title: Interactions of hepatocyte growth factor/scatter factor with various glycosaminoglycans reveal an important interplay between the presence of iduronate and sulfate density.
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.
authors.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.
authors.forename: Krista R
authors.initials: KR
authors.lastname: Catlow
authors.forename: Jon A
authors.initials: JA
authors.lastname: Deakin
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wei
authors.forename: Maryse
authors.initials: M
authors.lastname: Delehedde
authors.forename: David G
authors.initials: DG
authors.lastname: Fernig
authors.forename: Ermanno
authors.initials: E
authors.lastname: Gherardi
authors.forename: John T
authors.initials: JT
authors.lastname: Gallagher
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavão
authors.forename: Malcolm
authors.initials: M
authors.lastname: Lyon
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D006025:Glycosaminoglycans / Q000737:chemistry* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007067:Iduronic Acid / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D013431:Sulfates / Q000737:chemistry* / Q000378:metabolism; D014561:Urochordata / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; C066855:HGF protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D013431:Sulfates; C020341:glucosaminoglycans; D007067:Iduronic Acid; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met