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Mol. Cell. Biol. 27 (9): 3417-3428

Copyright © 2007 by the American Society for Microbiology. All rights reserved.

Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members{triangledown}

Regina Goetz,1 Andrew Beenken,1 Omar A. Ibrahimi,1 Juliya Kalinina,1 Shaun K. Olsen,1 Anna V. Eliseenkova,1 ChongFeng Xu,1,7 Thomas A. Neubert,1 Fuming Zhang,2,7 Robert J. Linhardt,2 Xijie Yu,3 Kenneth E. White,3 Takeshi Inagaki,4 Steven A. Kliewer,4 Masaya Yamamoto,5 Hiroshi Kurosu,5 Yasushi Ogawa,5 Makoto Kuro-o,5 Beate Lanske,6 Mohammed S. Razzaque,6, and Moosa Mohammadi1*

Department of Pharmacology,1 Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016,7 Department of Chemistry, Biology, and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180,2 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202,3 Department of Molecular Biology,4 Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, Texas 75390,5 Department of Oral and Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 021156

Received for publication 30 November 2006. Accepted for publication 15 February 2007.

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/ßKlotho 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 ß 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 ß1-ß2 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/ßKlotho 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.

* Corresponding author. Mailing address: Department of Pharmacology, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-2907. Fax: (212) 263-7133. E-mail: mohammad{at}saturn.med.nyu.edu

{triangledown} Published ahead of print on 5 March 2007.

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