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Antiangiogenic forms of antithrombin specifically bind to the anticoagulant heparin sequence
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2008 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, no 51, 13610-13619 p.Article in journal (Refereed) Published
Abstract [en]

A specific pentasaccharide sequence of heparin binds with high affinity to native antithrombin and induces a conformational change in the inhibitor by a previously described two-step interaction mechanism. In this work, the interactions of heparin with the antiangiogenic latent and cleaved antithrombin forms were studied. Binding of heparin to these antithrombin forms was specific for the same pentasaccharide sequence as native antithrombin. Rapid kinetic studies demonstrated that this pentasaccharide induced a conformational change also in latent and cleaved antithrombin. The binding affinities of these antithrombin forms for the pentasaccharide, as compared to native antithrombin, were approximately 30-fold lower due to two to three fewer ionic interactions, resulting in less stable conformationally altered states. Affinities of latent and cleaved antithrombin for longer heparin chains, containing the pentasaccharide sequence, were 2-fold lower than for the pentasaccharide itself. This contrasts the interaction with native antithrombin and demonstrates that residues flanking the pentasaccharide sequence of heparin are repelled by the latent and cleaved forms. These findings contribute to delineating the mechanism by which heparin or heparan sulfate mediates antiangiogenic activity of antithrombin.

Place, publisher, year, edition, pages
2008. Vol. 47, no 51, 13610-13619 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-98948DOI: 10.1021/bi801656uISI: 000261768100018PubMedID: 19035835OAI: oai:DiVA.org:uu-98948DiVA: diva2:201700
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2017-12-13Bibliographically approved

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