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

Yeh, Brian K.
Eliseenkova, Anna V.
Plotnikov, Alexander N.
Green, David
Pinnell, Jared
Polat, Tulay
Gritli-Linde, Amel
Linhardt, Robert J.
Mohammadi, Moosa
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate, B.K. Yeh, A.V. Eliseenkova, A.N. Plotnikov, D. Green, J. Pinnell, T. Polat, A. Gritli-Linde, R.J. Linhardt, M. Mohammadi, Molecular and Cellular Biology, 22, 7184-7192, 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.
Molecular and Cellular Biology, 22, 7184-7192
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
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Rensselaer Polytechnic Institute, Troy, NY
Molecular and Cellular Biology