Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density.

2.50
Hdl Handle:
http://hdl.handle.net/10541/67951
Title:
Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density.
Authors:
Catlow, Krista R; Deakin, Jon A; Wei, Zheng; Delehedde, Maryse; Fernig, David G; Gherardi, Ermanno; Gallagher, John T; Pavão, Mauro S G; Lyon, Malcolm
Abstract:
Hepatocyte growth factor/scatter factor (HGF/SF) has a cofactor requirement for heparan sulfate (HS) and dermatan sulfate (DS) in the optimal activation of its signaling receptor MET. However, these two glycosaminoglycans (GAGs) have different sugar backbones and sulfation patterns, with only the presence of iduronate in common. The structural basis for GAG recognition and activation is thus very unclear. We have clarified this by testing a wide array of natural and modified GAGs for both protein binding and activation. Comparisons between Ascidia nigra (2,6-O-sulfated) and mammalian (mainly 4-O-sulfated) DS species, as well as between a panel of specifically desulfated heparins, revealed that no specific sulfate isomer, in either GAG, is vital for interaction and activity. Moreover, different GAGs of similar sulfate density had comparable properties, although affinity and potency notably increase with increasing sulfate density. The weaker interaction with CS-E, compared with DS, shows that GlcA-containing polymers can bind, if highly sulfated, but emphasizes the importance of the flexible IdoA ring. Our data indicate that the preferred binding sites in DS in vivo will be comprised of disulfated, IdoA(2S)-containing motifs. In HS, clustering of N-/2-O-/6-O-sulfation in S-domains will lead to strong reactivity, although binding can also be mediated by the transition zones where sulfates are mainly at the N- and 6-O- positions. GAG recognition of HGF/SF thus appears to be primarily driven by electrostatic interactions and exhibits an interesting interplay between requirements for iduronate and sulfate density that may reflect in part a preference for particular sugar chain conformations.
Affiliation:
Cancer Research UK Glyco-Oncology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.
Citation:
Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density. 2008, 283 (9):5235-48 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
29-Feb-2008
URI:
http://hdl.handle.net/10541/67951
DOI:
10.1074/jbc.M706589200
PubMed ID:
18156180
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research; Medical Oncology

Full metadata record

DC FieldValue Language
dc.contributor.authorCatlow, Krista R-
dc.contributor.authorDeakin, Jon A-
dc.contributor.authorWei, Zheng-
dc.contributor.authorDelehedde, Maryse-
dc.contributor.authorFernig, David G-
dc.contributor.authorGherardi, Ermanno-
dc.contributor.authorGallagher, John T-
dc.contributor.authorPavão, Mauro S G-
dc.contributor.authorLyon, Malcolm-
dc.date.accessioned2009-05-12T16:33:52Z-
dc.date.available2009-05-12T16:33:52Z-
dc.date.issued2008-02-29-
dc.identifier.citationInteractions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density. 2008, 283 (9):5235-48 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid18156180-
dc.identifier.doi10.1074/jbc.M706589200-
dc.identifier.urihttp://hdl.handle.net/10541/67951-
dc.description.abstractHepatocyte growth factor/scatter factor (HGF/SF) has a cofactor requirement for heparan sulfate (HS) and dermatan sulfate (DS) in the optimal activation of its signaling receptor MET. However, these two glycosaminoglycans (GAGs) have different sugar backbones and sulfation patterns, with only the presence of iduronate in common. The structural basis for GAG recognition and activation is thus very unclear. We have clarified this by testing a wide array of natural and modified GAGs for both protein binding and activation. Comparisons between Ascidia nigra (2,6-O-sulfated) and mammalian (mainly 4-O-sulfated) DS species, as well as between a panel of specifically desulfated heparins, revealed that no specific sulfate isomer, in either GAG, is vital for interaction and activity. Moreover, different GAGs of similar sulfate density had comparable properties, although affinity and potency notably increase with increasing sulfate density. The weaker interaction with CS-E, compared with DS, shows that GlcA-containing polymers can bind, if highly sulfated, but emphasizes the importance of the flexible IdoA ring. Our data indicate that the preferred binding sites in DS in vivo will be comprised of disulfated, IdoA(2S)-containing motifs. In HS, clustering of N-/2-O-/6-O-sulfation in S-domains will lead to strong reactivity, although binding can also be mediated by the transition zones where sulfates are mainly at the N- and 6-O- positions. GAG recognition of HGF/SF thus appears to be primarily driven by electrostatic interactions and exhibits an interesting interplay between requirements for iduronate and sulfate density that may reflect in part a preference for particular sugar chain conformations.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshCarbohydrate Conformation-
dc.subject.meshGlycosaminoglycans-
dc.subject.meshHepatocyte Growth Factor-
dc.subject.meshHumans-
dc.subject.meshIduronic Acid-
dc.subject.meshProtein Binding-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshReceptors, Growth Factor-
dc.subject.meshRecombinant Proteins-
dc.subject.meshSpecies Specificity-
dc.subject.meshSulfates-
dc.subject.meshUrochordata-
dc.titleInteractions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Glyco-Oncology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen
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