Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3 PMID: 31932717

RQC and Longevity Regulation

2026-09-03

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

Nat Chem Biol. 2020 Mar;16(3):351-360. doi: 10.1038/s41589-019-0444-x.

Matilde de Las Rivas ^# ¹ , Earnest James Paul Daniel ^# ² , Yoshiki Narimatsu ^# ³ , Ismael Compañón ^# ⁴ , Kentaro Kato ³ ⁵ , Pablo Hermosilla ⁶ , Aurélien Thureau ⁷ , Laura Ceballos-Laita ¹ , Helena Coelho ⁸ ⁹ , Pau Bernadó ¹⁰ , Filipa Marcelo ⁸ , Lars Hansen ³ , Ryota Maeda ¹¹ , Anabel Lostao ⁶ ¹² ¹³ , Francisco Corzana ⁴ , Henrik Clausen ³ , Thomas A Gerken ² , Ramon Hurtado-Guerrero ¹⁴ ¹⁵ ¹⁶

Affiliations

1. BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain.
2. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA.
3. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen, Copenhagen, Denmark.
4. Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, Logroño, Spain.
5. Department of Eco-epidemiology, Institute of Tropical Medicine Nagasaki University, Nagasaki, Japan.
6. Laboratorio de Microscopías Avanzadas, Instituto de Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain.
7. Swing Beamline, Synchrotron SOLEIL, Gif sur Yvette, France.
8. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Nova de Lisboa, Caparica, Portugal.
9. CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
10. Centre de Biochimie Structurale. INSERM, CNRS, Université de Montpellier, Montpellier, France.
11. Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
12. Fundación ARAID, Zaragoza, Spain.
13. Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, Zaragoza, Spain.
14. BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain. [email protected].
15. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen, Copenhagen, Denmark. [email protected].
16. Fundación ARAID, Zaragoza, Spain. [email protected].
# Contributed equally.

Abstract

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.