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

Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman, Ming-Chang Hu, Orson W. Moe, Guang Liang, Xiaokun Li () and Moosa Mohammadi ()
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Gaozhi Chen: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University
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
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

Nature, 2018, vol. 553, issue 7689, 461-466

Abstract: 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.

Date: 2018
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DOI: 10.1038/nature25451

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