The B domain of Insulin-like Growth Factor I (IGF-I) is recognized by IGF carrier proteins but not by type II IGF receptors

Abstract

IGF-I and IGF-II are highly homologous to each other and to proinsulin. Although the IGFs and insulin have similar biological activities and receptor reactivity, IGF carrier proteins and one subtype of IGF receptors (Type II) interact exclusively with the IGFs and not with insulin. To determine the structural basis for this specificity, we have prepared 3 synthetic hybrid molecules that combine different portions of the IGF and insulin molecules: A27(Ins)-B(Ins), in which the A chain of insulin is extended by the D domain of IGF-II; A(Ins)-B(IGF-I) and A27(Ins)-B(IGF-I)in which the B domain of IGF-I is combined with the natural or extended A chain of insulin. In a competitive binding assay with acid stripped carrier protein from adult rat serum, 125I-rIGF-II binding was inhibited by the IGFs and by both hybrid molecules containing B-(IGF-I), but not by insulin or A27(Ins)-B(Ins). Qualitatively similar results were obtained with carrier proteins from human serum, neonatal rat serum and rat liver cell conditioned media By contrast, none of the three hybrids molecules inhibited 125I-rIGF-II binding to Type II IGF receptors on rat liver, placenta or chondrosarcoma cells. CONCLUSIONS: The B domain of IGF-I but not the D domain of IGF-II allow Insulin-IGF hybrid molecules to be recognized by IGF carrier proteins. Neither domain is involved in binding to Type II IGF receptors.