| Structural highlights
Disease
FGF23_HUMAN Defects in FGF23 are the cause of autosomal dominant hypophosphataemic rickets (ADHR) [MIM:193100. ADHR is characterized by low serum phosphorus concentrations, rickets, osteomalacia, leg deformities, short stature, bone pain and dental abscesses.[1] [2] [3] Defects in FGF23 are a cause of hyperphosphatemic familial tumoral calcinosis (HFTC) [MIM:211900. HFTC is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues.[4]
Function
FGF23_HUMAN Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization.[5] [6] [7] [8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members.,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 Mol Cell Biol. 2007 May;27(9):3417-28. Epub 2007 Mar 5. PMID:17339340[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ . Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000 Nov;26(3):345-8. PMID:11062477 doi:10.1038/81664
- ↑ Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. PMID:11409890 doi:10.1006/bbrc.2001.5084
- ↑ Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006 Jul 7;281(27):18370-7. Epub 2006 Apr 25. PMID:16638743 doi:10.1074/jbc.M602469200
- ↑ Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005 Feb 1;14(3):385-90. Epub 2004 Dec 8. PMID:15590700 doi:10.1093/hmg/ddi034
- ↑ . Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000 Nov;26(3):345-8. PMID:11062477 doi:10.1038/81664
- ↑ Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. PMID:11409890 doi:10.1006/bbrc.2001.5084
- ↑ Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004 Mar;19(3):429-35. Epub 2003 Dec 29. PMID:15040831 doi:10.1359/JBMR.0301264
- ↑ Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9;281(23):15694-700. Epub 2006 Apr 4. PMID:16597617 doi:10.1074/jbc.M601252200
- ↑ Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, Aubin JE, Maeda N. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res. 2008 Jun;23(6):939-48. doi: 10.1359/jbmr.080220. PMID:18282132 doi:10.1359/jbmr.080220
- ↑ 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. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol. 2007 May;27(9):3417-28. Epub 2007 Mar 5. PMID:17339340 doi:10.1128/MCB.02249-06
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