The developmental expression and activity of peptidylarginine deiminase in the mouse

Pritzker, Laura B.; Nguyen, Tao; Moscarello, Mario A.

doi:10.1016/s0304-3940(99)00276-1

Cited by 32 publications

(21 citation statements)

References 16 publications

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“…S2). The largest number of citrullinated proteins was found in the brain consistent with previous studies reporting high levels of citrullination in this organ and its role in the development of the central nervous system (CNS) (40,41). Our data covers many previously identified citrullinated proteins but >80% of the identified modifications sites were new and, for 56% of the proteins, citrullination was detected for the first time.…”

Section: The Landscape Of Protein Citrullination Of Human Tissuessupporting

confidence: 89%

Mining the Human Tissue Proteome for Protein Citrullination

Lee

Wang

Wilhelm

et al. 2018

Molecular & Cellular Proteomics

175

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SummaryCitrullination is a post-translational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations and while the modification has been linked to several diseases including rheumatoid arthritis and cancer, its physiological or pathophysiological roles remain largely unclear. In part this is owing to limitations in available methodology able to robustly enrich, detect and localize the modification. As a result, only few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of ~70 million tandem mass spectra yielded ~13,000 candidate spectra which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized ~2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes.Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination.

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Section: The Landscape Of Protein Citrullination Of Human Tissuessupporting

confidence: 89%

Mining the Human Tissue Proteome for Protein Citrullination

Lee

Wang

Wilhelm

et al. 2018

Molecular & Cellular Proteomics

175

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“…Neurochem Res (2007) 32: 137-158 141 Up-regulation of PAD in MS Of the various peptidylarginine deiminases, PAD2 is the most abundant isoform found in the brain and oligodendrocytes [108, [116][117][118]. The increased deimination of MBP in MS sparked interest in the involvement of PAD2 in the disease [119,120]. Increases in PAD activity and PAD mRNA levels have been observed in the ND4 model for demyelination, prior to an increase of the amount of citrullinated MBP, and the concomitant appearance of any clinical and pathological signs, preceding both by about 1 month [96, 97, 121].…”

Section: Modifications Of Mbp In Cns Development and In Neurodegeneramentioning

confidence: 99%

“…Increases in PAD activity and PAD mRNA levels have been observed in the ND4 model for demyelination, prior to an increase of the amount of citrullinated MBP, and the concomitant appearance of any clinical and pathological signs, preceding both by about 1 month [96, 97, 121]. The membrane-bound fraction of PAD2 (the cytosolic isoform) was preponderant compared to the soluble enzyme [120]. Thus, it has been suggested that the up-regulation of membranebound PAD2 activity represents an important early molecular change in demyelinating diseases, thereby precipitating the destabilisation of myelin in MS brain white matter [121,122].…”

Section: Modifications Of Mbp In Cns Development and In Neurodegeneramentioning

confidence: 99%

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

2006

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Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.

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“…Five mammalian PAD family members (PAD or PADI 1–4 and 6) are all encoded by a cluster of genes on chromosome 1p36.13 and have a described tissue-specific distribution in most body tissues 1. PAD-mediated post-translational citrullination is involved in various physiological and pathogenic activities by altering the structural stability of target proteins 2,3…”

Section: Introductionmentioning

confidence: 99%

Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

Guo¹,

Zheng²,

Xu³

et al. 2017

OTT

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BackgroundPeptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown.Materials and methodsImmunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR.ResultsImmunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments.ConclusionPADI2 expression is increased in many types of tumor tissues and patient blood samples. PADI2 may advance abnormal cell behavior in gastric cancers by mediating CXCR2, a well-known gene that stimulates cell proliferation and invasion. However, PADI2 might have deleterious effects on tumor growth and metastasis in liver tumor cells by regulating the expression of EPO, a gene with controversial functions in tumor growth. The results suggest that the effect of PADI2 on tumorigenesis is multifactorial, depending on the tumor type.

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The developmental expression and activity of peptidylarginine deiminase in the mouse

Cited by 32 publications

References 16 publications

Mining the Human Tissue Proteome for Protein Citrullination

Mining the Human Tissue Proteome for Protein Citrullination

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Investigating the expression, effect and tumorigenic pathway of PADI2 in tumors

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