School of Medicine Publications and Presentations

Document Type

Article

Publication Date

8-18-2025

Abstract

Fibroblast growth factor 23 (FGF23) requires both αKlotho and heparan sulfate proteoglycans (HSPGs) as obligatory coreceptors to bind, dimerize, and activate its FGF receptors (FGFRs) in the kidney, thereby regulating mineral ion and vitamin D homeostasis. Cryogenic electron microscopy studies reveal that FGF23 signaling proceeds through an asymmetric 1:2:1:1 FGF23–FGFR–αKlotho–HS assembly. According to this structural model, αKlotho simultaneously anchors FGF23 and one FGFR chain, referred to as the primary receptor (FGFRP), to form a 1:1:1 FGF23-FGFRP-αKlotho triplex, which boosts FGF23-FGFRP interaction. Subsequently, the HS coreceptor aids the triplex in recruiting a second FGFR chain, or secondary receptor (FGFRS), leading to asymmetric receptor dimerization. This recruitment is driven by the interactions of FGF23 and FGFRP from the triplex with the secondary receptor, with no direct involvement from αKlotho. This model outlines the possibility of heterodimerization among the renal cognate receptors of FGF23 (namely, FGFR1c, FGFR3c, and FGFR4), which may introduce signaling diversity affecting phosphate and vitamin D regulation. In addition, it proposes that kidney-specific HS structures could cooperate with renal αKlotho to home FGF23 to renal tissues. The proposed FGF23 signaling assembly provides a framework for further investigation and may inform the development of FGF23 antagonists or partial agonists for treating disorders associated with phosphate and vitamin D dysregulation.

Comments

© 2025 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

American Journal of Physiology-Cell Physiology

DOI

10.1152/ajpcell.01020.2024

Academic Level

faculty

Mentor/PI Department

Medical Education

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