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, ChongFeng Xu, Thomas A. Neubert, Fuming Zhang, Robert J. Linhardt, Xijie Yu, Kenneth White, Takeshi Inagaki, Steven A. Kliewer, Masaya Yamamoto, Hiroshi Kurosu, Yasushi Ogawa, Makoto Kuro-o, Beate Lanske, Mohammed S. Razzaque & 1 others Moosa Mohammadi

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301 Citations (Scopus)

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
Pages (from-to)3417-3428
Number of pages12
JournalMolecular and Cellular Biology
Volume27
Issue number9
DOIs
StatePublished - May 2007

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Fibroblast Growth Factors
Heparin
Heparitin Sulfate
Disaccharides
Bile Acids and Salts
Vitamin D
Homeostasis
Phosphates
Ligands
Lipids
Glucose

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Goetz, R., Beenken, A., Ibrahimi, O. A., Kalinina, J., Olsen, S. K., Eliseenkova, A. V., ... 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

Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. / Goetz, Regina; Beenken, Andrew; Ibrahimi, Omar A.; Kalinina, Juliya; Olsen, Shaun K.; Eliseenkova, Anna V.; Xu, ChongFeng; Neubert, Thomas A.; Zhang, Fuming; Linhardt, Robert J.; Yu, Xijie; White, Kenneth; Inagaki, Takeshi; Kliewer, Steven A.; Yamamoto, Masaya; Kurosu, Hiroshi; Ogawa, Yasushi; Kuro-o, Makoto; Lanske, Beate; Razzaque, Mohammed S.; Mohammadi, Moosa.

In: Molecular and Cellular Biology, Vol. 27, No. 9, 05.2007, p. 3417-3428.

Research output: Contribution to journalArticle

Goetz, R, Beenken, A, Ibrahimi, OA, Kalinina, J, Olsen, SK, Eliseenkova, AV, Xu, C, Neubert, TA, Zhang, F, Linhardt, RJ, Yu, X, White, K, Inagaki, T, Kliewer, SA, Yamamoto, M, Kurosu, H, Ogawa, Y, Kuro-o, M, Lanske, B, Razzaque, MS & Mohammadi, M 2007, 'Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members', Molecular and Cellular Biology, vol. 27, no. 9, pp. 3417-3428. https://doi.org/10.1128/MCB.02249-06
Goetz, Regina ; Beenken, Andrew ; Ibrahimi, Omar A. ; Kalinina, Juliya ; Olsen, Shaun K. ; Eliseenkova, Anna V. ; Xu, ChongFeng ; Neubert, Thomas A. ; Zhang, Fuming ; Linhardt, Robert J. ; Yu, Xijie ; White, Kenneth ; Inagaki, Takeshi ; Kliewer, Steven A. ; Yamamoto, Masaya ; Kurosu, Hiroshi ; Ogawa, Yasushi ; Kuro-o, Makoto ; Lanske, Beate ; Razzaque, Mohammed S. ; Mohammadi, Moosa. / Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 9. pp. 3417-3428.
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