The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signalling.
Insulin and insulin-like growth factor-I exhibit a set of non-classical receptor binding properties suggestive of negative co-operativity or site-site interactions between the two receptor halves: curvilinear Scatchard plots, acceleration of dissociation of bound labelled ligand at high dilution in the presence of unlabelled ligand. The alpha 2 beta 2 receptor dimer binds only one ligand molecule with high affinity. The dose-response curve for the acceleration of 125I-insulin by unlabelled insulin is bell-shaped, with a disappearance of the negative co-operativity at insulin concentrations over 0.1 mumol/l. This phenomenon had been attributed to insulin dimerization, but new data with non-dimerizing analogues and insulins modified at the hexamer-forming surface indicate the presence of a second binding site on the insulin molecule's hexamer face. This site binds to a second domain on the receptor. A new binding model for insulin and insulin-like growth factor-I is proposed where the bivalent ligand bridges the two receptor alpha subunits alternatively at opposite sites in a symmetrical receptor structure. The implications of the model for negative co-operativity, bell-shaped biological curves, and the divergence between mitogenic and metabolic signalling are discussed in the context of the evolution of the properties of insulin and insulin-like growth factor-I.
De Meyts
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P
Hagedorn Research Institute, Gentofte, Denmark.
D000595:Amino Acid Sequence; D000818:Animals; D001363:Awards and Prizes; D001530:Belgium; D002455:Cell Division; D003920:Diabetes Mellitus / Q000266:history; D005060:Europe; D005091:Exons; D049673:History, 20th Century; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008961:Models, Structural; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012955:Societies, Medical
D007328:Insulin; D046911:Macromolecular Substances; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin