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

  • Nature volume 553, pages 501505 (25 January 2018)
  • doi:10.1038/nature25010
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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 activation1,2. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues3,4. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss5. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains3,4. 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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The NSLS-SSRL is supported by P41GM111244, P41GM103393, DE-SC0012704 and by DE-AC02-76SF00515. We thank NE-CAT (P41 GM103403) and APS (DE-AC02-06CH11357). This research was also supported by NIH grant 1S10OD018007 and NIH Award S10RR026992-0110. J.St. thanks INSTRUCT (ESFRI, FWO) for financial support and I. Aboutaleb for technical assistance.

Author information


  1. Department of Pharmacology and Yale Cancer Biology Institute, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA

    • Sangwon Lee
    • , Jungyuen Choi
    • , Jyotidarsini Mohanty
    • , Leiliane P. Sousa
    • , Francisco Tome
    • , Mark A. Lemmon
    • , Irit Lax
    •  & Joseph Schlessinger
  2. VIB Center for Structural Biology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium

    • Els Pardon
    •  & Jan Steyaert


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S.L. designed, performed experiments and determined the crystal structures. J.C., J.M. and F.T. provided technical support. E.P. and J.St. generated nanobodies. L.P.S. and I.L. designed and analysed cell-based experiments. S.L., M.A.L. and J.Sc. designed experiments, analysed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joseph Schlessinger.

Reviewer Information Nature thanks N. Jura, K. White, H. E. Xu and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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