Journal
NATURE
Volume 553, Issue 7689, Pages 461-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature25451
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Funding
- NIH grant [R01 DE13686]
- National Key R&D Program of China [2017YFA0506000]
- NIH NIGMS
- [R01 DK092461]
- [P30 DK079328]
- [R01 DK091392]
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The ageing suppressor alpha-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 alpha-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, alpha-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 alpha-klotho is incompatible with its purported glycosidase activity. Thus, shed alpha-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.
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