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Reversal of insulin-induced negative cooperativity by monoclonal antibodies that stabilize the slowly dissociating (“Ksuper”) state of the insulin receptor

1988; Elsevier BV; Volume: 150; Issue: 2 Linguagem: Inglês

10.1016/0006-291x(88)90447-0

1090-2104

Jiali Gu, Ira D. Goldfine, John Forsayeth, Pierre De Meyts,

Protein Structure and Dynamics

Two monoclonal antibodies to the insulin receptor, MA-5 and MA-20, unlike other monoclonal antibodies, do not mimick the accelerating effect of insulin on the dissociation of 125I-insulin from the receptors (negative cooperativity). On the contrary, MA-5 and MA-20 markedly slow down the dissociation rate. We show now that MA-5 and MA-20 are potent antagonists of the negative cooperativity induced by insulin, and reverse the insulin-induced acceleration whether added simultaneously with insulin or after insulin. The reversal of the insulin-induced acceleration is almost immediate. These data strengthen the concept therefore that the insulin-receptor complex has access to alternative conformational states that can be stabilized by ligand-induced site-site interactions.