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

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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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Author notes

  1. P. De Meyts

    Present address: International Institute of Cellular and Molecular Pathology, 75 Avenue Hippocrate, B-1200, Brussels, Belgium

  2. P. De Meyts: To whom inquiries should be addressed.

Authors and Affiliations

  1. Diabetes Branch, National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland, 20014

    P. De Meyts, E. Van Obberghen & J. Roth

  2. Fachgebiet Struktur und Funktion der Proteine, Absteilung Physiologische Chemie, Rheinisch-Westfahlische Technische Hochschule, Aachen, FRG

    A. Wollmer

  3. Deutsches Wollforschungsinstitut an der Rheinisch-Westfallischen, Technischen Hochschule, Aachen, FRG

    D. Brandenburg

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  1. P. De Meyts
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  2. E. Van Obberghen
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  3. J. Roth
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  4. A. Wollmer
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  5. D. Brandenburg
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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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  • DOI: https://doi.org/10.1038/273504a0

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