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

Article

关键词: FIBROBLAST-GROWTH-FACTOR;    TRANSCRIPTS ENCODING MEMBRANE;    C-TERMINAL TAIL;    STRUCTURAL BASIS;    BETA-KLOTHO;    FIBROBLAST-GROWTH-FACTOR-1 FGF1;    METABOLIC-ACTIVITY;    CRYSTAL-STRUCTURE;    RECEPTOR;    HEPARIN;   

DOI  :  10.1038/nature25451

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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