7YSW

Cryo-EM Structure of FGF23-FGFR4-aKlotho-HS Quaternary Complex

7YSW の概要

• エントリーDOI: 10.2210/pdb7ysw/pdb
• EMDBエントリー: 34084
• 分子名称: Fibroblast growth factor receptor 4, Klotho, Fibroblast growth factor 23, ... (6 entities in total)
• 機能のキーワード: fgf hormones, fgf receptor, klotho co-receptor, heparan sulfate glycosaminoglycans, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 179194.76

構造登録者

Mohammadi, M.,Chen, L. (登録日: 2022-08-13, 公開日: 2023-06-14, 最終更新日: 2025-06-18)

主引用文献

Chen, L.,Fu, L.,Sun, J.,Huang, Z.,Fang, M.,Zinkle, A.,Liu, X.,Lu, J.,Pan, Z.,Wang, Y.,Liang, G.,Li, X.,Chen, G.,Mohammadi, M.
Structural basis for FGF hormone signalling.
Nature, 618:862-870, 2023

PubMed Abstract: α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling as therapeutics for human metabolic diseases and cancer.

PubMed: 37286607
DOI: 10.1038/s41586-023-06155-9

実験手法

ELECTRON MICROSCOPY (3.03 Å)