Download MendeleyMolecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.
de Las Rivas, M., Paul Daniel, E.J., 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, T.A., Hurtado-Guerrero, R.(2020) Nat Chem Biol 16: 351-360
- PubMed: 31932717
- DOI: https://doi.org/10.1038/s41589-019-0444-x
- Primary Citation of Related Structures:
6S22, 6S24 - PubMed Abstract:
Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178 R¡ýS. 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.
Organizational Affiliation:
BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain.
