Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members

Regina Goetz, Andrew Beenken, Omar A. Ibrahimi, Juliya Kalinina, Shaun K. Olsen, Anna V. Eliseenkova, Chong Feng Xu, Thomas A. Neubert, Fuming Zhang, Robert J. Linhardt, Xijie Yu, Kenneth E. White, Takeshi Inagaki, Steven A. Kliewer, Masaya Yamamoto, Hiroshi Kurosu, Yasushi Ogawa, Makoto Kuro-o, Beate Lanske, Mohammed S. RazzaqueMoosa Mohammadi

Research output: Contribution to journalArticle

332 Scopus citations

Abstract

Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/βKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between β strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the β1-β2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/βKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.

Original languageEnglish (US)
Pages (from-to)3417-3428
Number of pages12
JournalMolecular and cellular biology
Volume27
Issue number9
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Goetz, R., Beenken, A., Ibrahimi, O. A., Kalinina, J., Olsen, S. K., Eliseenkova, A. V., Xu, C. F., Neubert, T. A., Zhang, F., Linhardt, R. J., Yu, X., White, K. E., Inagaki, T., Kliewer, S. A., Yamamoto, M., Kurosu, H., Ogawa, Y., Kuro-o, M., Lanske, B., ... Mohammadi, M. (2007). Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Molecular and cellular biology, 27(9), 3417-3428. https://doi.org/10.1128/MCB.02249-06