Advertisement

Molecular Switches in Troponin

  • John Gergely
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 453)

Abstract

The contraction of vertebrate striated muscle contraction, and hence its work output, is controlled by Ca2+, which binds to troponin (Tn) associated with tropomyosin (TM) and actin in the thin filaments. Tn consists of three subunits: TnC, the Ca2+-receptor; TnI, an inhibitor of actomyosin activity; and TnT, anchoring Tn to T.M. Of the four Ca2+-binding sites, I and II in the N-terminal domain are Ca-specific sites, while sites III and IV, the high affinity Ca-Mg sites, are in the C-domain. The former are recognized as the functionally important triggering sites. TnC, whose structure has been solved by X-ray crystallography and recently by high-resolution NMR, contains two homologous globular domains connected by an unusual single α-helix. The C-terminal domain exhibits an open hydrophobic area regardless of whether Ca2+ or Mg2+ is bound to sites III and IV. In contrast, the N-terminal domain is a closed structure that opens a hydrophobic patch upon Ca2+-binding to its two “triggering” sites producing a TnI binding area. Crosslinking and fragment binding studies indicate that, in the main, the two polypeptide chains run in opposite directions in the complex of TnC with Tn. A model of TnC-TnI interactions based on low angle X-ray and neutron scattering is discussed in light of biochemical and other physico-chemical studies. The opening of the structure in the N-terminal domain of TnC may be regarded as a molecular switch. It activates a molecular switch in TnI, reflected in the movement of portions of its C-terminal half, including Cys l33, away from actin and closer to TnC, as well as other structural changes in Tnl. Finally the role of TnT in switching and transmitting the Ca2+-signal is discussed.

