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Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface

Abstract

G-PROTEIN-COUPLED receptors for catecholamines and some other small ligands are activated when agonists bind to the transmem-brane region of the receptor1. The docking interactions through which peptide agonists activate their receptors are less well characterized2–7. The thrombin receptor is a specialized peptide receptor. It is activated by binding its tethered ligand domain, which is unmasked upon receptor cleavage by thrombin8,9. Human and Xenopus thrombin receptor homologues are each selectively activated by the agonist peptide representing their respective tethered ligand domains. Here we identify receptor domains that confer this agonist specificity by replacing the Xenopus receptor's amino-terminal exodomain and three extracellular loops with the corresponding human structures. This switches receptor specificity from Xenopus to human. The specificity of these thrombin receptors for their respective peptide agonists is thus determined by their extracellular surfaces. Our results indicate that agonist interaction with extracellular domains is important for thrombin receptor activation.

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References

  1. Dohlman, H. G., Thorner, J., Caron, M. G & Lefkowitz, R. J. A. Rev. Biochem. 60, 651–688 (1992).

    Google Scholar 

  2. Fong, T. M., Huang, R.-R. C. & Strader, C. D. Biochemistry 31, 11806–11811 (1992).

    Article  CAS  Google Scholar 

  3. Fong, T. M., Huang, R.-R. C. & Strader, C. D. J. biol. Chem. 267, 25664–25667 (1992).

    CAS  PubMed  Google Scholar 

  4. Gether, U., Johansen, T. E. & Schwartz, T. W. J. biol. Chem. 268, 7893–7898 (1993).

    CAS  PubMed  Google Scholar 

  5. Gether, U. et al. Nature 362, 345–348 (1993).

    Article  ADS  CAS  Google Scholar 

  6. Lin, S-C. et al. Nature 364, 208–213 (1993).

    Article  ADS  CAS  Google Scholar 

  7. Fathi, Z., Benya, R. V., Shapira, H., Jensen, R. T. & Battey, J. F. J. biol. Chem. 268, 14622–14626 (1993).

    CAS  PubMed  Google Scholar 

  8. Vu, T.-K. H., Hung, D. T., Wheaton, V. I. & Coughlin, S. R. Cell 64, 1057–1068 (1991).

    Article  CAS  Google Scholar 

  9. Vu, T.-K. H., Wheaton, V. I., Hung, D. T. & Coughlin, S. R. Nature 353, 674–677 (1991).

    Article  ADS  CAS  Google Scholar 

  10. Fenton, J. W. Sem. Hemostas. Thrombos. 14, 234–240 (1988).

    Article  CAS  Google Scholar 

  11. Coughlin, S. R., Vu, T.-K. H., Hung, D. T. & Wheaton, V. I. J. clin. Invest. 89, 351–355 (1992).

    Article  CAS  Google Scholar 

  12. Vassallo, R. R. J., Kieber-Emmons, T., Cichowski, K. & Brass, L. F. J. biol. Chem. 267, 6081–6085 (1992).

    CAS  PubMed  Google Scholar 

  13. Scarborough, R. M. et al. J. biol. Chem. 267, 13146–13149 (1992).

    CAS  PubMed  Google Scholar 

  14. Ishii, K., Hein, L, Kobilka, B. & Coughlin, S. R. J. biol. Chem. 268, 9780–9786 (1993).

    CAS  PubMed  Google Scholar 

  15. Rydel, T. J. et al. Science 249, 277–280 (1990).

    Article  ADS  CAS  Google Scholar 

  16. Saiki, R. K. et al. Science 230, 1350–1354 (1985).

    Article  ADS  CAS  Google Scholar 

  17. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning (Cold Spring Harbor Press, New York, 1989).

    Google Scholar 

  18. Kunkel, T. A., Roberts, J. D. & Zakour, R. A. Meth. Enzym. 154, 367–382 (1987).

    Article  CAS  Google Scholar 

  19. Lanza, F. et al. J. biol. Chem. 266, 10638–10645 (1991).

    CAS  PubMed  Google Scholar 

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Gerszten, R., Chen, J., Ishli, M. et al. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface. Nature 368, 648–651 (1994). https://doi.org/10.1038/368648a0

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