**Abstract from The Journal of Biological Chemistry 2012, Sept 27 [Epub ahead of issue]; DOI: 10.1074/jbc.M112.398826
Background. Heparan sulfate (HS) regulates the transport and signaling activities of fibroblast growth factors (FGF).
Results. The molecular determinants of the interactions of FGFs and heparin were identified.
Conclusion. There are clear molecular specificities determining the interactions of FGFs with the polysaccharide.
Significance. The expansion of the FGFs in metazoan evolution parallels the diversification of the specificity of their interactions with heparin.
Summary. 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 signalling 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: 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 KD 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-1s-1, FGF-9, 130,000 M-1s-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 sub-families and may be more restricted within a FGF sub-family in accord with the known conservation of function within FGF sub-families.