The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
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Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
PHENIX : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463
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Krissinel, E., & Henrick, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.022 · Cited by 10,007
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334
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Laskowski, R., & Swindells, M. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci200227u · Cited by 6,159
Dali server: conservation mapping in 3D
Holm, L., & Rosenstr�m, P. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq366 · Cited by 3,640
Cellular signaling by fibroblast growth factor receptors
Eswarakumar, V. P., Lax, I., & Schlessinger, J. (2005) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2005.01.001 · Cited by 1,923
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The Klotho proteins in health and disease
Kuro-o, M. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-018-0078-3 · Cited by 707
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607
Liu, Y., Chen, K., Li, F., Gu, Z., Liu, Q., He, L., Shao, T., Song, Q., Zhu, F., Zhang, L., et al. (2019) · Hepatology · doi:10.1002/hep.30975 · Cited by 373
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311
Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors
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Metadata
- 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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