The glycosaminoglycan binding site governs ligand binding to the somatomedin B domain of vitronectin.
The ligand binding functions of vitronectin (Vn) are regulated by its conformational state/degree of multimerization. In the native plasma form of Vn, the C-terminal glycosaminoglycan (GAG) binding domain is believed to be cryptic. Here, evidence is provided that the addition of fucoidan or dextran sulfate to unfractionated plasma results in the formation of covalently and non-covalently stabilized Vn multimers. These multimers express conformationally sensitive antibody epitopes and ligand binding sites located in the N terminus of the Vn molecule. While heparin forms complexes with monomeric plasma Vn and induces conformational changes, a reduction in ionic strength is required for induction of multimerization. In addition, heparin serves as a template for the assembly of type 1 plasminogen activator inhibitor-induced disulfide-linked Vn multimers. These results support a new model for the structure of native Vn. The C-terminal GAG binding domain is predicted to be exposed in the native conformation, whereas the N terminus is cryptic. Ligand binding to the GAG binding site unfolds the N terminus, thereby exposing cryptic ligand binding sites.
Seiffert
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Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA. seiffeda@a1.lldmpc.umc.dupont.com
D000925:Anticoagulants / Q000494:pharmacology; D001665:Binding Sites; D002846:Chromatography, Affinity; D016264:Dextran Sulfate / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D009994:Osmolar Concentration; D011134:Polysaccharides / Q000494:pharmacology; D011487:Protein Conformation; D013002:Somatomedins / Q000737:chemistry / Q000378:metabolism*; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism*
D000925:Anticoagulants; D006025:Glycosaminoglycans; D011134:Polysaccharides; D013002:Somatomedins; D019096:Vitronectin; C016756:somatomedin B; D006493:Heparin; D016264:Dextran Sulfate; C007789:fucoidan