The interaction of insulin with its receptor: cross-linking via insulin association as the source of receptor clustering.

The extensive association of mammalian insulins in solution and the aggregation of insulin receptors in cell membranes are well documented. The hypothesis advanced here is that a direct connection exists between these observations. It is postulated that, after binding to its receptor, an insulin monomer can interact with another similarly bonded hormone-receptor complex through those groups on the insulin monomer faces utilized for dimer-dimer contacts in the crystal and in solution. Regarded thus, the insulin molecules are effectively bivalent as required for the formation of cross-links between receptors, with the accompanying enhancement of biological activity. A number of properties of native insulins from different animals, and of modified insulins, are considered in the light of this suggestion. It is shown to have considerable power in reconciling a diversity of such observations and to provide a plausible model for the experimentally observed receptor clustering phenomenon.