Keywords

Resonance Energy Transfer Thin Filament Myosin Light Chain Kinase Molecular Switch Globular Domain 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Leavis, P.C. & Gergely, J. CRC Crit. Rev. Biochem. 16, 235–305 (1984).PubMedCrossRefGoogle Scholar
  2. 2.
    Grabarek, Z., Tao, T. & Gergely, J. Journal of Muscle Research and Cell Motility 13, 383–393 (1992).PubMedCrossRefGoogle Scholar
  3. 3.
    Zot, A.S. & Potter, J.D. Annual Review of Biophysics & Biophysical Chemistry 16, 535–559 (1987).CrossRefGoogle Scholar
  4. 4.
    Farah, C.S. & Reinach, F.C. FASEB Journal 9, 755–767 (1995).PubMedGoogle Scholar
  5. 5.
    Huxley, H.E. Cold Spring Harbor Symp. Quant. Biol. 37, 361–376 (1972).CrossRefGoogle Scholar
  6. 6.
    Haselgrove, J.C. Cold Spring Harbor Symp. Quant. Biol. 37, 341–352 (1972).CrossRefGoogle Scholar
  7. 7.
    Parry, D.A. & Squire, J.M. J. Mol. Biol. 75, 33–55 (1973).PubMedCrossRefGoogle Scholar
  8. 8.
    Kress, M., Huxley, H.E., Faruqi, A.R. & Hendrix, J. J Mol Biol 188, 325–42 (1986).PubMedCrossRefGoogle Scholar
  9. 9.
    Milligan, R.A., Whittaker, M. & Safer, D. Nature 348, 217–21 (1990).PubMedCrossRefGoogle Scholar
  10. 10.
    Lehman, W., Vibert, P., Uman, P. & Craig, R.J Mol Biol 251, 191–6 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    Holmes, K.C. Biophys J 68, 2S–5S (1995).PubMedGoogle Scholar
  12. 12.
    Vibert, P., Craig, R. & Lehman, W. J Mol Biol 266, 8–14 (1997).PubMedCrossRefGoogle Scholar
  13. 13.
    Holmes, K.C., Popp, D., Gebhard, W. & Kabsch, W. Nature 347, 44–9 (1990).PubMedCrossRefGoogle Scholar
  14. 14.
    Kabsch, W., Mannherz, H.G., Suck, D., Pai, E.F. & Holmes, K.C. Nature 347, 37–44 (1990).PubMedCrossRefGoogle Scholar
  15. 15.
    Rayment, I., et al. Science 261, 58–65 (1993).PubMedCrossRefGoogle Scholar
  16. 16.
    Rayment, I., et al. Science 261, 50–8 (1993).PubMedCrossRefGoogle Scholar
  17. 17.
    Xie, X., et al. Nature 368, 306–312 (1994).PubMedCrossRefGoogle Scholar
  18. 18.
    Kretsinger, R.H. & Nockolds, C.E. J. Biol. Chem. 248, 3313–3326 (1973).PubMedGoogle Scholar
  19. 19.
    Strynadka, N.C.J. & James, M.N.G. Annu. Rev. Biochem. 58, 951–98 (1989).PubMedCrossRefGoogle Scholar
  20. 20.
    Sundaralingam, M., et al. Science 227, 945–948 (1985).PubMedCrossRefGoogle Scholar
  21. 21.
    Herzberg, O. & James, M.N. Nature 313, 653–659 (1985).PubMedCrossRefGoogle Scholar
  22. 22.
    Herzberg, O., Moult, J. & James, M.N. J. Biol. Chem. 261, 2638–2644 (1986).PubMedGoogle Scholar
  23. 23.
    Grabarek, Z., Tan, R.Y., Wang, J., Tao, T. & Gergely, J. Nature 345, 132–135 (1990).PubMedCrossRefGoogle Scholar
  24. 24.
    Gusev, N.B., Grabarek, Z. & Gergely, J. J. Biol. Chem. 266, 16622–6 (1991).PubMedGoogle Scholar
  25. 25.
    Fujimori, K., Sorenson, M., Herzberg, O., Moult, J. & Reinach, F.C. Nature 345, 182–184 (1990).PubMedCrossRefGoogle Scholar
  26. 26.
    Wang, Z., Gergely, J. & Tao, T. Proc. Natl. Acad. Sci. U.S.A. 89, 11814–11817 (1992).PubMedCrossRefGoogle Scholar
  27. 27.
    Gagné, S.M., Tsuda, S., Li, M.X., Smillie, L.B. & Sykes, B.D. Nature Struct. Biol. 2, 784–789 (1995).PubMedCrossRefGoogle Scholar
  28. 28.
    Slupsky, C.M. & Sykes, B.D. Biochemistry 34, 15953–15964 (1995).PubMedCrossRefGoogle Scholar
  29. 29.
    Houdusse, A., Love, M.L., Dominguez, R., Grabarek, Z. & Cohen, C Structure 5, 1695–1711 (1997).PubMedCrossRefGoogle Scholar
  30. 30.
    Strynadka, C.J., et al. J. Mol. Biol. 273, 238–235 (1997).PubMedCrossRefGoogle Scholar
  31. 31.
    Sia, S.K., et al. J. Biol. Chem. 272, 18216–18221 (1997).PubMedCrossRefGoogle Scholar
  32. 32.
    Li, M.X., Spyracopoulos, L. & Sykes, B.D. Biophys. J 74, A51 (1998).Google Scholar
  33. 33.
