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

Author

Listed:
  • Gaozhi Chen

    (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University
    New York University School of Medicine)

  • Yang Liu

    (New York University School of Medicine)

  • Regina Goetz

    (New York University School of Medicine)

  • Lili Fu

    (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University
    New York University School of Medicine)

  • Seetharaman Jayaraman

    (New York Structural Biology Center)

  • Ming-Chang Hu

    (and Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center)

  • Orson W. Moe

    (and Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center)

  • Guang Liang

    (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University)

  • Xiaokun Li

    (Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University)

  • Moosa Mohammadi

    (New York University School of Medicine)

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.

Suggested Citation

  • Gaozhi Chen & Yang Liu & Regina Goetz & Lili Fu & Seetharaman Jayaraman & Ming-Chang Hu & Orson W. Moe & Guang Liang & Xiaokun Li & Moosa Mohammadi, 2018. "α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling," Nature, Nature, vol. 553(7689), pages 461-466, January.
    • Handle: RePEc:nat:nature:v:553:y:2018:i:7689:d:10.1038_nature25451
    DOI: 10.1038/nature25451
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