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Molecular and Cellular Biology, October 2002, p. 7184-7192, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7184-7192.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate

Brian K. Yeh,1 Anna V. Eliseenkova,1 Alexander N. Plotnikov,1,{dagger} David Green,2 Jared Pinnell,2 Tulay Polat,3 Amel Gritli-Linde,4 Robert J. Linhardt,3 and Moosa Mohammadi1*

Departments of Pharmacology,1 Medicine, New York University School of Medicine, New York, New York 10016,2 Departments of Chemistry, Medicinal and Natural Products Chemistry, and Chemical and Biochemical Engineering, University of Iowa, Iowa City, Iowa 52242,3 Department of Oral Biochemistry, Göteborg University, Göteborg, Sweden4

Received 9 May 2002/ Returned for modification 9 July 2002/ Accepted 19 July 2002

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.

* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: mohammad{at}saturn.med.nyu.edu.

{dagger} Present address: Plexxikon Inc., Berkeley, CA 94710.

Molecular and Cellular Biology, October 2002, p. 7184-7192, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7184-7192.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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