Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin

Abstract

Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) and heparan sulphate proteoglycan in a specific complex on the cell surface. Direct involvement of the heparan sulphate glycosaminoglycan polysaccharide in the molecular association between FGF and its receptor is essential for biological activity. Although crystal structures of binary complexes of FGF-heparin and FGF-FGFR have been described, the molecular architecture of the FGF signalling complex has not been elucidated. Here we report the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking two FGF1 ligands into a dimer that bridges between two receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling.

The Kaposi's sarcoma-associated herpesvirus complement control protein (KCP) binds to heparin and cell surfaces via positively charged amino acids in CCP1–2

“…Approaching heparin molecules in solution can therefore bind with only small torsional changes on its stable conformation, which is consistent with previous observations of experimental heparin structures (PDB code 1hpn) or co-crystallysed complexes (eg. PDB codes 1rid, 1bfc and 1e0o) (Faham et al, 1996;Ganesh et al, 2004;Mulloy et al, 1993;Pellegrini et al, 2000).…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…Data from microscopy, covalent cross-linking, and x-ray crystallography experiments have revealed that cell surface receptors from many structural classes assemble into multi-receptor complexes; these include some heptahelical G-protein coupled receptors (GPCRs), [36][37][38] methyl-accepting chemotaxis proteins (MCPs), [39] gated ion channels, [40] receptor protein tyrosine kinases (RPTKs), [41,42] and multichain immune recognition receptors (MIRRs). [22,33,35,[43][44][45] The size of these ensembles varies: Some complexes are composed of two receptors while others contain thousands.…”

Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena

“…At the cell surface, HSPGs contribute to the formation of a ternary complex with two FGF molecules and one growth factor receptor chain, which form an "activated" unit (34). The HSPGs can also serve as important reservoirs for other angiogenic factors.…”