Glycobiology Advance Access published online on May 22, 2008
Glycobiology, doi:10.1093/glycob/cwn045
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The ligand-binding profile of hare: hyaluronan and chondroitin sulfates A, C, and D bind to overlapping sites distinct from the sites for heparin, acetylated low-density lipoprotein, dermatan sulfate and CS-E
Department of Biochemistry & Molecular Biology, and The Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190
+ To whom correspondence should be addressed: T: 405-271-1288 F: 405-271-3092, paul-weigel{at}ouhsc.edu
Received on April 11, 2008; accepted on May 18, 2008
The Hyaluronic Acid Receptor for Endocytosis (HARE)/Stabilin-2 is the primary systemic scavenger receptor for hyaluronan (HA), the chondroitin sulfates (CS), dermatan sulfate (DS), and non-glycosaminoglycan (GAG) ligands such as acetylated low density lipoprotein (AcLDL), pro-collagen propeptides, and advanced glycation end-products. We recently discovered that HARE is also a systemic scavenger receptor for heparin (Harris et al, J. Biol. Chem. 283, 2008;ePub Apr 22). Our goal was to map the binding sites of eight different ligands within HARE. We used biotinylated GAGs and radio-iodinated streptavidin or AcLDL to assess the binding activities of ligands directly or indirectly (by competition with unlabeled ligands) in endocytosis assays using stable cell lines expressing the 315- or 190-HARE isoforms, and ELISA-like assays, with purified recombinant soluble 190-HARE ecto-domain. For example, Hep binding to HARE was competed by DS, CS-E, AcLDL, and dextran sulfate, but not by other CS types, HA, dextran, or heparosan. 125I-AcLDL binding to HARE was partially competed by Hep and dextran sulfate, but not competed by HA. Two ligands, DS and CS-E, competed with both Hep and HA to some degree. Heparin and HA-binding or endocytosis are mutually inclusive; binding of these two GAGs occurs with functionally separate, non-competitive, and apparently non-interacting domains. Thus, HARE binds to HA and Hep simultaneously. Although, the domain(s) responsible for Hep-binding remains unknown, the Link domain was required for HARE binding to HA, CS-A, CS-C, and CS-D. These results enable us to outline, for the first time, a binding-activity map for multiple ligands of HARE.
Key words: chondroitin sulfate / endocytosis / glycosaminoglycan turnover / heparin / Stabilin-2
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