Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling
Open accessAbstract
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.
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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 [148]
Cellular FGF21 signaling is mediated by a receptor complex including FGFR1c and beta-Klotho (Klb), with Klb providing cellular specificity and FGFR driving intracellular signaling.
“Cellular FGF21 signaling is mediated by a receptor complex that includes a classic FGF receptor (FGFR1c) and a co-receptor known as beta-Klotho (Klb), with Klb functioning as the primary binding/targeting factor providing cellular specificity and FGFR functioning as the catalytic subunit that drives intracellular signaling”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [112]
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- Authors
- Lee, S., Choi, J., Mohanty, J., Sousa, L. P., Tome, F., Pardon, E., Steyaert, J., Lemmon, M. A., Lax, I., & Schlessinger, J.
- Affiliations
- Yale University (US)
- Vrije Universiteit Brussel (BE)
- Corresponding author
- Schlessinger, Joseph
- Venue
- Nature
- Published
- 2018-01
- Volume
- 553
- Issue
- 7689
- Pages
- 501-505
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6594174
- OpenAlex
- W2784316575
- Cited by
- 236
- References
- 33
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 31 · 2023: 34 · 2022: 23 · 2021: 33 · 2020: 24 · 2019: 29 · 2018: 22
- FWCI
- 9.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Nature
- Funders
- Fonds Wetenschappelijk Onderzoek
- National Institutes of Health (DE-AC02–06CH11357, 1s10od018007-01, DE-AC02-76SF00515, GM103403)
- National Cancer Institute (U54CA193417)
- National Institute of General Medical Sciences (P41GM111244, P41GM103393, P41GM103403)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- β-Klotho, FGF21, fibroblast growth factor receptor, FGF19, fibroblast growth factor 23, heparan sulfate proteoglycans, ligand specificity, extracellular domain crystal structure, metabolic hormones, bile acid synthesis, insulin sensitivity
- MeSH terms
- Protein Domains, Fibroblast Growth Factor-23, Klotho Proteins, Binding Sites, Extracellular Space, Fibroblast Growth Factors, Glycoside Hydrolases, Humans, Ligands, Membrane Proteins, Models, Molecular, Protein Binding, Substrate Specificity, Signal Transduction, Receptors, Fibroblast Growth Factor, Crystallography, X-Ray, HEK293 Cells
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