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Molecular and Cellular Biology, September 2001, p. 5946-5957, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5946-5957.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of Receptor and Heparin Binding Sites in Fibroblast Growth Factor 4 by Structure-Based Mutagenesis

Paola Bellosta,1,dagger Akiyo Iwahori,1 Alexander N. Plotnikov,2 Anna V. Eliseenkova,2 Claudio Basilico,1 and Moosa Mohammadi2,*

Departments of Microbiology1 and Pharmacology,2 New York University School of Medicine, New York, New York 10016

Received 26 March 2001/Returned for modification 22 May 2001/Accepted 11 June 2001

Fibroblast growth factors (FGFs) comprise a large family of multifunctional, heparin-binding polypeptides that show diverse patterns of interaction with a family of receptors (FGFR1 to -4) that are subject to alternative splicing. FGFR binding specificity is an essential mechanism in the regulation of FGF signaling and is achieved through primary sequence differences among FGFs and FGFRs and through usage of two alternative exons, IIIc and IIIb, for the second half of immunoglobulin-like domain 3 (D3) in FGFRs. While FGF4 binds and activates the IIIc splice forms of FGFR1 to -3 at comparable levels, it shows little activity towards the IIIb splice forms of FGFR1 to -3 as well as towards FGFR4. To begin to explore the structural determinants for this differential affinity, we determined the crystal structure of FGF4 at a 1.8-Å resolution. FGF4 adopts a beta -trefoil fold similar to other FGFs. To identify potential receptor and heparin binding sites in FGF4, a ternary FGF4-FGFR1-heparin model was constructed by superimposing the FGF4 structure onto FGF2 in the FGF2-FGFR1-heparin structure. Mutation of several key residues in FGF4, observed to interact with FGFR1 or with heparin in the model, produced ligands with reduced receptor binding and concomitant low mitogenic potential. Based on the modeling and mutational data, we propose that FGF4, like FGF2, but unlike FGF1, engages the beta C'-beta E loop in D3 and thus can differentiate between the IIIc and IIIb splice isoforms of FGFRs for binding. Moreover, we show that FGF4 needs to interact with both the 2-O- and 6-O-sulfates in heparin to exert its optimal biological activity.

* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: mohammad{at}saturn.med.nyu.edu.

dagger Present address: Department of Zoology, University of Zurich, Zurich, Switzerland.

Molecular and Cellular Biology, September 2001, p. 5946-5957, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5946-5957.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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