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Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands

Regina Goetz1, Mutsuko Ohnishi, Xunshan Ding

  • 1Department of Pharmacology, New York University School of Medicine, New York, New York, USA.

Molecular and Cellular Biology
|March 28, 2012
PubMed

Insights

Klotho coreceptors bind endocrine FGFs and FGFRs through distinct sites. This interaction enhances FGF receptor binding for endocrine FGFs while suppressing binding for paracrine FGF8 subfamily ligands.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • Klotho coreceptors are essential for fibroblast growth factor (FGF) receptor tyrosine kinase (FGFR) signaling by endocrine FGFs.
  • The precise molecular mechanisms of FGF-FGFR-Klotho ternary complex formation are not fully elucidated.

Purpose of the Study:

  • To investigate the molecular interactions between βKlotho, endocrine FGF ligands (FGF19/FGF21), and FGFRs.
  • To elucidate how Klotho coreceptors modulate the binding of different FGF subfamilies to FGFRs.

Main Methods:

  • Biochemical assays to analyze binding interactions.
  • Structural analysis of protein-ligand complexes.
  • Investigating binding sites on βKlotho and FGFRs.

Main Results:

  • βKlotho binds both its cognate endocrine FGF ligand and FGFR independently via two distinct sites.
  • FGF19 and FGF21 utilize their C-terminal tails to bind a common site on βKlotho.
  • Klotho coreceptors bind FGFRs through a conserved hydrophobic groove in the FGFR immunoglobulin-like domain III (D3).
  • This groove is also a binding site for paracrine FGF8 subfamily ligands.

Conclusions:

  • Klotho coreceptors enhance FGFR affinity for endocrine FGFs.
  • Klotho coreceptors actively inhibit the binding of FGF8 subfamily ligands to FGFRs due to overlapping binding sites.
  • This differential binding mechanism regulates FGF signaling pathways.

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