title: Probing structural selectivity of synthetic heparin binding to Stabilin protein receptors.
abstract: As one of the most widely used drugs worldwide, heparin is an essential anticoagulant required for surgery, dialysis, treatment of thrombosis, cancer, and general circulatory management. Stabilin-2 is a scavenger clearance receptor with high expression in the sinusoidal endothelium of liver. It is believed that Stabilin-2 is the primary receptor for the clearance of unfractionated and low molecular weight heparins in the liver. Here, we identify the modifications and length of the heparin polymer that are required for binding and endocytosis by both human Stabilin receptors: Stabilin-2 and its homolog Stabilin-1 (also found in liver endothelium). Using enzymatically synthesized (35)S-labeled heparan sulfate oligomers, we identified that sulfation of the 3-OH position of N-sulfated glucosamine (GlcNS) is the most beneficial modification for binding and endocytosis via both Stabilin receptors. In addition, our data suggest that a decasaccharide is the minimal size for binding to the Stabilin receptors. These findings define the physical parameters of the heparin structure required for efficient clearance from blood circulation. These results will also aid in the design of synthetic heparins with desired clearance rates.
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Pempe
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xu
authors.forename: Sandhya
authors.initials: S
authors.lastname: Gopalakrishnan
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Edward N
authors.initials: EN
authors.lastname: Harris
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002236:Carbohydrate Conformation; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006493:Heparin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016201:Receptors, Lymphocyte Homing / Q000235:genetics / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D015816:Cell Adhesion Molecules, Neuronal; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human; C449927:STAB2 protein, human; C486732:Stab1 protein, mouse; C486733:Stab2 protein, mouse; D006493:Heparin