Abstract
SummaryThe aging suppressor αKlotho 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 αKlotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, αKlotho 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 αKlotho is incompatible with its purported glycosidase activity. Thus, shed αKlotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signaling.
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