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

Nature. 2018 Jan 25;553(7689):461-466. doi: 10.1038/nature25451. Epub 2018 Jan 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Body Fluids / metabolism
  • Female
  • Fibroblast Growth Factors / chemistry*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Glucuronidase / chemistry*
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Heparitin Sulfate / metabolism
  • Humans
  • Ligands
  • Male
  • Mice
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation
  • Paracrine Communication*
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • Receptor, Fibroblast Growth Factor, Type 1 / chemistry*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Signal Transduction*
  • Solubility

Substances

  • Ligands
  • Multiprotein Complexes
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Heparitin Sulfate
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Glucuronidase
  • klotho protein