Catalytic and glycan-binding abilities of ppGalNAc-T2 are regulated by acetylation

Zlocowski, Natacha; Sendra, Víctor G.; Lorenz, Virginia O.; Villarreal, Marcos Ariel; Jorge, Alberto; Núñez, Yolanda; Bennett, Eric; Clausen, Henrik; Nores, Gustavo A.; Irazoqui, Fernando J.

doi:10.1016/j.bbrc.2011.05.125

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…Specific glycosyltransferase activity of ppGalNAc-T2 was reduced 95% by acetylation of five lysines in the catalytic core. Acetylation of lysines in the lectin domain results in alteration of the carbohydrate-binding ability of ppGalNAc-T2 (Zlocowski et al, 2011).…”

Section: Cross-regulation Of Ptm Regulatorsmentioning

confidence: 99%

Evolution and functional cross‐talk of protein post‐translational modifications

Beltrão

Bork

Krogan

et al. 2013

Molecular Systems Biology

308

292

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Protein post-translational modifications (PTMs) allow the cell to regulate protein activity and play a crucial role in the response to changes in external conditions or internal states. Advances in mass spectrometry now enable proteome wide characterization of PTMs and have revealed a broad functional role for a range of different types of modifications. Here we review advances in the study of the evolution and function of PTMs that were spurred by these technological improvements. We provide an overview of studies focusing on the origin and evolution of regulatory enzymes as well as the evolutionary dynamics of modification sites. Finally, we discuss different mechanisms of altering protein activity via post-translational regulation and progress made in the large-scale functional characterization of PTM function.

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Section: Cross-regulation Of Ptm Regulatorsmentioning

confidence: 99%

Evolution and functional cross‐talk of protein post‐translational modifications

Beltrão

Bork

Krogan

et al. 2013

Molecular Systems Biology

308

292

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“…The lectin domain of ppGalNAc-Ts promotes their catalytic GalNAc-transferase activity for full glycosylation of partially preglycosylated acceptor peptides (Wandall et al , 2007 ;Raman et al , 2008 ). The acetylation of ppGalNAc-T2 alters the CRD of the C-terminal domain and, thereby, reduces the catalytic activity (Zlocowski et al , 2011 ). Here, a mutation of the acetylation site K521 in the lectin domain of ppGalNAc-T2 was created, and its effect on the O -glycan biosynthetic pathway was studied.…”

Section: Discussionmentioning

confidence: 99%

“…The processes of the cellular homeostasis are determined by PTMs such as phosphorylation in signal transduction, attachment of fatty acids in membrane anchoring, glycosylation in changes of protein half-life or targeting of substrates, and acetylation in chromatin regulation and gene expression (Fukuda et al , 2006 ;Yang and Seto , 2008 ). We recently described the modification of the biological properties of ppGalNAc-T2 by acetylation (Zlocowski et al , 2011 ). The presence of acetyl residues significantly reduces the enzyme activity of ppGalNAc-T2 and modifies the carbohydrate recognition form of the lectin domain.…”

Section: Introductionmentioning

confidence: 99%

An acetylation site in lectin domain modulates the biological activity of polypeptide GalNAc-transferase-2

Zlocowski

Lorenz

Bennett

et al. 2012

Biological Chemistry

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Polypeptide GalNAc-transferases (ppGalNAc-Ts) are a family of enzymes that catalyze the initiation of mucin-type O-glycosylation. All ppGalNAc-T family members contain a common (QXW)3 motif, which is present in the R-type lectin group. The acetylation site K521 is part of the QKW motif of β-trefoil in the lectin domain of ppGalNAc-T2. We used a combination of acetylation and site-directed mutagenesis approaches to examine the functional role of K521 in ppGalNAc-T2. Binding assays of non-acetylated and acetylated forms of the mutant ppGalNAc-T2K521Q to various naked and αGalNAc-glycosylated mucin peptides indicated that the degree of interaction of lectin domain with αGalNAc depends on the peptide sequence of mucin. Studies of the inhibitory effect of various carbohydrates on the interactions of ppGalNAc-T2 with MUC1αGalNAc indicate that point K521Q mutation enhance the carbohydrate specificity of lectin domain for αGalNAc. K521Q mutation resulted in an enzyme activity lower than that of the wild-type ppGalNAc-T2, similar to the acetylation of ppGalNAc-T2. We conclude that an acetylation site in the QKW motif of the lectin domain modulates carbohydrate recognition specificity and catalytic activity of ppGalNAc-T2 for partially preglycosylated acceptors and a certain naked peptide. Posttranslational modifications of ppGalNAc-Ts, such as acetylation, may play key roles in modulating the functions of the R-type lectin domains in cellular homeostasis.

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“…There were a few researches on ppGalNAc ts (Topaz et al, 2005;Brooks et al, 2007;Perrine et al, 2009;Kato et al, 2010;Zlocowski et al, 2011;Liu et al, 2011;Tran et al, 2012). Brooks S A, et found that expression of normally tightly restricted ppGalNAc-Ts may result in initiation of O-linked glycosylation at normally unoccupied potential glycosylation sites leading to altered glycoforms of proteins with changed biological activity which may contribute to the pathogenesis of cancer.Expression of ppGalNAc T1 gene was statistically significantly inversely associated with epithelial ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%