5W21

Crystal Structure of a 1:1:1 FGF23-FGFR1c-aKlotho Ternary Complex

Summary for 5W21

• Entry DOI: 10.2210/pdb5w21/pdb
• Descriptor: Klotho, Fibroblast growth factor 23, Fibroblast growth factor receptor 1, ... (6 entities in total)
• Functional Keywords: complex, ligand, receptor, co-receptor, hydrolase-protein binding complex, hydrolase/protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 165062.43

Authors

Mohammadi, M. (deposition date: 2017-06-05, release date: 2018-01-24, Last modification date: 2024-10-09)

Primary citation

Chen, G.,Liu, Y.,Goetz, R.,Fu, L.,Jayaraman, S.,Hu, M.C.,Moe, O.W.,Liang, G.,Li, X.,Mohammadi, M.
alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.
Nature, 553:461-466, 2018

PubMed 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.

PubMed: 29342138
DOI: 10.1038/nature25451

Experimental method

X-RAY DIFFRACTION (3 Å)