Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate
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Authors
Yeh, Brian K.
Eliseenkova, Anna V.
Plotnikov, Alexander N.
Green, David
Pinnell, Jared
Polat, Tulay
Gritli-Linde, Amel
Linhardt, Robert J.
Mohammadi, Moosa
Issue Date
2002-10-01
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Alternative Title
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.
Description
Molecular and Cellular Biology, 22, 7184-7192
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Full Citation
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.
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DOI
ISSN
2707306