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Oligomerization Dynamics of Cell Surface Receptors in Living Cells by Total Internal Reflection Fluorescence Microscopy Combined with Number and Brightness Analysis
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Identification and concerted function of two receptor binding surfaces on basic fibroblast growth factor required for

B A Springer1, M W Pantoliano, F A Barbera

  • 1Department of Crystallography, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0228.

The Journal of Biological Chemistry
|October 28, 1994
PubMed

Insights

Basic fibroblast growth factor (bFGF) uses two distinct binding sites to interact with fibroblast growth factor receptors (FGFRs), enabling cell proliferation. This monomeric ligand mechanism facilitates FGFR dimerization for signal transduction.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Protein Structure

Background:

  • Fibroblast growth factors (FGFs) are crucial signaling molecules involved in angiogenesis, wound repair, neuronal development, and disease pathogenesis.
  • FGFs mediate cellular responses by interacting with fibroblast growth factor receptors (FGFRs) and heparan sulfate proteoglycans on the cell surface, leading to mitogenesis.

Purpose of the Study:

  • To identify and characterize the specific fibroblast growth factor receptor (FGFR) binding sites on basic fibroblast growth factor (bFGF) using protein structure-based mutagenesis.
  • To elucidate the mechanism by which bFGF initiates signal transduction through FGFR interaction.

Main Methods:

  • Site-directed mutagenesis of basic fibroblast growth factor (bFGF) guided by protein structure analysis.
  • Characterization of FGFR binding interactions and their contribution to signal transduction.

Main Results:

  • Two distinct FGFR binding sites were identified on bFGF, separate from the heparan sulfate proteoglycan binding domain.
  • The primary binding site, with higher affinity, is dominated by hydrophobic interactions and contributes ~75% of the binding energy.
  • A secondary, lower affinity binding site involves specific amino acids in a beta-turn.
  • A 2:1 stoichiometry of FGFR to bFGF binding is required for growth factor-mediated cell proliferation.

Conclusions:

  • Basic fibroblast growth factor (bFGF) functions as a monomeric ligand that facilitates fibroblast growth factor receptor (FGFR) dimerization.
  • This dimerization process, mediated by two distinct binding surfaces on bFGF, is essential for initiating downstream signal transduction and subsequent cell proliferation.

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