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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; Brown, K; Bezos, Anna; Ferro, Vito; Parish, Christopher

Description

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...[Show more]

dc.contributor.authorFreeman, Craig
dc.contributor.authorLiu, Ligong
dc.contributor.authorBanwell, Martin
dc.contributor.authorBrown, K
dc.contributor.authorBezos, Anna
dc.contributor.authorFerro, Vito
dc.contributor.authorParish, Christopher
dc.date.accessioned2015-12-13T22:42:56Z
dc.identifier.issn0021-9258
dc.identifier.urihttp://hdl.handle.net/1885/78972
dc.description.abstractHeparin 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 cfaemokine, 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.
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc
dc.sourceJournal of Biological Chemistry
dc.subjectKeywords: Carbon; Hydrophobicity; Negative ions; Sugars; Sulfur; Alkyl spacers; Glycosaminoglycans (GAG); Heparan sulfate (HS); Sulfation; Proteins; cathepsin G; elastase; eotaxin; fibroblast growth factor 1; fibroblast growth factor 2; glycosaminoglycan; heparan s
dc.titleUse of sulfated linked cyclitols as heparan sulfate mimetics to probe the heparin/heparan sulfate binding specificity of proteins
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume280
dc.date.issued2005
local.identifier.absfor110704 - Cellular Immunology
local.identifier.ariespublicationMigratedxPub7514
local.type.statusPublished Version
local.contributor.affiliationFreeman, Craig, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLiu, Ligong, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationBanwell, Martin, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationBrown, K, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBezos, Anna, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationFerro, Vito, Progen Industries Ltd
local.contributor.affiliationParish, Christopher, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue10
local.bibliographicCitation.startpage8842
local.bibliographicCitation.lastpage8849
local.identifier.doi10.1074/jbc.M410769200
dc.date.updated2015-12-11T10:09:42Z
local.identifier.scopusID2-s2.0-15744392518
CollectionsANU Research Publications

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