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The mannose 6-phosphate⁄insulin-like growth factor II receptor has diverse ligand-binding properties contributing to its roles in lysosome biogenesis and growth suppression. Optimal receptor binding and internalization of mannose 6-phosphate (Man-6-P)-bearing ligands requires a dimeric struc-ture leading to bivalent high-affinity binding, presumably mediated by cooperation between sites on both subunits. | ỊFEBS Journal High-affinity ligand binding by wild-type mutant heteromeric complexes of the mannose 6-phosphate insulin-like growth factor II receptor Michelle A. Hartman1 Jodi L. Kreiling2 James C. Byrd1 and Richard G. MacDonald1 1 Department of Biochemistry and Molecular Biology University of Nebraska MedicalCenter Omaha NE USA 2 Department of Chemistry University of Nebraska Omaha NE USA Keywords insulin-like growth factor II ligand binding mannose 6-phosphate mannose 6-phosphate insulin-like growth factor II receptor oligomerization Correspondence R. G. MacDonald Department of Biochemistry and Molecular Biology University of Nebraska MedicalCenter 985870 Nebraska MED CTR Omaha NE 68198 5870 USA Fax 1 402 559 6650 Tel 1 402 559 7824 E-mail rgmacdon@unmc.edu Received 17 October 2008 revised 19 December 2008 accepted 21 January 2009 doi 10.1111 j.1742-4658.2009.06917.x The mannose 6-phosphate insulin-like growth factor II receptor has diverse ligand-binding properties contributing to its roles in lysosome biogenesis and growth suppression. Optimal receptor binding and internalization of mannose 6-phosphate Man-6-P -bearing ligands requires a dimeric structure leading to bivalent high-affinity binding presumably mediated by cooperation between sites on both subunits. Insulin-like growth factor II IGF-II binds to a single site on each monomer. It is hypothesized that IGF-II binding to cognate sites on each monomer occurs independently but bivalent Man-6-P ligand binding requires cooperative contributions from sites on both monomers. To test this hypothesis we co-immunoprecipitated differentially epitope-tagged soluble mini-receptors and assessed ligand binding. Pairing of wild-type and point-mutated IGF-II binding sites between two dimerized mini-receptors had no effect on the function of the contralateral binding site indicating IGF-II binding to each side of the dimer is independent and manifests no intersubunit effects. As expected heterodimeric receptors .
