Summary
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 α2β2 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 μmol/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 a 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 insulinlike growth factor-I.
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Abbreviations
- BHK cells:
-
baby hamster kidney cells
- IGF-I:
-
Insulin-like growth factor-I
- bp:
-
base pair
- Gly:
-
glycine
- Glu:
-
glutamic acid
- Gln:
-
glutamine
- Tyr:
-
tyrosine
- Asn:
-
asparagine
- Val:
-
valine
- Phe:
-
phenylalanine
- Leu:
-
leucine
- Ser:
-
serine
- Thr:
-
threonine
- Pro:
-
proline
- DHPP:
-
desheptapeptide insulin
- NMR:
-
nuclear magnetic resonance
- PDGF:
-
platelet derived growth factor
- CSF:
-
colony stimulating factor
- GH:
-
growth hormone
- His:
-
histidine
- GH:
-
growth hormone
- IRS-1:
-
insulin receptor substrate-1
- Lys:
-
lysine
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De Meyts, P. 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. Diabetologia 37 (Suppl 2), S135–S148 (1994). https://doi.org/10.1007/BF00400837
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DOI: https://doi.org/10.1007/BF00400837