title: Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands.
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 αKlotho, 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.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Xunshan
authors.initials: X
authors.lastname: Ding
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurosu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Junko
authors.initials: J
authors.lastname: Akiyoshi
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: Weiming
authors.initials: W
authors.lastname: Gai
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Sidis
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Razzaque
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008024:Ligands; D019899:Paracrine Communication; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496456:FGF8 protein, human; D008024:Ligands; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D051524:Fibroblast Growth Factor 8; D005966:Glucuronidase; D000090265:Klotho Proteins