Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.
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.
Goetz
Regina
R
Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Beenken
Andrew
A
Ibrahimi
Omar A
OA
Kalinina
Juliya
J
Olsen
Shaun K
SK
Eliseenkova
Anna V
AV
Xu
ChongFeng
C
Neubert
Thomas A
TA
Zhang
Fuming
F
Linhardt
Robert J
RJ
Yu
Xijie
X
White
Kenneth E
KE
Inagaki
Takeshi
T
Kliewer
Steven A
SA
Yamamoto
Masaya
M
Kurosu
Hiroshi
H
Ogawa
Yasushi
Y
Kuro-o
Makoto
M
Lanske
Beate
B
Razzaque
Mohammed S
MS
Mohammadi
Moosa
M
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
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