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
StatePublished - Jan 25 2018

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Fibroblast Growth Factor Receptors
Paracrine Communication
Hormones
Heparitin Sulfate
Glycoside Hydrolases
Dimerization
Vitamin D
Minerals
Homeostasis
Ions
Ligands
Proteins

ASJC Scopus subject areas

  • General

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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

α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. / Chen, Gaozhi; Liu, Yang; Goetz, Regina; Fu, Lili; Jayaraman, Seetharaman; Hu, Ming C; Moe, Orson W; Liang, Guang; Li, Xiaokun; Mohammadi, Moosa.

In: Nature, Vol. 553, No. 7689, 25.01.2018, p. 461-466.

Research output: Contribution to journalArticle

Chen, G, Liu, Y, Goetz, R, Fu, L, Jayaraman, S, Hu, MC, Moe, OW, Liang, G, Li, X & Mohammadi, M 2018, 'α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling', Nature, vol. 553, no. 7689, pp. 461-466. https://doi.org/10.1038/nature25451
Chen G, Liu Y, Goetz R, Fu L, Jayaraman S, Hu MC et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018 Jan 25;553(7689):461-466. https://doi.org/10.1038/nature25451
Chen, Gaozhi ; Liu, Yang ; Goetz, Regina ; Fu, Lili ; Jayaraman, Seetharaman ; Hu, Ming C ; Moe, Orson W ; Liang, Guang ; Li, Xiaokun ; Mohammadi, Moosa. / α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. In: Nature. 2018 ; Vol. 553, No. 7689. pp. 461-466.
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