scholarly journals Protein Arginine Deiminase 4 Antagonizes Methylglyoxal-induced Histone Glycation

2019 ◽  
Author(s):  
Qingfei Zheng ◽  
Adewola Osunsade ◽  
Yael David
Keyword(s):  
Metabolic Stress ◽  
Arginine Methylation ◽  
Arginine Deiminase ◽  
Side Chains ◽  
Epigenetic Landscape ◽  
Chromatin Architecture ◽  
Protein Arginine Deiminase ◽  
Arginine Residues ◽  
Histone Citrullination ◽  
Oxygen Substitution

AbstractProtein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it was shown to associate with general chromatin decompaction and to compete with arginine methylation. Recently, we showed that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications. Here we report that PAD4 antagonizes histone MGO-glycation by protecting the reactive sites with oxygen substitution, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4’s oncogenic properties.SignificanceMetabolic syndromes and diabetes increase the risk for certain diseases such as cancer. However, the mechanism behind this correlation is poorly understood. Methylglyoxal (MGO), a reactive dicarbonyl sugar metabolite found in cells under metabolic stress, can non-enzymatically modify arginine and lysine residues in histone proteins, making it a new epigenetic marker linking metabolism and disease. Histone MGO-glycation induces changes in chromatin architecture and the epigenetic landscape, and abrogates gene transcription. In this study, we found that protein arginine deiminase 4 (PAD4) exhibits dual functions to antagonize histone MGO-glycation: removing glycation adducts from arginines and converting the unmodified side chains into citrulline, which protects them from undergoing glycation. This unprecedented biochemical mechanism demonstrates a potential function of PAD4 in cancer cells.

scholarly journals Discovery of new inhibitor for the protein arginine deiminase type 4 (PAD4) by rational design of α-enolase-derived peptides

2021 ◽  
Vol 92 ◽  
pp. 107487
Author(s):  
Izzuddin Ahmad Nadzirin ◽  
Adam Leow Thean Chor ◽  
Abu Bakar Salleh ◽  
Mohd Basyaruddin Abdul Rahman ◽  
Bimo A. Tejo
Keyword(s):  
Rational Design ◽  
Arginine Deiminase ◽  
Protein Arginine Deiminase

scholarly journals Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4

2004 ◽  
Vol 379 (2) ◽  
pp. 283-289 ◽  
Author(s):  
Marie-Chloé BOULANGER ◽  
Tina Branscombe MIRANDA ◽  
Steven CLARKE ◽  
Marco di FRUSCIO ◽  
Beat SUTER ◽  
...  
Keyword(s):  
Rna Binding ◽  
Developmental Stages ◽  
Rna Binding Proteins ◽  
Genetic System ◽  
Arginine Methylation ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Arginine Residues ◽  
Drosophila Protein

The role of arginine methylation in Drosophila melanogaster is unknown. We identified a family of nine PRMTs (protein arginine methyltransferases) by sequence homology with mammalian arginine methyltransferases, which we have named DART1 to DART9 (Drosophilaarginine methyltransferases 1–9). In keeping with the mammalian PRMT nomenclature, DART1, DART4, DART5 and DART7 are the putative homologues of PRMT1, PRMT4, PRMT5 and PRMT7. Other DART family members have a closer resemblance to PRMT1, but do not have identifiable homologues. All nine genes are expressed in Drosophila at various developmental stages. DART1 and DART4 have arginine methyltransferase activity towards substrates, including histones and RNA-binding proteins. Amino acid analysis of the methylated arginine residues confirmed that both DART1 and DART4 catalyse the formation of asymmetrical dimethylated arginine residues and they are type I arginine methyltransferases. The presence of PRMTs in D. melanogaster suggest that flies are a suitable genetic system to study arginine methylation.

scholarly journals Autodeimination of Protein Arginine Deiminase 4 Alters Protein–Protein Interactions but Not Activity

Biochemistry ◽  
2011 ◽  
Vol 50 (19) ◽  
pp. 3997-4010 ◽  
Author(s):  
Jessica L. Slack ◽  
Larry E. Jones ◽  
Monica M. Bhatia ◽  
Paul R. Thompson
Keyword(s):  
Protein Interactions ◽  
Arginine Deiminase ◽  
Protein Protein Interactions ◽  
Protein Arginine Deiminase

scholarly journals ATP Induces Protein Arginine Deiminase 2-Dependent Citrullination in Mast Cells through the P2X7 Purinergic Receptor

2012 ◽  
Vol 189 (8) ◽  
pp. 4112-4122 ◽  
Author(s):  
Sanja Arandjelovic ◽  
Katherine R. McKenney ◽  
Sunamita S. Leming ◽  
Kerri A. Mowen
Keyword(s):  
Mast Cells ◽  
Purinergic Receptor ◽  
Arginine Deiminase ◽  
Protein Arginine Deiminase

Methylation of the nuclear poly(A)-binding protein by type I protein arginine methyltransferases – how and why

2013 ◽  
Vol 394 (8) ◽  
pp. 1029-1043 ◽  
Author(s):  
Elmar Wahle ◽  
Bodo Moritz
Keyword(s):  
Active Sites ◽  
Binding Protein ◽  
Arginine Methylation ◽  
Fine Tuning ◽  
General Mechanism ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Low Protein ◽  
Backbone Conformation ◽  
Arginine Residues

Abstract Asymmetric dimethylation of arginine side chains in proteins is a frequent posttranslational modification, catalyzed by type I protein arginine methyltransferases (PRMTs). This article summarizes what is known about this modification in the nuclear poly(A)-binding protein (PABPN1). PABPN1 contains 13 dimethylated arginine residues in its C-terminal domain. Three enzymes, PRMT1, 3, and 6, can methylate PABPN1. Although 26 methyl groups are transferred to one PABPN1 molecule, the PRMTs do so in a distributive reaction, i.e., only a single methyl group is transferred per binding event. As PRMTs form dimers, with the active sites accessible from a small central cavity, backbone conformation around the methyl-accepting arginine is an important determinant of substrate specificity. Neither the association of PABPN1 with poly(A) nor its role in poly(A) tail synthesis is affected by arginine methylation. At least at low protein concentration, methylation does not affect the protein’s tendency to oligomerize. The dimethylarginine residues of PABPN1 are located in the binding site for its nuclear import receptor, transportin. Arginine methylation weakens this interaction about 10-fold. Very recent evidence suggests that arginine methylation as a way of fine-tuning the interactions between transportin and its cargo may be a general mechanism.

Evaluation of protein arginine deiminase-4 inhibitor in TNBS- induced colitis in mice

2020 ◽  
Vol 84 ◽  
pp. 106583
Author(s):  
Tingting Zhang ◽  
Yinliu Mei ◽  
Wanfa Dong ◽  
Jingxun Wang ◽  
Fengjie Huang ◽  
...  
Keyword(s):  
Arginine Deiminase ◽  
Protein Arginine Deiminase
Sign in / Sign up

Export Citation Format

Share Document