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.

Leer más

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

01-10-2020

C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins...

Read more

Expression of the long non-coding RNA TCL6 is associated with clinical outcome in pediatric B-cell acute lymphoblastic leukemia

31-08-2020

The reciprocal translocation t(12;21)(p13;q22)[ETV6/RUNX1] is the most frequent chromosomal rearrangement in pediatric B-cell acute lymphoblastic leukemia(B-ALL). Long non-coding RNAs (lncRNAs) play important roles in numerous diseases and they represent an...

Read more

Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles

30-07-2020

Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades...

Read more

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

01-07-2020

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism...

Read more

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

29-05-2020

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca2+ peak that triggers muscle contraction, but mechanistic details remain unknown...

Read more

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Read more

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

31-03-2020

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...

Read more

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Read more

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Read more

Mip6 binds directly to the Mex67 UBA domainto maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Read more

Protector Members