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Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin

Abstract

Insulin binding to its receptor leads to negatively cooperative interactions among the receptor sites. Studies with 29 insulin analogues (animal insulins and proinsulin, insulin-like growth factor and chemically modified insulins) which vary 1,000-fold in their affinity for the receptor and in their biological potency, suggest that a discrete invariable region on the surface of the insulin monomer is responsible for inducing the negative cooperativity. This domain comprises some of the eight carboxy-terminal residues of the B-chain and the A21 asparagine. Burying of this ‘cooperative site’ in the dimerisation of insulin leads to a loss of negative cooperativity. A revised mapping of the insulin molecule is proposed, featuring distinct bioactive and cooperative sites.

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References

  1. Freychet, P., Roth, J. & Neville, D. M., Jr Proc. natn. Acad. Sci. U.S.A. 68, 1833–1837 (1971).

    Article  ADS  CAS  Google Scholar 

  2. Blundell, T. L., Dodson, G. G., Hodgkin, D. C. & Mercola, D. A. Adv. Protein Chem. 26, 279–402 (1972).

    Article  CAS  Google Scholar 

  3. Wood, S. P., Blundell, T. L., Wollmer, A., Lazarus, N. R. & Neville, R. W. J. Eur. J. Biochem. 55, 531–542 (1975).

    Article  CAS  Google Scholar 

  4. Pullen, R. A., Jenkins, J. A., Tickle, I. J., Wood, S. P. & Blundell, T. L. Molec. cell. Endocr. 8, 5–20 (1975).

    CAS  Google Scholar 

  5. Blundell, T. L. & Wood, S. P. Nature 257, 197–203 (1975).

    Article  ADS  CAS  Google Scholar 

  6. Freychet, P., Brandenburg, D. & Wollmer, A. Diabetologia 10, 1–5 (1974).

    Article  CAS  Google Scholar 

  7. Gliemann, J. & Gammeltoft, S. Diabetologia 10, 105–113 (1974).

    Article  CAS  Google Scholar 

  8. Pullen, R. A. et al. Nature 259, 369–373 (1976).

    Article  ADS  CAS  Google Scholar 

  9. Emdin, S. O., Gammeltoft, S. & Gliemann, J. Diabetologia 11, 340 (1975); J. biol. Chem. 252, 602–608 (1977).

    Google Scholar 

  10. Muggeo, M., Ginsberg, B. H., Roth, J., De Meyts, P. & Falkmer, S. Diabetes 26, Suppl. 1, 353 (1977).

    Google Scholar 

  11. De Meyts, P., Roth, J., Neville, D. M. Jr, Gavin, J. R., III & Lesniak, M. A. Biochem. biophys. Res. Commun. 55, 154–161 (1973).

    Article  CAS  Google Scholar 

  12. De Meyts, P. J. supramolec. Struct. 4, 241–258 (1976).

    Article  CAS  Google Scholar 

  13. De Meyts, P., Kahn, C. R., Ginsberg, B. & Roth, J. Diabetes 24, Suppl. 2, 393 (1975).

    Google Scholar 

  14. Schlesinger, J. & Levitzki, A. J. molec. Biol. 82, 547–561 (1974).

    Article  Google Scholar 

  15. De Meyts, P., Bianco, A. R. & Roth, J. J. biol. Chem. 251, 1877–1888 (1976).

    CAS  Google Scholar 

  16. Gavin, J. R., III, Gorden, P., Roth, J., Archer, J. A. & Buell, D. N. J. biol. Chem. 248, 2202–2207 (1973).

    CAS  Google Scholar 

  17. De Meyts, P. in Methods in Receptor Research, Vol. 1 (ed. Blecher M ) 301–383 (M. Dekker, New York, 1976).

    Google Scholar 

  18. Gavin, J. R., III, Kahn, C. R., Gorden, P., Roth, J. & Neville, D. M., Jr J. clin. Endocr. Metab. 41, 438–445 (1975).

