title: Cooperative heparin-mediated oligomerization of fibroblast growth factor-1 (FGF1) precedes recruitment of FGFR2 to ternary complexes.
abstract: Fibroblast growth factors (FGFs) utilize cell surface heparan sulfate as a coreceptor in the assembly of signaling complexes with FGF-receptors on the plasma membrane. Here we undertake a complete thermodynamic characterization of the assembly of the FGF signaling complex using isothermal titration calorimetry. Heparin fragments of defined length are used as chemical analogs of the sulfated domains of heparan sulfate and examined for their ability to oligomerize FGF1. Binding is modeled using the McGhee-von Hippel formalism for the cooperative binding of ligands to a monodimensional lattice. Oligomerization of FGFs on heparin is shown to be mediated by positive cooperativity (α = 6). Heparin octasaccharide is the shortest length capable of dimerizing FGF1 and on longer heparin chains FGF1 binds with a minimal footprint of 4.2 saccharide units. The thermodynamics and stoichiometry of the ternary complex suggest that in solution FGF1 binds to heparin in a trans-dimeric manner before FGFR recruitment.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. ab604@cam.ac.uk
authors.forename: Alan
authors.initials: A
authors.lastname: Brown
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Robinson
authors.forename: John T
authors.initials: JT
authors.lastname: Gallagher
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000595:Amino Acid Sequence; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D046912:Multiprotein Complexes; D005346:Fibroblast Growth Factors; D006493:Heparin; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2