title: Diversification of the structural determinants of fibroblast growth factor-heparin interactions: implications for binding specificity.
abstract: The functions of a large number (>435) of extracellular regulatory proteins are controlled by their interactions with heparan sulfate (HS). In the case of fibroblast growth factors (FGFs), HS binding determines their transport between cells and is required for the assembly of high affinity signaling complexes with their cognate FGF receptor. However, the specificity of the interaction of FGFs with HS is still debated. Here, we use a panel of FGFs (FGF-1, FGF-2, FGF-7, FGF-9, FGF-18, and FGF-21) spanning five FGF subfamilies to probe their specificities for HS at different levels as follows: binding parameters, identification of heparin-binding sites (HBSs) in the FGFs, changes in their secondary structure caused by heparin binding and structures in the sugar required for binding. For interaction with heparin, the FGFs exhibit K(D) values varying between 38 nM (FGF-18) and 620 nM (FGF-9) and association rate constants spanning over 20-fold (FGF-1, 2,900,000 M(-1) s(-1) and FGF-9, 130,000 M(-1) s(-1)). The canonical HBS in FGF-1, FGF-2, FGF-7, FGF-9, and FGF-18 differs in its size, and these FGFs have a different complement of secondary HBS, ranging from none (FGF-9) to two (FGF-1). Differential scanning fluorimetry identified clear preferences in these FGFs for distinct structural features in the polysaccharide. These data suggest that the differences in heparin-binding sites in both the protein and the sugar are greatest between subfamilies and may be more restricted within a FGF subfamily in accord with the known conservation of function within FGF subfamilies.
authors.affiliation: Institute of Integrative Biology, Department of Chemical and Structural Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Xu
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ori
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rudd
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Uniewicz
authors.forename: Yassir A
authors.initials: YA
authors.lastname: Ahmed
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.forename: Mark A
authors.initials: MA
authors.lastname: Skidmore
authors.forename: Giuliano
authors.initials: G
authors.lastname: Siligardi
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Yates
authors.forename: David G
authors.initials: DG
authors.lastname: Fernig
mesh_terms: D000818:Animals; D001665:Binding Sites; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D005346:Fibroblast Growth Factors; D006493:Heparin