Understanding the Physical Interactions in the FGF21/FGFR/β‐Klotho Complex: Structural Requirements and Implications in FGF21 Signaling
Open accessAbstract
The endocrine fibroblast growth factor 21 (FGF21) requires both fibroblast growth factor receptor (FGFR) and β‐Klotho for signaling. In this study, we sought to understand the inter‐molecular physical interactions in the FGF21/FGFR/β‐Klotho complex by deleting key regions in FGFR1c or FGF21. Deletion of the D1 and the D1‐D2 linker (the D1/linker region) from FGFR1c led to β‐Klotho‐independent receptor activation by FGF21, suggesting that there may be a direct interaction between FGF21 and the D1/linker region‐deficient FGFR1c. Consistent with this, the extracellular portion of FGFR1c lacking the D1/linker region blocked FGF21 action in a reporter assay, presumably by binding to and sequestering FGF21 from acting on cell surface receptor complex. In addition, the D1/linker region‐deficient FGFR1c had enhanced interaction with β‐Klotho. Further, we demonstrated that deletion of the D1/linker region enhanced the formation of the FGF21/β‐Klotho/FGFR1c ternary complex in both Biacore and asymmetrical flow field flow fractionation studies. Finally, we found that the N‐terminus of FGF21 is involved in the interaction with FGFR1c and FGF21/β‐Klotho/FGFR1c ternary complex formation. Taken together, our data suggest that the D1/linker region regulates both the FGF21/FGFR1c and FGFR1c/β‐Klotho interaction, and a direct interaction of FGF21 with FGFR1c may be an important step in receptor‐mediated FGF21 signaling.
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FGF21 binding promotes formation of a dimeric FGFR1c-KLB complex, activates tyrosine kinase domains and propagates signalling through ERK phosphorylation.
“FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
From Metabolic messengers: FGF21 (2021) · cites this paper as [59]
FGF21 directly binds to KLB, which facilitates binding to FGFR1c and initiates downstream signaling.
“FGF21 directly binds to KLB, which then facilitates binding to FGFR1c and then initiates downstream signaling events [[146], [147], [148], [149]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [146]
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- Authors
- Yie, J., Wang, W., Deng, L., Tam, L., Stevens, J., Chen, M. M., Li, Y., Xu, J., Lindberg, R., Hecht, R., Véniant, M., Chen, C., & Wang, M.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Yie, Junming
- ORCID
- Venue
- Chemical Biology & Drug Design
- Publisher
- Wiley
- Published
- 2012-02
- Volume
- 79
- Issue
- 4
- Pages
- 398-410
- ISSN
- 1747-0277 (ISSN-L)
- 1747-0285
- OpenAlex
- W1486302655
- Cited by
- 99
- References
- 29
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 11 · 2023: 11 · 2022: 5 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 5
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Chemical Biology & Drug Design (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- FGF21, β-Klotho, receptor activation, protein-protein interaction
- MeSH terms
- Klotho Proteins, Cell Line, Fibroblast Growth Factors, Humans, Membrane Proteins, Signal Transduction, Receptor, Fibroblast Growth Factor, Type 1, Protein Interaction Domains and Motifs
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