6S24

Crystal structure of the TgGalNAc-T3 in complex with UDP, manganese and the peptide 3

6S24 の概要

• エントリーDOI: 10.2210/pdb6s24/pdb
• 分子名称: Polypeptide N-acetylgalactosaminyltransferase, ALA-THR-GLY-ALA-GLY-ALA-GLY-ALA-GLY-THR-THR-PRO-GLY-PRO, TRIS(HYDROXYETHYL)AMINOMETHANE, ... (9 entities in total)
• 機能のキーワード: galnac-ts, galnac-t3, long-range glycosylation preference, (glyco)peptides, molecular dynamics, specificity, enzyme kinetics, fgf23, phosphate homeostasis, transferase
• 由来する生物種: Taeniopygia guttata (Zebra finch); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76035.18

構造登録者

de las Rivas, M.,Daniel, E.J.P.,Narimatsu, Y.,Companon, I.,Kato, K.,Hermosilla, P.,Thureau, A.,Ceballos-Laita, L.,Coelho, H.,Bernado, P.,Marcelo, F.,Hansen, L.,Lostao, A.,Corzana, F.,Clausen, H.,Gerken, T.A.,Hurtado-Guerrero, R. (登録日: 2019-06-20, 公開日: 2019-12-25, 最終更新日: 2024-01-24)

主引用文献

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.
Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.
Nat.Chem.Biol., 16:351-360, 2020

PubMed Abstract: Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHTR↓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.

PubMed: 31932717
DOI: 10.1038/s41589-019-0444-x

実験手法

X-RAY DIFFRACTION (2.12 Å)