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

M. de las Rivas, E. J. P. Daniel, Y. Narimatsu, I. Compañón, K. Kato, P. Hermosilla, A. Thureau, L. Ceballos-Laita, H. Coelho, P. Bernadó, F. Marcelo, L. Hansen, A. Lostao, F. Corzana, H. Clausen, T. A. Gerken, R. Hurtado-Guerrero. Molecular basis for Fibroblast growth factor 23 O-glycosylation by GalNAc-T3. Nature Chemical Biology, doi:10.1038/s41589-019-0444-x

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.

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