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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Published on: September 30, 2019

Mutations uncouple human fibroblast growth factor (FGF)-7 biological activity and receptor binding and support broad

I Sher1, A Weizman, S Lubinsky-Mink

  • 1Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

The Journal of Biological Chemistry
|November 27, 1999
PubMed

Insights

The fibroblast growth factor (FGF) loop is crucial for receptor activation, not just binding. This finding impacts understanding FGF signaling and designing targeted therapies.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Protein Structure-Function Relationships

Background:

  • Fibroblast growth factors (FGFs) and their tyrosine kinase receptors (FGFRs) regulate vital physiological and pathological processes.
  • The precise mechanism of FGF-induced FGFR activation and the role of specific structural elements remain areas of active investigation.
  • FGFs exhibit diverse receptor binding and cell-specific activities, suggesting unique interaction mechanisms.

Purpose of the Study:

  • To investigate the functional role of a specific beta-strand loop in FGF-7's interaction with its cognate FGFR.
  • To elucidate how structural variations in this loop contribute to FGF family members' distinct receptor binding specificities.
  • To explore the relationship between receptor binding affinity and biological activity in FGF-7 signaling.

Main Methods:

  • Site-directed mutagenesis was employed to alter specific residues within the FGF-7 loop.
  • Loop replacement experiments were conducted between FGF-7 and FGF-2 to assess functional conservation.
  • Receptor binding affinity, mitogenic potency, and FGFR-mediated phosphorylation were measured to evaluate functional consequences.

Main Results:

  • Point mutations in the FGF-7 loop did not affect receptor binding affinity but significantly reduced mitogenic potency and FGFR phosphorylation.
  • These findings indicate the loop's role in facilitating receptor activation rather than initial low-affinity binding.
  • Reciprocal loop exchanges between FGF-2 and FGF-7 did not alter their established receptor binding or specificity.

Conclusions:

  • The studied loop in FGF-7 functions as a low-affinity binding site essential for receptor activation, supporting a bivalent receptor dimerization model.
  • The observed uncoupling of binding and activity suggests potential for developing FGF-7 antagonists.
  • Despite structural differences, the loop appears to serve a functionally analogous role in both FGF-2 and FGF-7.

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