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A catalytic role of heparin within the extracellular matrix

easytest 添加于 2009-9-28 12:33 | 1538 次阅读 | 0 个评论

作者
Mitsi M, Forsten-Williams K, Gopalakrishnan M, Nugent MA
摘要
We investigated the mechanism by which heparin enhances the binding of vascular endothelial growth factor (VEGF) to the extracellular matrix protein fibronectin. In contrast to other systems, where heparin acts as a protein scaffold, we found that heparin functions catalytically to modulate VEGF binding site availability on fibronectin. By measuring the binding of VEGF and heparin to surface-immobilized fibronectin, we show that substoichiometric amounts of heparin exposed cryptic VEGF binding sites within fibronectin that remain available after heparin removal. Measurement of association and dissociation kinetics for heparin binding to fibronectin indicated that the interaction is rapid and transient. We localized the heparin-responsive element to the C-terminal 40-kDa Hep2 domain of fibronectin. A mathematical model of this catalytic process was constructed that supports a mechanism whereby the heparin-induced conformational change in fibronectin is accompanied by release of heparin. Experiments with endothelial extracellular matrix suggest that this process may also occur within biological matrices. These results indicate a novel mechanism whereby heparin catalyzes the conversion of fibronectin to an open conformation by transiently interacting with fibronectin and progressively hopping from molecule to molecule. Catalytic activation of the extracellular matrix might be an important mechanism for heparin to regulate function during normal and disease states.
详细资料
- 关键词: Animals; Anticoagulants/pharmacology; Binding Sites; Catalysis; Cattle; Extracellular Matrix/*metabolism; Fibronectins/chemistry; Heparin/*chemistry/pharmacology; Humans; Kinetics; Models, Chemical; Protein Binding; Protein Structure, Tertiary; Recombinant Proteins/chemistry; Vascular Endothelial Growth Factor A/chemistry
- 文献种类:期刊
- 期刊名称: The Journal of Biological Chemistry
- 期刊缩写: J Biol Chem
- 期卷页: 2008年第283卷第50期 34796-34807页
- 地址: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
- ISBN: 0021-9258
- 备注:PMID:18845539
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