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J. Biol. Chem., Vol. 282, Issue 26, 18886-18894, June 29, 2007

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A Novel Binding Site for the Human Insulin-like Growth Factor-II (IGF-II)/Mannose 6-Phosphate Receptor on IGF-II^*

Carlie Delaine¹, Clair L. Alvino¹², Kerrie A. McNeil, Terrance D. Mulhern, Lisbeth Gauguin^¶, Pierre De Meyts^¶, E. Yvonne Jones^||3, James Brown^||, John C. Wallace, and Briony E. Forbes⁴

From the School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia, the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia, ^¶Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark, and ^||Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, University of Oxford, Oxford, United Kingdom

The mammalian insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (IGF2R) binds IGF-II with high affinity. By targeting IGF-II to lysosomal degradation, it plays a role in the maintenance of correct IGF-II levels in the circulation and in target tissues. Loss of IGF2R function is associated with tumor progression; therefore, the IGF2R is often referred to as a tumor suppressor. The interaction between IGF2R and IGF-II involves domains 11 and 13 of the 15 extracellular domains of the receptor. Recently, a hydrophobic binding region was identified on domain 11 of the IGF2R. In contrast, relatively little is known about the residues of IGF-II that are involved in IGF2R binding and the determinants of IGF2R specificity for IGF-II over the structurally related IGF-I. Using a series of novel IGF-II analogues and surface plasmon resonance assays, this study revealed a novel binding surface on IGF-II critical for IGF2R binding. The hydrophobic residues Phe¹⁹ and Leu⁵³ are critical for IGF2R binding, as are residues Thr¹⁶ and Asp⁵². Furthermore, Thr¹⁶ was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.

Received for publication, January 19, 2007 , and in revised form, April 30, 2007.

^* The Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, was supported by National Institutes of Health Grant P41 RR-01081. 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 These authors have contributed equally to this work.

² Supported by a University of Adelaide postgraduate scholarship.

³ A CR-UK Principal Research Fellow.

⁴ To whom correspondence should be addressed: School of Molecular and Biomedical Science, University of Adelaide, South Australia, Adelaide 5005, Australia. Tel.: 61-8-8303-5581; Fax: 61-8-8303-4362; E-mail: briony.forbes{at}adelaide.edu.au.

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