Cited by 236Fibroblast Growth Factor ResearchParathyroid Disorders and TreatmentsReceptor Mechanisms and Signaling

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Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling

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Lee, Sangwon, Choi, Jungyuen, Mohanty, Jyotidarsini, Sousa, Leiliane P., Tome, Francisco, Pardon, Els, Steyaert, Jan, Lemmon, Mark A., Lax, Irit, Schlessinger, Joseph·2018·Nature

DOI 10.1038/nature25010PMC PMC6594174

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Abstract

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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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
ORCID: Pardon, Els
Steyaert, Jan
Lemmon, Mark A.
Schlessinger, Joseph
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-01
Volume: 553
Issue: 7689
Pages: 501-505
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature25010
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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Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling

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