Protein Arginine Methylation and Citrullination in Epigenetic Regulation

Fuhrmann, Jakob; Thompson, Paul R.

doi:10.1021/acschembio.5b00942

Cited by 88 publications

(106 citation statements)

References 156 publications

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“…This active-site alteration now allows for methylated arginines to bind more favorably and is better suited to accommodate a methylated nitrogen atom near the THW loop, allowing the other terminal nitrogen atom (positioned near the double E loop) to become methylated. A specific role of the THW loop in determining PRMT product specificity was first suggested in two recent reviews from Thompson and co-workers (2,20).…”

Section: Discussionmentioning

confidence: 99%

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

Jain¹,

Warmack²,

Debler³

et al. 2016

Journal of Biological Chemistry

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In the family of protein arginine methyltransferases (PRMTs) that predominantly generate either asymmetric or symmetric dimethylarginine (SDMA), PRMT7 is unique in producing solely monomethylarginine (MMA) products. The type of methylation on histones and other proteins dictates changes in gene expression, and numerous studies have linked altered profiles of methyl marks with disease phenotypes. Given the importance of specific inhibitor development, it is crucial to understand the mechanisms by which PRMT product specificity is conferred. We have focused our attention on active-site residues of PRMT7 from the protozoan Trypanosoma brucei. We have designed 26 single and double mutations in the active site, including residues in the Glu-Xaa 8 -Glu (double E) loop and the Met-Gln-Trp sequence of the canonical Thr-His-Trp (THW) loop known to interact with the methyl-accepting substrate arginine. Analysis of the reaction products by high resolution cation exchange chromatography combined with the knowledge of PRMT crystal structures suggests a model where the size of two distinct subregions in the active site determines PRMT7 product specificity.

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Section: Discussionmentioning

confidence: 99%

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

Jain¹,

Warmack²,

Debler³

et al. 2016

Journal of Biological Chemistry

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“…Deregulation of PADs expression or activity and increased citrullinated protein levels have also been found in other diseases such as cancer, multiple sclerosis and Alzheimer's disease but the functional role of the modification remains largely unclear (reviewed in (7) and (8)). Furthermore, citrullination has recently been shown to participate in epigenetic regulation via the modification of histones (13). The interaction between coactivators and histone-modifying enzymes can also be regulated by citrullination exemplified by the enhanced interaction between the coactivator GRIP1 and the histone acetyltransferase p300 when p300 was citrullinated (14).…”

Section: Introductionmentioning

confidence: 99%

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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“…These neurodegenerative iPSC models will be useful functional tools for continuing studies on effects of PAD-mediated EV shedding, and the efficacy of pharmacological modulation of PAD-mediated mechanisms to ameliorate neurodegenerative disease pathologies. While Cl-Am [141] remains the most used experimental inhibitor to date, the therapeutic potential and generation of second generation and selective isozyme-specific PAD inhibitors is receiving ever increasing attention [72,82,[142][143][144][145][146]. Ongoing work aims at dissecting the roles of individual PAD isozymes in EV biogenesis, to identify further deiminated key target proteins, assess the epigenetic impact of histone deimination, and to evaluate disease-specific EV cargo.…”

Section: Discussionmentioning

confidence: 99%

“…PAD4 has previously been shown to regulate histone arginine methylation levels in the nucleus [67]. It may be postulated that the PAD-mediated EV release cascade causing translocation of PADs to the nucleus also causes upregulation in TNFα as part of the inflammatory response, and as TNFα is implicated in nuclear translocation of PAD4 [59,72] this may cause in turn additional EV shedding. The pan-PAD inhibitor Cl-Am had a dose-dependent inhibitory effect also on EV release in normal prostate control cell lines (PNT2) [7], indicating that PAD activity impacts cell communication via this pathway also in non-cancerous cells [7].…”

Section: The Interplay Of Evs and Pads In Prostate Cancermentioning

confidence: 99%

“…Also, the phosphorylation of tau differs in exosomes compared to total cell lysates, indicating functional consequences for its seeding capability [106]. In AD neuroinflammation has been linked to circulating TNFα [121][122][123], which causes nuclear translocation of PADs [59,72], and to neutrophil extracellular trap formation [124], which is PAD4-dependent [23,72]. In addition, in PD, α-synuclein induces TNF-α containing exosomes from microglia [110] while TNF-α has been shown to promote EV shedding from endothelial cells [125].…”

Section: Evs In Neurodegenerative Diseasesmentioning

confidence: 99%

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Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Protein Arginine Methylation and Citrullination in Epigenetic Regulation

Cited by 88 publications

References 156 publications

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

Mining the Human Tissue Proteome for Protein Citrullination

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

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