title: Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation.
abstract: 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.
authors: Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors: Regina
authors: R
authors: Goetz
authors: Yuji
authors: Y
authors: Nakada
authors: Ming Chang
authors: MC
authors: Hu
authors: Hiroshi
authors: H
authors: Kurosu
authors: Lei
authors: L
authors: Wang
authors: Teruyo
authors: T
authors: Nakatani
authors: Mingjun
authors: M
authors: Shi
authors: Anna V
authors: AV
authors: Eliseenkova
authors: Mohammed S
authors: MS
authors: Razzaque
authors: Orson W
authors: OW
authors: Moe
authors: Makoto
authors: M
authors: Kuro-o
authors: Moosa
authors: M
authors: Mohammadi
mesh_terms: D000818:Animals; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017674:Hypophosphatemia / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009893:Opossums; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C000717427:FGF23 protein, human; C488187:FRS2alpha protein, mouse; C000717428:Fgf23 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D010455:Peptides; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins