Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3
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Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3. / de las Rivas, Matilde; Paul Daniel, Earnest James; Narimatsu, Yoshiki; Compañón, Ismael; Kato, Kentaro; Hermosilla, Pablo; Thureau, Aurélien; Ceballos-Laita, Laura; Coelho, Helena; Bernadó, Pau; Marcelo, Filipa; Hansen, Lars; Maeda, Ryota; Lostao, Anabel; Corzana, Francisco; Clausen, Henrik; Gerken, Thomas A.; Hurtado-Guerrero, Ramon.
I: Nature Chemical Biology, Bind 16, 2020, s. 351–360.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3
AU - de las Rivas, Matilde
AU - Paul Daniel, Earnest James
AU - Narimatsu, Yoshiki
AU - Compañón, Ismael
AU - Kato, Kentaro
AU - Hermosilla, Pablo
AU - Thureau, Aurélien
AU - Ceballos-Laita, Laura
AU - Coelho, Helena
AU - Bernadó, Pau
AU - Marcelo, Filipa
AU - Hansen, Lars
AU - Maeda, Ryota
AU - Lostao, Anabel
AU - Corzana, Francisco
AU - Clausen, Henrik
AU - Gerken, Thomas A.
AU - Hurtado-Guerrero, Ramon
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1038/s41589-019-0444-x
DO - 10.1038/s41589-019-0444-x
M3 - Journal article
C2 - 31932717
AN - SCOPUS:85078044367
VL - 16
SP - 351
EP - 360
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
ER -
ID: 236669109