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

Regina Goetz, Mutsuko Ohnishi, Xunshan Ding, Hiroshi Kurosu, Lei Wang, Junko Akiyoshi, Jinghong Ma, Weiming Gai, Yisrael Sidis, Nelly Pitteloud, Makoto Kuro-o, Mohammed S. Razzaque, Moosa Mohammadi

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to βKlotho, βKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on βKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR.

Original languageEnglish (US)
Pages (from-to)1944-1954
Number of pages11
JournalMolecular and cellular biology
Volume32
Issue number10
DOIs
StatePublished - May 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Goetz, R., Ohnishi, M., Ding, X., Kurosu, H., Wang, L., Akiyoshi, J., Ma, J., Gai, W., Sidis, Y., Pitteloud, N., Kuro-o, M., Razzaque, M. S., & Mohammadi, M. (2012). Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Molecular and cellular biology, 32(10), 1944-1954. https://doi.org/10.1128/MCB.06603-11