Reference

Nat Chem Biol. 2020 Mar;16(3): 351-360. doi: 10.1038/s41589-019-0444-x. 2020NatureChemBio Mar20 COVER

Authors

de las Rivas, M., Daniel, E. J. P., Narimatsu, Y., Compañón, I., Kato, K., Hermosilla, P., Thureau, A., Ceballos-Laita, L., Coelho, H., Bernadó, P., Marcelo, F., Hansen, L., Maeda, R., Lostao, A., Corzana, F., Clausen, H., Gerken, TA. & Hurtado-Guerrero, R.

Abstract

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178R ↓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.

Description

En este artículo se describe por primera vez cómo un miembro de la familia de las N-acetil galactosaminiltransferasas polipeptídicas, la GalNAc-T3, O-glicosila al factor de crecimiento del fibroblasto 23 (FGF23) añadiendo un grupo GalNAc sobre su Thr178. Los autores logran descifrar las bases moleculares de esta adición, en la que resulta clave la baja especificidad entre la enzima y el sustrato, que permite controlar los niveles circulantes en sangre de éste. Cuando esta glicosilación no se da, se generan problemas en el metabolismo del fosfato que conducen al desarrollo de la enfermedad rara conocida como calcinosis tumoral. En el trabajo se desvelan también las bases estructurales de los mutantes de la enzima que se habían asociado directamente con la aparición de dicha enfermedad.

 

 

 Foto grupo GaNAc T3

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo del investigador ARAID Ramón Hurtado Guerrero desarrolla su trabajo en el Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) de la Universidad de Zaragoza. En colaboración con universidades nacionales e internacionales, lleva más de una década estudiando cómo se produce la unión entre los azúcares y diversas proteínas que reconocen carbohidratos, y busca explicación a los mecanismos que subyacen detrás de las enfermedades asociadas. El objetivo final es desvelar sus mecanismos de reacción y poder diseñar inhibidores selectivos que modulen su actividad en procesos patológicos, así como vacunas y tratamientos selectivos.

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