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Title

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

AuthorsRivas, Matilde de las; Paul Daniel, Earnest James; Narimatsu, Yoshiki; Compañón, Ismael; Kato, Kentaro; Hermosilla, Pablo; Thureau, Aurélien; Ceballos-Laita, Laura ; Coelho, Helena; Bernardó, Pau; Marcelo, Filipa ; Hansen, Lars; Maeda, Ryota; Lostao, Anabel; Corzana, Francisco; Clausen, Henrik; Gerken, Thomas A.; Hurtado-Guerrero, Ramón
Issue Date2020
PublisherSpringer Nature
CitationNature Chemical Biology 16: 351–360 (2020)
AbstractPolypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT178R↓S. 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.
Publisher version (URL)https://doi.org/10.1038/s41589-019-0444-x
URIhttp://hdl.handle.net/10261/219035
DOI10.1038/s41589-019-0444-x
ISSN1552-4450
E-ISSN1552-4469
Appears in Collections:(ICMA) Artículos
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