Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Freeman, Craig, Liu, Ligong, Banwell, Martin G., Brown, Kathryn J., Bezos, Anna, Ferro, Vito and Parish, Christopher R. (2005) Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins. Journal of Biological Chemistry, 280 10: 8842-8849. doi:10.1074/jbc.M410769200

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Author Freeman, Craig
Liu, Ligong
Banwell, Martin G.
Brown, Kathryn J.
Bezos, Anna
Ferro, Vito
Parish, Christopher R.
Title Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2005
Sub-type Article (original research)
DOI 10.1074/jbc.M410769200
Open Access Status File (Publisher version)
Volume 280
Issue 10
Start page 8842
End page 8849
Total pages 8
Place of publication Bethesda, MD
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 030401 Biologically Active Molecules
Abstract Heparin and heparan sulfate (HS) are structurally diverse glycosaminoglycans (GAG) that are known to interact, via unique structural motifs, with a wide range of functionally distinct proteins and modulate their biological activity. To define the GAG motifs that interact with proteins, we assessed the ability of 15 totally synthetic HS mimetics to interact with 10 functionally diverse proteins that bind heparin/HS. The HS mimetics consisted of cyclitol-based pseudo-sugars coupled by linkers of variable chain length, flexibility, orientation, and hydrophobicity, with variations in sulfation also being introduced into some molecules. Three of the proteins tested, namely hepatocyte growth factor, eotaxin, and elastase, failed to interact with any of the sulfated linked cyclitols. In contrast, each of the remaining seven proteins tested exhibited a unique reactivity pattern with the panel of HS mimetics, with tetrameric cyclitols linked by different length alkyl chains being particularly informative. Thus, compounds with short alkyl spacers (2–3 carbon atoms) effectively blocked the interaction of fibroblast growth factor-1 (FGF-1) and lipoprotein lipase with heparin/HS, whereas longer chain spacers (7–10 carbon atoms) were required for optimal inhibition of FGF-2 and vascular endothelial growth factor binding. This effect was most pronounced with the chemokine, interleukin-8, where alkyl-linked tetrameric cyclitols were essentially inactive unless a spacer of >7 carbon atoms was used. The heparin-inhibitable enzymes heparanase and cathepsin G also displayed characteristic inhibition patterns, cathepsin G interacting promiscuously with most of the sulfated cyclitols but heparanase activity being inhibited most effectively by HS mimetics that structurally resemble a sulfated pentasaccharide. These data indicate that a simple panel of HS mimetics can be used to probe the HS binding specificity of proteins, with the position of anionic groups in the HS mimetics being critical.
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
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