Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members

R Goetz, A Beenken, OA Ibrahimi… - … and cellular biology, 2007 - Taylor & Francis
R Goetz, A Beenken, OA Ibrahimi, J Kalinina, SK Olsen, AV Eliseenkova, CF Xu, TA Neubert…
Molecular and cellular biology, 2007Taylor & Francis
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 …
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.
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