title: Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
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/betaKlotho 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 beta 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 beta1-beta2 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/betaKlotho 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.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.forename: Andrew
authors.initials: A
authors.lastname: Beenken
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ibrahimi
authors.forename: Juliya
authors.initials: J
authors.lastname: Kalinina
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Olsen
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: ChongFeng
authors.initials: C
authors.lastname: Xu
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Xijie
authors.initials: X
authors.lastname: Yu
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurosu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Razzaque
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004703:Endocrine System; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019899:Paracrine Communication; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: C117476:FGF19 protein, human; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D006493:Heparin; D005966:Glucuronidase; D000090265:Klotho Proteins