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

• DOI: 10.1073/pnas.0902006107
• Publication Date: 2009-12-06T20:26:48Z
• Authors: Regina Goetz; Yuji Nakada; Ming Chang Hu; Hiroshi Kurosu; Lei Wang; Teruyo Nakatani; Mingjun Shi; Anna V. Eliseenkova; Mohammed S. Razzaque; Orson W. Moe; Makoto Kuro-o; Moosa Mohammadi
• Keywords: 0301 basic medicine; Hypophosphatemia; Membrane Proteins; Opossums; Cell Line; Protein Structure, Tertiary; Rats; Fibroblast Growth Factors; Mice, Inbred C57BL; Rats, Sprague-Dawley; Fibroblast Growth Factor-23; Mice; 03 medical and health sciences; Kidney Tubules; Multiprotein Complexes; Animals; Humans; Receptor, Fibroblast Growth Factor, Type 1; Mitogen-Activated Protein Kinases; Peptides; Klotho Proteins; Glucuronidase

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.