Structural basis for FGF hormone signalling

作者：Lingfeng Chen, Lili Fu, Jingchuan Sun, Zhiqiang Huang, Mingzhen Fang, Allen Zinkle, Xin Liu, Junliang Lu, Zixiang Pan, Yang Wang, Guang Liang, Xiaokun Li, Gaozhi Chen, Moosa Mohammadi · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06155-9 · 被引用次数：132 · 研究领域：Fibroblast Growth Factor Research、Proteoglycans and glycosaminoglycans research

Abstract α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) 1,2 and their cognate cell-surface FGF receptors (FGFR1–4) thereby stabilizing the endocrine FGF–FGFR complex 3–6 . 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 6 . 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 2 as therapeutics for human metaboli...