    Meador, W.E., Means, A.R. & Quiocho, F.A. Science 257, 1251–5 (1992).PubMedCrossRefGoogle Scholar
  34. 34.
    Ikura, M., Barbato, G., Klee, C.B. & Bax, A. Cell Calcium 13, 391–400 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    Trewhella, J., Blumenthal, D.K., Rokop, S.E. & Seeger, P.A. Biochemistry 29, 9316–24 (1990).PubMedCrossRefGoogle Scholar
  36. 36.
    Gong, B.-J., Wang, Z., Tao, T. & Gergely, J. Biophys. J. 66, A346 (1994).Google Scholar
  37. 37.
    Blechner, S.L., Olah, G.A., Strynadka, N.C, Hodges, R.S. & Trewhella, J. Biochemistry 31, 11326–34 (1992).PubMedCrossRefGoogle Scholar
  38. 38.
    Olah, G.A., Rokop, S.E., Wang, C-L.A., Blechner, S.L. & Trewhella, J. Biochemistry 33, 8233–8239 (1994).PubMedCrossRefGoogle Scholar
  39. 39.
    Wang, C.L., Zhan, Q., Tao, T. & Gergely, J. J. Biol. Chem. 262, 9636–40 (1987).PubMedGoogle Scholar
  40. 40.
    Vassylyev, D.G., Takeda, S., Wakatsuki, S., Maeda, K. & Maeda, Y. Proc. Natl. Acad. Sci. (U.S.) (1998).Google Scholar
  41. 41.
    Farah, C.S., et al. J. Biol. Chem. 269, 5230–5240 (1994).PubMedGoogle Scholar
  42. 42.
    Kobayashi, T., Tao, T., Gergely, J. & Collins, J. J. Biol. Chem. 269, 5725–5729 (1994).PubMedGoogle Scholar
  43. 43.
    Olah, G.A. & Trewhella, J. Biochemistry 33, 12800–12806 (1994).PubMedCrossRefGoogle Scholar
  44. 44.
    Luo, Y., Wu., J.-L., Gergely, J. & Tao, T. Biophys. J. 74 (1998).Google Scholar
  45. 45.
    Leszyk, J., Tao, T., Nuwaysir, L.M. & Gergely, J. J. Muscle Res. & Cell Motility (1998).Google Scholar
  46. 46.
    Syska, H., Wilkinson, J.M., Grand, R.J. & Perry, S.V. Biochem. J. 153, 375–387 (1976).PubMedGoogle Scholar
  47. 47.
    Van Eyk, J.E., et al. J. Biol. Chem. 272, 10529–10537 (1997).PubMedCrossRefGoogle Scholar
  48. 48.
    Tripet, B., Van Eyk, J.E. & Hodges, R.S. J. Mol Biol. 271, 728–750 (1997).PubMedCrossRefGoogle Scholar
  49. 49.
    McKay, M., R. T., Tripet, B.P., Hodges, R.S. & Sykes, B.D. J. Biol. Chem. 272, 28494–28500 (1997).PubMedCrossRefGoogle Scholar
  50. 50.
    Luo, Y., Qian, Y., Leszyk, J., Gergely, J. & Tao, T. Biophys. J. 74, A143 (1998).CrossRefGoogle Scholar
  51. 51.
    Pearlstone, J.R., Sykes, B.D. & Smillie, L.B. Biochemistry 36, 7601–7606 (1997).PubMedCrossRefGoogle Scholar
  52. 52.
    Tao, T., Gong, B.J. & Leavis, P.C. Science 247, 1339–1341 (1990).PubMedCrossRefGoogle Scholar
  53. 53.
    Luo, Y., Wu, J.L., Gergely, J. & Tao, T. Biochemistry 36, 11027–11035 (1997).PubMedCrossRefGoogle Scholar
  54. 54.
    Ohtsuki, I. J. Biochem. 86, 491–497 (1979).PubMedGoogle Scholar
  55. 55.
    Schaertl, S., Lehrer, S.S. & Geeves, M.A. Biochemistry 34, 15890–15894 (1995).PubMedCrossRefGoogle Scholar
  56. 56.
    Potter, J.D., Sheng, Z., Pan, B.S. & Zhao, J. J. Biol. Chem. 270, 2557–2562 (1995).PubMedCrossRefGoogle Scholar
  57. 57.
    Jha, P.K., Leavis, P.C. & Sarkar, S. Biochemistry 35, 16573–16580 (1996).PubMedCrossRefGoogle Scholar
  58. 58.
    Pearlstone, J.R. & Smillie, L.B. Canad. J. Biochem. Cell Biol. 63, 212–218 (1985).CrossRefGoogle Scholar
  59. 59.
    Stefancsik, R., Jha, P.K. & Sarkar, S. Proc. Natl. Acad. Sci. (U.S.A) 95, 957–962 (1998).CrossRefGoogle Scholar
  60. 60.
    Sheng, Z., Pan, B.S., Miller, T.E. & Potter, J.D. J. Biol. Chem. 267, 25407–25413 (1992).PubMedGoogle Scholar
  61. 61.
    Malnic, B., Farah, C.S. & Reinach, F.C. J. Biol. Chem. 273 (1998).Google Scholar

Copyright information

© Plenum Press, New York 1998

Authors and Affiliations

  • John Gergely
    • 1
    • 2
    • 3
  1. 1.Muscle Research GroupBoston Biomedical Research InstituteUSA
  2. 2.Department of NeurologyMassachusetts General HospitalUSA
  3. 3.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolMassachusettsUSA

Personalised recommendations