A new secreted insect protein belonging to the immunoglobulin superfamily binds insulin and related peptides and inhibits their activities

Insulin and related peptides are key hormones for the regulation of growth and metabolism. Here we describe a novel high affinity insulin-related pept ide-binding protein (IBP) secreted from cells of the insect Spodoptera frug iperda. This IBP is composed of two Ig-like C2 domains, has a molecular mas s of 27 kDa, binds human insulin with an affinity of 79 pM and inhibits ins ulin signaling through the insulin receptor. The binding protein also binds insulin-like growth factors I and II, proinsulin, mini-proinsulin, and an insulin analog lacking the last 8 amino acids of the B-chain (des-octa pept ide insulin) with high affinity, whereas an insulin analog with a Asp-B10 m utation bound with only 1% of the affinity of human insulin. This binding p rofile suggests that IBP recognizes a region that is highly conserved in th e insulin superfamily but distinct from the classical insulin receptor bind ing site. The closest homologue of the Spodoptera frugiperda binding protei n is the essential gene product IMP-L2, found in Drosophila, where it is im plicated in neural and ectodermal development (Garbe, J. C., Yang, E., and Fristrom, J. W. (1993) Development 119, 1237-1250). Here we show that the I MP-L2 protein also binds insulin and related peptides, offering a possible functional explanation to the IMP-L2 null lethality.