title: Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate.
abstract: Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-A resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed "two-end" model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.
authors.affiliation: Departments of Pharmacology. Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Yeh
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.forename: Jared
authors.initials: J
authors.lastname: Pinnell
authors.forename: Tulay
authors.initials: T
authors.lastname: Polat
authors.forename: Amel
authors.initials: A
authors.lastname: Gritli-Linde
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D006493:Heparin / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry*; D015398:Signal Transduction; D013395:Sucrose / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D013395:Sucrose; D006493:Heparin; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C053081:sucrose octasulfate