Work

Cooperative Heparin-Mediated Oligomerization of Fibroblast Growth Factor-1 (FGF1) Precedes Recruitment of FGFR2 to Ternary Complexes

Year: 2013

Type: article

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.

Source: Biophysical Journal

DOI: 10.1016/j.bpj.2013.02.051

Authors: Alan Brown, Christopher J. Robinson, John T. Gallagher, Tom L. Blundell

Institutions: University of Cambridge, Cancer Research UK, University of Manchester, Cancer Research UK Manchester Institute

Language: English

Topic: Fibroblast Growth Factor Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $3,000

Funders: Wellcome Trust, Biotechnology and Biological Sciences Research Council