Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate

Brian K. Yeh, Anna V. Eliseenkova, Alexander N. Plotnikov, David Green, Jared Pinnell, Tulay Polat, Amel Gritli-Linde, Robert J. Linhardt, Moosa Mohammadi

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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-Å 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.

Original languageEnglish
Pages (from-to)7184-7192
Number of pages9
JournalMolecular and Cellular Biology
Volume22
Issue number20
DOIs
StatePublished - Oct 2002
Externally publishedYes

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