Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3
Research output: Contribution to journal › Journal article › Research › peer-review
Polypeptide 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.
Original language | English |
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Journal | Nature Chemical Biology |
Volume | 16 |
Pages (from-to) | 351–360 |
ISSN | 1552-4450 |
DOIs | |
Publication status | Published - 2020 |
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923394/pdf/nihms-1670397.pdf
Accepted author manuscript
ID: 236669109