Diversification of the Structural Determinants of Fibroblast Growth Factor-Heparin Interactions IMPLICATIONS FOR BINDING SPECIFICITY



Xu, Ruoyan, Ori, Alessandro, Rudd, Timothy R ORCID: 0000-0003-4434-0333, Uniewicz, Katarzyna A, Ahmed, Yassir A, Guimond, Scott E, Skidmore, Mark A, Siligardi, Giuliano, Yates, Edwin A ORCID: 0000-0001-9365-5433 and Fernig, David G ORCID: 0000-0003-4875-4293
(2012) Diversification of the Structural Determinants of Fibroblast Growth Factor-Heparin Interactions IMPLICATIONS FOR BINDING SPECIFICITY. JOURNAL OF BIOLOGICAL CHEMISTRY, 287 (47). pp. 40061-40073.

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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.

Item Type: Article
Additional Information: ## TULIP Type: Articles/Papers (Journal) ##
Uncontrolled Keywords: Animals, Humans, Rats, Heparin, Fibroblast Growth Factors, Binding Sites, Protein Binding, Structure-Activity Relationship
Depositing User: Symplectic Admin
Date Deposited: 17 Jun 2015 13:36
Last Modified: 24 Jan 2023 19:19
DOI: 10.1074/jbc.M112.398826
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2013820