6s22
From Proteopedia
Crystal structure of the TgGalNAc-T3 in complex with UDP, manganese and FGF23c
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] Publication Abstract from PubMedPolypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT(178)R downward arrowS. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions. Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.,de Las Rivas M, Paul Daniel EJ, Narimatsu Y, Companon I, Kato K, Hermosilla P, Thureau A, Ceballos-Laita L, Coelho H, Bernado P, Marcelo F, Hansen L, Maeda R, Lostao A, Corzana F, Clausen H, Gerken TA, Hurtado-Guerrero R Nat Chem Biol. 2020 Jan 13. pii: 10.1038/s41589-019-0444-x. doi:, 10.1038/s41589-019-0444-x. PMID:31932717[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Large Structures | Poephila guttata | Bernado, P | Ceballos-Laita, L | Clausen, H | Coelho, H | Companon, I | Corzana, F | Daniel, E J.P | Gerken, T A | Hansen, L | Hermosilla, P | Hurtado-Guerrero, R | Kato, K | Lostao, A | Marcelo, F | Narimatsu, Y | Rivas, M de las | Thureau, A | Enzyme kinetic | Fgf23 | Galnac-t | Galnac-t3 | Long-range glycosylation preference | Molecular dynamic | Phosphate homeostasis | Specificity | Transferase
