α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling

Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman, Ming C Hu, Orson W Moe, Guang Liang, Xiaokun Li, Moosa Mohammadi

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Abstract

The ageing suppressor α-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 and 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 that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-Terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.

Original languageEnglish (US)
Pages (from-to)461-466
Number of pages6
JournalNature
Volume553
Issue number7689
DOIs
Publication statusPublished - Jan 25 2018

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Chen, G., Liu, Y., Goetz, R., Fu, L., Jayaraman, S., Hu, M. C., ... Mohammadi, M. (2018). α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature, 553(7689), 461-466. https://doi.org/10.1038/nature25451