HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 283/5/2604    most recent M709220200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gauguin, L. Articles by De Meyts, P. Search for Related Content PubMed PubMed Citation Articles by Gauguin, L. Articles by De Meyts, P. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. L. Alvino, K. A. McNeil, S. C. Ong, C. Delaine, G. W. Booker, J. C. Wallace, J. Whittaker, and B. E. Forbes A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II J. Biol. Chem., March 20, 2009; 284(12): 7656 - 7664. [Abstract] [Full Text] [PDF]

				L. Gauguin, C. Delaine, C. L. Alvino, K. A. McNeil, J. C. Wallace, B. E. Forbes, and P. De Meyts Alanine Scanning of a Putative Receptor Binding Surface of Insulin-like Growth Factor-I J. Biol. Chem., July 25, 2008; 283(30): 20821 - 20829. [Abstract] [Full Text] [PDF]

				Q.-x. Hua, S. H. Nakagawa, W. Jia, K. Huang, N. B. Phillips, S.-q. Hu, and M. A. Weiss Design of an Active Ultrastable Single-chain Insulin Analog: SYNTHESIS, STRUCTURE, AND THERAPEUTIC IMPLICATIONS J. Biol. Chem., May 23, 2008; 283(21): 14703 - 14716. [Abstract] [Full Text] [PDF]