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| Subject Categories: Cell & Tissue Architecture |
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| The EMBO Journal
(2002) 21, 6303–6311, doi: 10.1093/emboj/cdf638 |
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| Role of heparan sulfate domain organization in endostatin inhibition of endothelial cell function |
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| Johan Kreuger2, Taro Matsumoto3, Maarten Vanwildemeersch1, Takako Sasaki4, Rupert Timpl4, Lena Claesson-Welsh3, Dorothe Spillmann1 and Ulf Lindahl1 |
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1 Department of Medical Biochemistry and Microbiology, Uppsala University, PO Box 582, SE-75123 Uppsala, Sweden 2 Present address: European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany 3 Department of Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsväg 20, SE-75185 Uppsala, Sweden 4 Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany To whom correspondence should be addressed Ulf Lindahl, Ulf.Lindahl@imbim.uu.se Received 28 February 2002; Revised 20 September 2002; Accepted 10 October 2002. |
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| Abstract |
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The anti-angiogenic activity of endostatin (ES) depends on interactions with heparan sulfate (HS). In the present study, intact HS chains of  15 kDa bound quantitatively to ES whereas N-sulfated HS decasaccharides, with affinity for several fibroblast growth factor (FGF) species, failed to bind. Instead, ES-binding oligosaccharides composed of mixed N-sulfated and N-acetylated disaccharide units were isolated from pig intestinal HS. A 10/12mer ES-binding epitope was identified, with two N-sulfated regions separated by at least one N-acetylated glucosamine unit (SAS-domain). Cleavage at the N-acetylation site disrupted ES binding. These findings point to interaction between discontinuous sulfated domains in HS and arginine clusters at the ES surface. The inhibitory effect of ES on vascular endothelial growth factor-induced endothelial cell migration was blocked by the ES-binding SAS-domains and by heparin oligosaccharides (12mers) similar in length to the ES-binding SAS-domains, but not by 6mers capable of FGF binding. We propose that SAS-domains modulate the biological activities of ES and other protein ligands with extended HS-binding sites. The results provide a rational explanation for the preferential interaction of ES with certain HS proteoglycan species. |
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| Keywords: endostatin, heparan sulfate, heparin, oligosaccharides, sulfate groups |
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