期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 3, 页码 351-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-019-0444-x
关键词
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资金
- Diamond Light Source (Oxford) [MX14739-6, MX14739-11, 99170088]
- ARAID
- MEC [CTQ2013-44367-C2-2-P, BFU2016-75633-P, RTI2018-099592-B-C21]
- National Institutes of Health [GM113534, GM113534-01S]
- Danish National Research Foundation [DNRF107]
- FCT-Portugal [UID/Multi/04378/2013, IF/00780/2015, PTDC/BIA-MIB/31028/2017, UID/Multi/04378/2019]
- Gobierno de Aragon [E34_R17, E35_17R, LMP58_18]
- FEDER [2014-2020]
- Universidad de La Rioja
- PTNMR [ROTEIRO/0031/2013, PINFRA/22161/2016]
- Labex EpiGenMed, an 'Investissements d'avenir' program [ANR-10-LABX-12-01]
- FP7 (2007-2013) under BioStruct-X [283570, BIOSTRUCTX_5186]
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-MIB/31028/2017] Funding Source: FCT
Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif (RHTR)-R-178 down arrow 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.
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