Protein Structure and Folding
Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1*

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Tissue-specific alternative splicing in the second half of Ig-like domain 3 (D3) of fibroblast growth factor receptors 1–3 (FGFR1 to -3) generates epithelial FGFR1b-FGFR3b and mesenchymal FGFR1c-FGFR3c splice isoforms. This splicing event establishes a selectivity filter to restrict the ligand binding specificity of FGFRb and FGFRc isoforms to mesenchymally and epithelially derived fibroblast growth factors (FGFs), respectively. FGF1 is termed the “universal FGFR ligand” because it overrides this specificity barrier. To elucidate the molecular basis for FGF1 cross-reactivity with the “b” and “c” splice isoforms of FGFRs, we determined the first crystal structure of FGF1 in complex with an FGFRb isoform, FGFR2b, at 2.1 Å resolution. Comparison of the FGF1-FGFR2b structure with the three previously published FGF1-FGFRc structures reveals that plasticity in the interactions of the N-terminal region of FGF1 with FGFR D3 is the main determinant of FGF1 cross-reactivity with both isoforms of FGFRs. In support of our structural data, we demonstrate that substitution of three N-terminal residues (Gly-19, His-25, and Phe-26) of FGF2 (a ligand that does not bind FGFR2b) for the corresponding residues of FGF1 (Phe-16, Asn-22, and Tyr-23) enables the FGF2 triple mutant to bind and activate FGFR2b. These findings taken together with our previous structural data on receptor binding specificity of FGF2, FGF8, and FGF10 conclusively show that sequence divergence at the N termini of FGFs is the primary regulator of the receptor binding specificity and promiscuity of FGFs.

Crystal Structure
Fibroblast Growth Factor (FGF)
Fibroblast Growth Factor Receptor (FGFR)
Receptor Regulation
Surface Plasmon Resonance (SPR)
Ligand-Receptor Specificity

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The atomic coordinates and structure factors (codes 3OJ2, 3OJM, and 3OJV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

*

This work was supported, in whole or in part, by National Institutes of Health (NIH) Grant DE13686 (to M. M.).

This article contains supplemental Figs. 1–7.

1

Both authors contributed equally to this work.

2

Supported in part by the Training in Pharmacological Sciences grant (NIH/NIGMS Grant T32 GM066704).

3

Present addresses: Dept. of Dermatology, University of Connecticut Health Center, Farmington, CT 06032 and the Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.

4

Present address: Dept. of Structural Biology, Sloan-Kettering Institute, New York, NY 10065.