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J. Biol. Chem., Vol. 283, Issue 5, 2604-2613, February 1, 2008

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Structural Basis for the Lower Affinity of the Insulin-like Growth Factors for the Insulin Receptor^*

Lisbeth Gauguin¹, Birgit Klaproth, Waseem Sajid, Asser S. Andersen, Kerrie A. McNeil^¶, Briony E. Forbes^¶, and Pierre De Meyts

From the Receptor Systems Biology Laboratory, Hagedorn Research Institute, 2820 Gentofte, Denmark, Protein Expression, Novo Nordisk A/S, 2760 Måløv, Denmark, and the ^¶School of Molecular and Biomedical Science, University of Adelaide, South Australia, Adelaide 5005, Australia

Insulin and the insulin-like growth factors (IGFs) bind with high affinity to their cognate receptor and with lower affinity to the noncognate receptor. The major structural difference between insulin and the IGFs is that the IGFs are single chain polypeptides containing A-, B-, C-, and D-domains, whereas the insulin molecule contains separate A- and B-chains. The C-domain of IGF-I is critical for high affinity binding to the insulin-like growth factor I receptor, and lack of a C-domain largely explains the low affinity of insulin for the insulin-like growth factor I receptor. It is less clear why the IGFs have lower affinity for the insulin receptor. In this study, 24 insulin analogues and four IGF analogues were expressed and analyzed to explore the role of amino acid differences in the A- and B-domains between insulin and the IGFs in binding affinity for the insulin receptor. Using the information obtained from single substituted analogues, four multiple substituted analogues were produced. A "quadruple insulin" analogue ([Phe^A8, Ser^A10, Thr^B5, Gln^B16]Ins) showed affinity as IGF-I for the insulin receptor, and a "sextuple insulin" analogue ([Phe^A8, Ser^A10, Thr^A18, Thr^B5, Thr^B14, Gln^B16]Ins) showed an affinity close to that of IGF-II for the insulin receptor, whereas a "quadruple IGF-I" analogue ([His⁴, Tyr¹⁵, Thr⁴⁹, Ile⁵¹]IGF-I) and a "sextuple IGF-II" analogue ([His⁷, Ala¹⁶, Tyr¹⁸, Thr⁴⁸, Ile⁵⁰, Asn⁵⁸]IGF-II) showed affinities similar to that of insulin for the insulin receptor. The mitogenic potency of these analogues correlated well with the binding properties. Thus, a small number of A- and B-domain substitutions that map to the IGF surface equivalent to the classical binding surface of insulin weaken two hotspots that bind to the insulin receptor site 1.

Received for publication, November 9, 2007

^* The Receptor Systems Biology Laboratory and the Hagedorn Research Institute are basic research components of Novo Nordisk A/S. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by an Industrial Ph.D. scholarship from the Danish Ministry of Science, Technology, and Innovation. To whom correspondence should be addressed: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. Tel.: 45-44439317; Fax: 45-44438000; E-mail: LGau{at}hagedorn.dk.

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