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 peptide-binding protein (IBP) secreted from cells of the insect Spodoptera frugiperda. This IBP is composed of two Ig-like C2 domains, has a molecular mass of 27 kDa, binds human insulin with an affinity of 70 pm, and inhibits insulin 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 peptide insulin) with high affinity, whereas an insulin analog with a Asp-B10 mutation bound with only 1% of the affinity of human insulin. This binding profile suggests that IBP recognizes a region that is highly conserved in the insulin superfamily but distinct from the classical insulin receptor binding site. The closest homologue of the Spodoptera frugiperda binding protein is the essential gene product IMP-L2, found in Drosophila, where it is implicated in neural and ectodermal development (Garbe, J. C., Yang, E., and Fristrom, J. W. (1993) Development 119, 1237-1250). Here we show that the IMP-L2 protein also binds insulin and related peptides, offering a possible functional explanation to the IMP-L2 null lethality.
Sloth Andersen
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Insulin Research, Novo Nordisk, Novo Allé, DK-2880 Bagsvaerd, Denmark.asa@novo.dk
Hertz Hansen
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P
Schaffer
L
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Kristensen
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D019476:Insect Proteins / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018411:Spodoptera / Q000235:genetics*
D002352:Carrier Proteins; D018076:DNA, Complementary; C410231:IBP protein, Spodoptera frugiperda; D007136:Immunoglobulins; D019476:Insect Proteins; D007328:Insulin; D011972:Receptor, Insulin