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

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.