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

Nature Chemical Biology volume 16, pages 351–360 (2020)Cite this article

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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.

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Fig. 1: In vitro evidence that GalNAc-T3 glycosylates FGF23 Thr178 using its lectin domain.
Fig. 2: Glycosylation of Thr178 in FGF23 by GalNAc-T3 in cells requires its lectin domain activity.
Fig. 3: Glycosylation kinetics of human GalNAc-T3 against a series of (glyco)peptides.
Fig. 4: Crystal structures of TgGalNAc-T3 in ternary complexes with UDP-Mn+2-P3 and UDP-Mn+2-FGF23c.
Fig. 5: Structural features of the peptide, UDP and lectin-domain GalNAc-binding sites of TgGalNAc-T3.
Fig. 6: Mapping HsGalNAc-T3 FTC mutations to the structure of TgGalNAc-T3.

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Data availability

The crystal structures of TgGalNAc-T3-UDP-P3 and TgGalNAc-T3-UDP–FGF23c complexes were deposited at the RCSB PDB with accession codes 6S24 and 6S22, respectively.

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Acknowledgements

We thank the Diamond Light Source (Oxford) synchrotron beamline I24 (experiment nos. MX14739-6 and MX14739-11) and the SOLEIL synchrotron (Gif-sur-Yvette) SWING beamline (experiment nos. 99170088). We thank ARAID, MEC (grant no. CTQ2013-44367-C2-2-P, BFU2016-75633-P and RTI2018-099592-B-C21), the National Institutes of Health (grant no. GM113534 and instrument grant no. GM113534-01S), the Danish National Research Foundation (grant no. DNRF107), the FCT-Portugal (grant no. UID/Multi/04378/2013) and Gobierno de Aragón (grant nos. E34_R17, E35_17R and LMP58_18) with FEDER (grant no. 2014-2020) funds for ‘Building Europe from Aragón’ for financial support. I.C. thanks the Universidad de La Rioja for the FPI grant. F.M. and H.C. thank FCT-Portugal for IF Investigator (IF/00780/2015), PTDC/BIA-MIB/31028/2017 and UID/Multi/04378/2019 projects, and PTNMR (grant no. ROTEIRO/0031/2013 and PINFRA/22161/2016). P.B. acknowledges support from the Labex EpiGenMed, an ‘Investissements d’avenir’ program (grant no. ANR-10-LABX-12-01). The CBS (Montpellier) is a member of France-BioImaging (FBI, ANR-10-INBS-04-01) and the French Infrastructure for Integrated Structural Biology (FRISBI, ANR-10-INBS-05). The research leading to these results has also received funding from the FP7 (2007–2013) under BioStruct-X (grant agreement nos. 283570 and BIOSTRUCTX_5186). We also thank I. Echániz for technical support and K. Moremen from the University of Georgia, Complex Carbohydrate Research Center, for supplying the pGEn2-HsGalNAc-T6 and pGEn2-HsGalNAc-T12 plasmids.

Author information

Author notes

  1. These authors contributed equally: Matilde de las Rivas, Earnest James Paul Daniel, Yoshiki Narimatsu, Ismael Compañón.

Authors and Affiliations

  1. BIFI, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain

    Matilde de las Rivas, Laura Ceballos-Laita & Ramon Hurtado-Guerrero

  2. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA

    Earnest James Paul Daniel & Thomas A. Gerken

  3. Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen, Copenhagen, Denmark

    Yoshiki Narimatsu, Kentaro Kato, Lars Hansen, Henrik Clausen & Ramon Hurtado-Guerrero

  4. Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, Logroño, Spain

    Ismael Compañón & Francisco Corzana

  5. Department of Eco-epidemiology, Institute of Tropical Medicine Nagasaki University, Nagasaki, Japan

    Kentaro Kato

  6. Laboratorio de Microscopías Avanzadas, Instituto de Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain

    Pablo Hermosilla & Anabel Lostao

  7. Swing Beamline, Synchrotron SOLEIL, Gif sur Yvette, France

    Aurélien Thureau

  8. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Nova de Lisboa, Caparica, Portugal

    Helena Coelho & Filipa Marcelo

  9. CIC bioGUNE, Bizkaia Technology Park, Derio, Spain

    Helena Coelho

  10. Centre de Biochimie Structurale. INSERM, CNRS, Université de Montpellier, Montpellier, France

    Pau Bernadó

  11. Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Ryota Maeda

  12. Fundación ARAID, Zaragoza, Spain

    Anabel Lostao & Ramon Hurtado-Guerrero

  13. Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, Zaragoza, Spain

    Anabel Lostao

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  1. Matilde de las Rivas
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Contributions

R.H.-G. designed the crystallization construct and solved the crystal structures. M.R. and R.H.-G. purified the enzymes, crystallized the complexes and refined the crystal structures. I.C. and F.C. synthesized the glycopeptides. F.C. performed the MD simulations. H.Coelho and F.M. performed and analyzed the NMR experiments. T.A.G. and E.J.P.D. performed the kinetic studies together with the Edman amino acid sequencing. Y.N., K.K. and R.M. performed the experiments in cells and did the MALDI–TOF MS mass spectrometry experiments. P.H. and A.L. performed the AFM studies. A.T. and P.B. performed the SAXS experiments. L.C.-L. conducted the expression and purification of GalNAc-T6 and T12 in HEK293 cells. L.H. identified the GalNAc-T3 mutations associated to disease. R.H.-G., T.A.G. and H.Clausen wrote the article with the other authors’ contributions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ramon Hurtado-Guerrero.

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Supplementary information

Supplementary Information

Supplementary Figs 1–17 and Tables 1–6.

Reporting Summary

Supplementary Video 1

A 500 ns MD simulation of TgGalNAc-T3 complexed to UDP-Mn+2 and FGF23c in explicit water

Supplementary Video 2

A 500 ns MD simulation of HsGalNAc-T4 complexed to UDP-Mn+2 and FGF23c in explicit water

Supplementary Video 3

A 500 ns MD simulation of HsGalNAc-T6 complexed to UDP-Mn+2 and FGF23c in explicit water

Supplementary Video 4

A 500 ns MD simulation of HsGalNAc-T12 complexed to UDP-Mn+2 and FGF23c in explicit water

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de las Rivas, M., Paul Daniel, E.J., Narimatsu, Y. et al. Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3. Nat Chem Biol 16, 351–360 (2020). https://doi.org/10.1038/s41589-019-0444-x

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