossRefGoogle Scholar
  42. Landis, C., Back, N., Homsher, E., and Tobacman, L. S., 1999, Effects of tropomyosin internal deletions on thin filament function. J. Biol. Chem. 274:31279–31285.PubMedCrossRefGoogle Scholar
  43. Landis, C. A., Bobkova, A., Homsher, E., and Tobacman, L. S., 1997, The active state of the thin filament is destabilized by an internal deletion in tropomyosin. J. Biol. Chem. 272:14051–14056.PubMedCrossRefGoogle Scholar
  44. Li, Y., Mui, S., Brown, J. H., Strand, J., Reshetnikova, L., Tobacman, L. S., and Cohen, C., 2002, The crystal structure of the C-terminal fragment of striated-muscle alpha-tropomyosin reveals a key troponin T recognition site. Proc. Natl. Acad. Sci. USA 99:7378–7383.PubMedCrossRefGoogle Scholar
  45. Lin, J. J., Hegmann, T. E., and Lin, J. L., 1988, Differential localization of tropomyosin isoforms in cultured nonmuscle cells. J. Cell. Biol. 107:563–572.PubMedCrossRefGoogle Scholar
  46. McLachlan, A. D., and Stewart, M., 1976, The 14-fold periodicity in alpha-tropomyosin and the interaction with actin. J. Mol. Biol. 103:271–298.PubMedCrossRefGoogle Scholar
  47. Mahadev, K., Raval, G., Bharadwaj, S., Willingham, M. C., Lange, E. M., Vonderhaar, B., Salomon, D., and Prasad, G. L., 2002, Suppression of the transformed phenotype of breast cancer by tropomyosin-1. Exp. Cell Res. 279:40–51.PubMedCrossRefGoogle Scholar
  48. Matsumura, F., Lin, J. J., Yamashiro-Matsumura, S., Thomas, G. P., and Topp, W. C. (1983a). Differential expression of tropomyosin forms in the microfilaments isolated from normal and transformed rat cultured cells. J. Biol. Chem. 258:13954–13964.PubMedGoogle Scholar
  49. Matsumura, F., Yamashiro-Matsumura, S., and Lin, J. J. (1983b). Isolation and characterization of tropomyosin-containing microfilaments from cultured cells. J. Biol. Chem. 258:6636–6644.PubMedGoogle Scholar
  50. Monteiro, P. B., Lataro, R. C., Ferro, J. A., and Reinach, F. C., 1994, Functional alpha tropomyosin produced in Escherichia coli. A dipeptide extension can substitute the amino-terminal acetyl group. J. Biol. Chem. 269.Google Scholar
  51. Moraczewska, J., and Hitchcock-DeGregori, S. E., 2000, Independent functions for the N-and C-termini in the overlap region of tropomyosin. Biochemistry 39:6891–6897.PubMedCrossRefGoogle Scholar
  52. Pan, B. S., Gordon, A. M., and Luo, Z. X., 1989, Removal of tropomyosin overlap modifies cooperative binding of myosin S-1 to reconstituted thin filaments of rabbit striated muscle. J. Biol. Chem. 264:8495–8498.PubMedGoogle Scholar
  53. Percival, J. M., Hughes, J. A., Brown, D. L., Schevzov, G., Heimann, K., Vrhovski, B., Bryce, N., Stow, J. L., and Gunning, P. W., 2004, Targeting of a tropomyosin isoform to short microfilaments associated with the Golgi complex. Mol. Biol. Cell 15:268–280.PubMedCrossRefGoogle Scholar
  54. Perry, S. V., 2001, Vertebrate tropomyosin: distribution, properties and function. J. Muscle Res. Cell Motil. 22:5–49.PubMedCrossRefGoogle Scholar
  55. Phillips, G. N., Jr., 1986, Construction of an atomic model for tropomyosin and implications for interactions with actin. J. Mol. Biol. 192:128–131.PubMedCrossRefGoogle Scholar
  56. Pollard, T. D., and Borisy, G. G., 2003, Cellular motility driven by assembly and disassembly of actin filaments. Cell 112:453–465.PubMedCrossRefGoogle Scholar
  57. Raval, G. N., Bharadwaj, S., Levine, E. A., Willingham, M. C., Geary, R. L., Kute, T., and Prasad, G. L., 2003, Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors. Oncogene 22:6194–6203.PubMedCrossRefGoogle Scholar
  58. Singh, A., and Hitchcock-DeGregori, S. E., 2006, Dual requirement for flexibility and specificity for binding of the coiled coil tropomyosin to its target, actin. Structure, 14:43–50.PubMedCrossRefGoogle Scholar
  59. Tang, N., and Ostap, E. M., 2001, Motor domain-dependent localization of myo1b (myr-1). Curr. Biol. 11:1131–1135.PubMedCrossRefGoogle Scholar
  60. Tobacman, L. S., and Butters, C. A., 2000, A new model of cooperative myosin-thin filament binding [In Process Citation]. J. Biol. Chem. 275:27587–27593.PubMedGoogle Scholar
  61. Ueno, H., Tawada, Y., and Ooi, T., 1976, Properties of non-polymerizable tropomyosin obtained by carboxypeptidase A digestion. J. Biochem. (Tokyo) 80:283–290.PubMedGoogle Scholar
  62. Urbancikova, M., and Hitchcock-DeGregori, S. E., 1994, Requirement of amino-terminal modification for striated muscle alpha-tropomyosin function. J. Biol. Chem. 269:24310–24315.PubMedGoogle Scholar
  63. Walsh, T. P., Trueblood, C. E., Evans, R., and Weber, A., 1985, Removal of tropomyosin overlap and the co-operative response to increasing calcium concentrations of the acto-subfragment-1 ATPase. J. Mol. Biol. 182:265–269.PubMedCrossRefGoogle Scholar
  64. Wang, C. L., 2001, Caldesmon and smooth-muscle regulation. Cell Biochem. Biophys. 35:275–88.PubMedCrossRefGoogle Scholar
  65. Whitby, F. G., and Phillips, G. N., Jr., 2000, Crystal structure of tropomyosin at 7 Angstroms resolution. Proteins 38:49–59.PubMedCrossRefGoogle Scholar
  66. Xu, C., Craig, R., Tobacman, L., Horowitz, R., and Lehman, W., 1999, Tropomyosin positions in regulated thin filaments revealed by cryoelectron microscopy. Biophys. J. 77:985–992.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Sarah E. Hitchcock-DeGregori
    • 1
  • Norma J. Greenfield
    • 1
  • Abhishek Singh
    • 1
  1. 1.Department of Neuroscience and Cell BiologyRobert Wood Johnson Medical SchoolPiscatawayUSA

Personalised recommendations