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

ABSTRACT: The ageing suppressor ?-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 ?-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, ?-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 ?-klotho is incompatible with its purported glycosidase activity. Thus, shed ?-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.

SUBMITTER: Chen G 

PROVIDER: S-EPMC6007875 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature