Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation

Regina Goetz, Yuji Nakada, Ming C Hu, Hiroshi Kurosu, Lei Wang, Teruyo Nakatani, Mingjun Shi, Anna V. Eliseenkova, Mohammed S. Razzaque, Orson W Moe, Makoto Kuro-o, Moosa Mohammadi

Research output: Contribution to journalArticlepeer-review

282 Scopus citations


Fibroblast growth factor (FGF) 23 inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent fashion. The phosphaturic activity of FGF23 is abrogated by proteolytic cleavage at the RXXR motif that lies at the boundary between the FGF core homology domain and the 72-residue-long C-terminal tail of FGF23. Here, we show that the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with FGF23 in vitro. The C-terminal tail of FGF23 mediates binding of FGF23 to a de novo site generated at the composite FGFR1c-Klotho interface. Consistent with this finding, the isolated 72-residue-long C-terminal tail of FGF23 impairs FGF23 signaling by competing with full-length ligand for binding to the binary FGFR-Klotho complex. Injection of the FGF23 C-terminal tail peptide into healthy rats inhibits renal phosphate excretion and induces hyperphosphatemia. In a mouse model of renal phosphate wasting attributable to high FGF23, the FGF23 C-terminal peptide reduces phosphate excretion, leading to an increase in serum phosphate concentration. Our data indicate that proteolytic cleavage at the RXXR motif abrogates FGF23 activity by a dual mechanism: by removing the binding site for the binary FGFR-Klotho complex that resides in the C-terminal region of FGF23, and by generating an endogenous inhibitor of FGF23. We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting.

Original languageEnglish (US)
Pages (from-to)407-412
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - 2010


  • Binary FGF receptor 1c-klotho complex
  • Composite FGF receptor 1c-klotho interface
  • Endogenous inhibitor of FGF23
  • FGF23 C-terminal peptide
  • FGF23 antagonist

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation'. Together they form a unique fingerprint.

Cite this