Structural basis for FGF hormone signalling

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 () and Moosa Mohammadi ()
Additional contact information
Lingfeng Chen: Wenzhou Medical University
Lili Fu: Wenzhou Medical University
Jingchuan Sun: Wenzhou Medical University
Zhiqiang Huang: Wenzhou Medical University
Mingzhen Fang: Wenzhou Medical University
Allen Zinkle: Columbia University Irving Medical Center
Xin Liu: Wenzhou Medical University
Junliang Lu: Wenzhou Medical University
Zixiang Pan: Wenzhou Medical University
Yang Wang: Wenzhou Medical University
Guang Liang: Hangzhou Medical College
Xiaokun Li: Wenzhou Medical University
Gaozhi Chen: Wenzhou Medical University
Moosa Mohammadi: Wenzhou Medical University

Nature, 2023, vol. 618, issue 7966, 862-870

Abstract: 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 complex3–6. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities6. 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 signalling2 as therapeutics for human metabolic diseases and cancer.

Date: 2023
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DOI: 10.1038/s41586-023-06155-9

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