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

Nature volume 553, pages 461466 (25 January 2018) | Download Citation


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.

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We thank N. J. Cowan for critically reading and editing the manuscript, and C.-S. Huang for help with diffraction data processing with XDS. This work was primarily supported by NIH grant R01 DE13686 (to M.M.). Support was also provided by National Key R&D Program of China (#2017YFA0506000 to X.L.). Funding for mouse studies was provided by R01 DK092461, P30 DK079328 (to O.W.M.), and R01 DK091392 (to M.C.H). Beamlines at the Northeastern Collaborative Access Team (NE-CAT) facility at the Advanced Photon Source of Argonne National Laboratory are primarily funded by NIH NIGMS and member institutions.

Author information

Author notes

    • Gaozhi Chen
    •  & Yang Liu

    These authors contributed equally to this work.


  1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China

    • Gaozhi Chen
    • , Lili Fu
    • , Guang Liang
    •  & Xiaokun Li
  2. Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA

    • Gaozhi Chen
    • , Yang Liu
    • , Regina Goetz
    • , Lili Fu
    •  & Moosa Mohammadi
  3. New York Structural Biology Center, New York, New York 10027, USA

    • Seetharaman Jayaraman
  4. Departments of Internal Medicine and Physiology, and Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Ming-Chang Hu
    •  & Orson W. Moe


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G.C. purified and crystallized the ternary complex, analysed the crystal structure, generated SEC–MALS data (Figs 4a, 5a, b, f), cell-based data (Fig. 4), enzyme and thermostability assay data (Fig. 2c), and participated in the design of experiments and the writing/revising of the manuscript. Y.L. helped with data collection and analysis of the crystal structure, generated cell-based data (Fig. 5), and participated in manuscript revision. R.G. established expression and purification protocols for the ternary complex, performed ternary complex characterization, analysed mouse data, and participated in editing and revising the manuscript. L.F. generated expression constructs for FGF23, FGFR1cecto, α-klothoecto and their structure-based mutated forms, and helped with ternary complex purification. S.J. assisted with diffraction data collection and performed excitation/emission scanning of the FGF23–FGFR1cecto–α-klothoecto crystal (Extended Data Fig. 2c). M.-C.H. and O.W.M. generated the mouse data (Extended Data Figs 1c, d and 7a, b). G.L. and X.L. (mentors of G.C. and L.F.) participated in manuscript revision. M.M. developed and directed the project, solved, refined, analysed and interpreted the crystal structure of the ternary complex, and wrote the manuscript.

Competing interests

O.W.M. has done paid consultation for AbbVie, Allena, Amgen, and Tricida. He also sits on the board of Klotho Therapeutics. All of the other authors have no competing financial interests to declare.

Corresponding authors

Correspondence to Xiaokun Li or Moosa Mohammadi.

Reviewer Information Nature thanks M. Kuro-o and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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