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Related Experiment Video

Updated: Jan 18, 2026

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Structural basis for FGF hormone signalling.

Lingfeng Chen1,2, Lili Fu1,3,4, Jingchuan Sun1,5

  • 1Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

Nature
|June 7, 2023
PubMed
Summary
This summary is machine-generated.

Heparan sulfate (HS) acts as a coreceptor, enabling fibroblast growth factor (FGF) hormones to activate FGF receptors (FGFRs) via asymmetric dimerization. This finding challenges existing models and offers new therapeutic targets for metabolic diseases and cancer.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Endocrinology

Background:

  • Fibroblast growth factor (FGF) hormones require αKlotho coreceptors and heparan sulfate (HS) proteoglycans for metabolic signaling.
  • The precise molecular mechanism of HS as a coreceptor in FGF-FGFR complex activation remains incompletely understood.

Purpose of the Study:

  • To elucidate the structural basis of HS's coreceptor function in FGF23-mediated signaling.
  • To determine the mechanism of FGF receptor (FGFR) dimerization and activation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to solve structures of FGF23-FGFR-αKlotho-HS quaternary complexes.
  • Cell-based receptor complementation and heterodimerization assays.

Main Results:

  • Structural determination of three distinct FGF23-FGFR-αKlotho-HS complexes revealed a 1:1:1 ternary complex recruiting a secondary FGFR via HS.
  • A single HS chain facilitates asymmetric FGFR dimerization and activation, a mechanism also applicable to paracrine FGF signaling.
  • αKlotho was found not to directly participate in secondary receptor recruitment or dimerization.

Conclusions:

  • The study overturns the symmetric FGFR dimerization model, establishing an asymmetric mechanism driven by HS.
  • These findings provide a structural foundation for developing novel therapeutics targeting FGF signaling in metabolic diseases and cancer.