TY - JOUR
T1 - Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands
AU - Goetz, Regina
AU - Ohnishi, Mutsuko
AU - Ding, Xunshan
AU - Kurosu, Hiroshi
AU - Wang, Lei
AU - Akiyoshi, Junko
AU - Ma, Jinghong
AU - Gai, Weiming
AU - Sidis, Yisrael
AU - Pitteloud, Nelly
AU - Kuro-o, Makoto
AU - Razzaque, Mohammed S.
AU - Mohammadi, Moosa
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.06603-11
DO - 10.1128/MCB.06603-11
M3 - Article
C2 - 22451487
AN - SCOPUS:84861355961
SN - 0270-7306
VL - 32
SP - 1944
EP - 1954
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 10
ER -