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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Nature 2018 ; 553 (7689): 461-6 Nephropedia Template TP
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?Klotho is a Non-Enzymatic Molecular Scaffold for FGF23 Hormone Signaling #MMPMID29342138
Chen G; Liu Y; Goetz R; Fu L; Jayaraman S; Hu MC; Moe OW; Liang G; Li X; Mohammadi M
Nature 2018[Jan]; 553 (7689): 461-6 PMID29342138show ga
The aging suppressor ?Klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion/vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex consisting of the shed extracellular domain of ?Klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, ?Klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. The endocrine character of FGF23 notwithstanding, dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signaling. The structure of ?Klotho is incompatible with its purported glycosidase activity. Thus, shed ?Klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signaling.