    Article  CAS  Google Scholar 

  19. Kotaki, A. J. Biochem. 51, 301–309 (1962); 53, 61–70 (1963).

    Article  CAS  Google Scholar 

  20. Smith, L. F. Am. J. Med. 40, 662–666 (1966).

    Article  CAS  Google Scholar 

  21. Peterson, J. D., Coulter, C. L. & Steiner, D. F. Nature 251, 239–240 (1974).

    Article  ADS  CAS  Google Scholar 

  22. Chance, R. E., Ellis, R. M. & Bromer, W. W. Science 161, 165–167 (1968).

    Article  ADS  CAS  Google Scholar 

  23. Chance, R. G. in Proc. 7th Congr. Int. Diabetes Fedn, Buenos Aires, 1970 (eds Rodriguez, R. R. & Vallance-Owen, J.) Int. Congr. Ser. No. 231, 292–305 (Excerpta Medica, Amsterdam, 1971).

    Google Scholar 

  24. Lindsay, D. G. & Shall, S. Biochem. J. 121, 737–745 (1971).

    Article  CAS  Google Scholar 

  25. Brandenburg, D. Hoppe-Seyler's Z. physiol. Chem. 350, 741–750 (1969).

    Article  CAS  Google Scholar 

  26. Brandenburg, D. & Ooms, H. Excerpta med. Found. Int. Congr. Ser. 161, 482–484 (1968).

    Google Scholar 

  27. Africa, B. & Carpenter, F. H. Biochemistry 9, 1962–1972 (1970).

    Article  CAS  Google Scholar 

  28. Carpenter, F. H. Am. J. Med. 40, 750–758 (1966).

    Article  CAS  Google Scholar 

  29. Brandenburg, D., Gattner, H. G. & Wollmer, A. Hoppe-Seyler's Z. physiol. Chem. 353, 599–617 (1962).

    Article  Google Scholar 

  30. Busse, W. D. & Carpenter, F. H. Biochemistry 15, 1649–1657 (1976).

    Article  CAS  Google Scholar 

  31. Brandenburg, D. et al. in Proc. 7th Congr. Int. Diabetes Fedn, Buenos-Aires, 1970 (eds Rodriguez, R. R. & Vallance-Owen, J.) Int. Congr. Ser. No. 231, 363–376 (Excerpta Medica, Amsterdam, 1971).

    Google Scholar 

  32. Boesel, R. W. & Carpenter, F. H. Fedn Proc. 31, 255) 1972).

    Google Scholar 

  33. Rinderknecht, E. & Humbel, R. E. Proc. natn. Acad. Sci. U.S.A. 73, 4379–4381 (1976).

    Article  ADS  CAS  Google Scholar 

  34. Brandenburg, D. et al. in Proc. 12th Eur. Peptide Symp. (eds Hanson, H. & Jakubke, H. D.) 270–283 (North-Holland, Amsterdam, 1973).

    Google Scholar 

  35. Wilson, A., Jakus, C. & Logan, L. 8th Congr. Int. Diabetes Fedn, Brussels, 1973, Abstr. Excerpta med. Int. Congr. Ser., No. 280, 136 (Excerpta Medica, Amsterdam, 1973).

  36. The Shanghai Insulin Research Group Scientia sin. 16, 61–70 (1973).

  37. Goldman, J. & Carpenter, F. H. Biochemistry 13, 4566–4574 (1974).

    Article  CAS  Google Scholar 

  38. Zimmermann, A. E., Kells, D. I. C. & Yip, C. C. Biochem. biophys. Res. Commun. 46, 2127–2133 (1972).

    Article  Google Scholar 

  39. Zimmermann, A. E. & Yip, C. C. J. biol. Chem. 249, 4021–4025 (1974).

    Google Scholar 

  40. Cuatrecasas, P. & Hollenberg, M. D. Biochem. biophys. Res. Commun. 62, 31–41 (1975).

    Article  CAS  Google Scholar 

  41. Cutfield, J. F., Cutfield, S. M., Dodson, E. J., Dodson, G. G. & Sabesan, M. N. J. molec. Biol. 87, 23 (1974).

    Article  CAS  Google Scholar 

  42. De Meyts, P. & Waelbroeck, M. Diabetes 26, Suppl. 1, 354 (1977).

    Google Scholar 

Download references

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Meyts, P., Van Obberghen, E., Roth, J. et al. Mapping of the residues responsible for the negative cooperativity of the receptor-binding region of insulin. Nature 273, 504–509 (1978). https://doi.org/10.1038/273504a0

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