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M009402200v1
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Papers In Press, published online ahead of print January 12, 2001
J. Biol. Chem, 10.1074/jbc.M009402200
Submitted on October 16, 2000
Revised on December 5, 2000
Accepted on January 11, 2001

Dimeric Fragment of the Insulin Receptor alpha -Subunit Binds Insulin with Full Holoreceptor Affinity

Jakob Brandt, Asser Sloth Andersen, and Claus Kristensen

Molecular Biology 528, Insulin Research, 2880 Bagsvaerd, - DK-2880

Corresponding Author: jakb{at}novonordisk.com

The insulin receptor (IR) is a dimeric receptor and its activation is thought to involve cross-linking between monomers initiated by binding of a single insulin molecule to separate epitopes on each monomer. We have previously shown that a minimized insulin receptor consisting of the first three domains of the human IR fused to 16 amino acids from the C-terminal of the alpha -subunit was monomeric and bound insulin with nanomolar affinity (Kristensen, C., Wiberg, F. C., Schäffer, L., and Andersen, A. S. (1998) J. Biol. Chem. 273, 17780-17786). To investigate the insulin binding properties of dimerized alpha -subunits, we have reintroduced the domains containing a-a disulfide bonds into this minireceptor. When inserting either the first fibronectin type III domain or the full-length sequence of exon 10, the receptor fragments were predominantly secreted as disulfide-linked dimers that both had nanomolar affinity for insulin, similar to the affinity found for the minireceptor. However, when both these domains were included we obtained a soluble dimeric receptor that bound insulin with 1000 fold higher affinity (4-8 pM) similar to what is obtained for the solubilized holoreceptor (14-24 pM). Moreover, dissociation of labeled insulin from this receptor was accelerated in the presence of unlabeled insulin, demonstrating another characteristic feature of the holoreceptor. This is the first direct demonstration that the alpha -subunit of IR contains all the epitopes required for binding insulin with full holoreceptor affinity.


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