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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 Phe(19) and Leu(53) are critical for IGF2R binding, as are residues Thr(16) and Asp(52). Furthermore, Thr(16) was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.

Original publication

DOI

10.1074/jbc.M700531200

Type

Journal article

Journal

J Biol Chem

Publication Date

29/06/2007

Volume

282

Pages

18886 - 18894

Keywords

Amino Acid Substitution, Aspartic Acid, Binding Sites, Circular Dichroism, Humans, Hydrophobic and Hydrophilic Interactions, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Leucine, Mutagenesis, Site-Directed, Phenylalanine, Protein Folding, Protein Structure, Quaternary, Protein Structure, Tertiary, Receptor, IGF Type 2, Surface Plasmon Resonance, Threonine