2. Academic Validation
  3. Structural basis for FGF hormone signalling

Structural basis for FGF hormone signalling

  • Nature. 2023 Jun 7. doi: 10.1038/s41586-023-06155-9.
Lingfeng Chen # 1 2,  Lili Fu # 1 3 4,  Jingchuan Sun # 1 5,  Zhiqiang Huang # 1 3,  Mingzhen Fang # 1 3,  Allen Zinkle 6,  Xin Liu 1 3,  Junliang Lu 1 3,  Zixiang Pan 1 3,  Yang Wang 1 7,  Guang Liang 2,  Xiaokun Li 8 9 10,  Gaozhi Chen 11 12 13,  Moosa Mohammadi 14 15
Affiliations

Affiliations

  • 1 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 2 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China.
  • 3 Institute of Cell Growth Factor, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, China.
  • 4 State Key Laboratory for Macromolecule Drugs and Large-scale Preparation, Wenzhou Medical University, Wenzhou, China.
  • 5 Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
  • 6 Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
  • 7 Center of Biomedical Physics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
  • 8 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 9 State Key Laboratory for Macromolecule Drugs and Large-scale Preparation, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 10 National Engineering Research Center of Cell Growth Factor Drugs and Protein Biologics, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 11 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 12 Institute of Cell Growth Factor, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, China. [email protected].
  • 13 Institute of chronic kidney disease, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 14 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. [email protected].
  • 15 Institute of Cell Growth Factor, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, China. [email protected].
  • # Contributed equally.
PMID: 37286607 DOI: 10.1038/s41586-023-06155-9
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.

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