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.

journal_name

Mol Cell Biol

authors

Goetz R,Beenken A,Ibrahimi OA,Kalinina J,Olsen SK,Eliseenkova AV,Xu C,Neubert TA,Zhang F,Linhardt RJ,Yu X,White KE,Inagaki T,Kliewer SA,Yamamoto M,Kurosu H,Ogawa Y,Kuro-o M,Lanske B,Razzaque MS,Mohammadi M

doi

10.1128/MCB.02249-06

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

3417-28

issue

9

eissn

0270-7306

issn

1098-5549

pii

MCB.02249-06

journal_volume

27

pub_type

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