Journal Article

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

Liang, Guang, Mohammadi, Moosa, Hu, Ming-Chang, Moe, Orson W., Liu, Yang, Fu, Lili, Goetz, Regina, Jayaraman, Seetharaman, Li, Xiaokun, Chen, Gaozhi

2018

Overview

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. The crystal structure of shed ectodomain of α-klotho bound to the FGFR1c ligand-binding domain and FGF23 unveils the mechanism by which klotho co-receptors promote hormonal FGF signalling. Mechanisms of metabolic hormones The endocrine fibroblast growth factors (FGF19, FGF21 and FGF23) are circulating hormones that regulate important metabolic and physiological functions in vertebrates. Canonical FGFs require heparan sulfate proteoglycans to activate FGF receptors, but endocrine FGFs instead depend on klotho proteins for this process. There are two klothos, encoded by different genes: β-klotho is essential for FGF19- and FGF21-dependent signaling, whereas α-klotho is required for FGF23-dependent signalling. In this issue, Joseph Schlessinger and colleagues report crystal structures of the β-klotho extracellular domain, in ligand-free form and bound to a C-terminal peptide of FGF21. Moosa Mohammadi and colleagues report the atomic structure of a 1:1:1 ternary complex, which consists of the extracellular domain that is shed from membrane-anchored α-klotho into body fluids, the FGFR1c ligand-binding domain and FGF23. These hormones and their receptors are highly desirable drug targets owing to their central role in metabolism and physiology. Their structures offer the first glimpse of klotho and provide long-awaited mechanistic insights into the signalling pathways that are regulated by endocrine FGFs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/109 / 631/443/319 / 631/443/7 / 631/535/1266 / 64/60 / 82 / 82/80 / 82/83 / 96 / Aging / Animals / Atomic structure / Binding / Binding Sites - genetics / Body Fluids - metabolism / Crystal structure / Dimerization / Female / Fibroblast growth factor 23 / Fibroblast growth factor receptors / Fibroblast Growth Factors - chemistry / Fibroblast Growth Factors - genetics / Fibroblast Growth Factors - metabolism / Fibroblasts / Glucuronidase - chemistry / Glucuronidase - genetics / Glucuronidase - metabolism / Growth factors / Heparan sulfate / Heparitin Sulfate - metabolism / Homeostasis / Humanities and Social Sciences / Humans / Klotho protein / Ligands / Male / Metabolism / Mice / Models, Molecular / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Mutation / Paracrine Communication / Paracrine signalling / Protein Binding / Protein Domains / Protein Multimerization / Proteins / Receptor mechanisms / Receptor, Fibroblast Growth Factor, Type 1 - chemistry / Receptor, Fibroblast Growth Factor, Type 1 - metabolism / Science / Signal Transduction / Solubility / Sulfates / Tethers / Vitamin D