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PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications.

ABSTRACT: Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoylation, acetylation, and phosphorylation as characterized and putative regulative factors of DUB function. Although this aspect of DUB functionality has not been yet thoroughly studied, PTMs represent a versatile and reversible method of controlling the role of DUBs in biological processes. In several cases PTMs might constitute a feedback mechanism insuring proper functioning of the ubiquitin proteasome system and other DUB-related pathways.

SUBMITTER: Kessler BM

PROVIDER: S-EPMC3094536 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications.

Kessler Benedikt M BM Edelmann Mariola J MJ

Cell biochemistry and biophysics 20110601 1-2

Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoy ...[more]

PMID: 21480003

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Project description:Histones are abundant chromatin constituents carrying numerous post-translational modifications (PTMs). Such PTMs mediate a variety of biological functions, including recruitment of enzymatic readers, writers and erasers that modulate DNA replication, transcription and repair. Individual histone molecules contain multiple coexisting PTMs, some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. Here, we present an integrated experimental and computational systems level molecular characterization of histone PTMs and PTM crosstalk. Using wild type and engineered mouse embryonic stem cells (mESCs) knocked out in components of the Polycomb Repressive Complex 2 (PRC2, Suz12(-/-)), PRC1 (Ring1A/B(-/-)) and (Dnmt1/3a/3b(-/-)) we performed comprehensive PTM analysis of histone H3 tails (50 aa) by utilizing quantitative middle-down proteome analysis by tandem mass spectrometry. We characterized combinatorial PTM features across the four mESC lines and then applied statistical data analysis to predict crosstalk between histone H3 PTMs. We detected an overrepresentation of positive crosstalk (codependent marks) between adjacent mono-methylated and acetylated marks, and negative crosstalk (mutually exclusive marks) among most of the seven characterized di- and tri-methylated lysine residues in the H3 tails. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites, including H3R2me, H3R8me and H3K37me. Integration of the H3 data with RNAseq data by coabundance clustering analysis of histone PTMs and histone modifying enzymes revealed correlations between PTM and enzyme levels. We conclude that middle-down proteomics is a powerful tool to determine conserved or dynamic interdependencies between histone marks, which paves the way for detailed investigations of the histone code. Histone H3 PTM data is publicly available in the CrossTalkDB repository at http://crosstalkdb.bmb.sdu.dk.

Project description:BackgroundEarly diagnosis of chronic pancreatitis by mass spectrometry-based proteomics may result in therapies to retard or modify disease progression. We aimed to identify differences in posttranslational modifications (PTMs) in pancreatic fluid proteins from individuals with chronic pancreatitis (n=9) and non-pancreatitis controls (n=9).MethodsWe collected proteomic data from pancreatic fluid using mass spectrometry techniques. We performed database searches with emphasis on PTMs using ProteinPilot. We compared the frequency of specific PTMs in pancreatic fluid between cohorts and also to those identified in bile, gastroduodenal fluid, urine, and pancreatic duct and stellate cell lysates.ResultsWe identified 97 PTMs in endoscopically-collected pancreatic fluid, of which 11 were identified exclusively in one cohort and 9 others were significantly different in frequency between cohorts. Comparing pancreatic fluid with other specimens revealed differences in specific PTM frequencies, indicating that the identified PTMs were not merely artifacts of sample processing.ConclusionsWe determined PTMs of proteins extracted from pancreatic fluid which differed in frequency in chronic pancreatitis patients verses controls. Such PTMs may serve as biomarker candidates of chronic pancreatitis upon validation with larger cohorts. The analysis of the PTM profile of pancreatic fluid proteins offers an alternative method to standard protein-based biomarker discovery.Biological significanceThe early diagnosis of chronic pancreatitis is paramount in developing strategies to modify, retard, or halt disease progression. In the present study, we compared post-transitional modifications (PTMs) of proteins extracted from pancreatic fluid of chronic pancreatitis patients verses a control cohort. With many mass spectrometry-based proteomics workflows aimed to identify and quantify proteins, data for PTMs typically comes gratis, in that such data are collected during protein sequencing and, as such, require only downstream bioinformatics processing. We identified a total of 20 PTMs which were exclusive to or significantly different between cohorts. Upon validation with larger cohorts and enrichment of these PTMs may serve as biomarker candidates of chronic pancreatitis. PTM profiling of pancreatic fluid proteins is complementary to standard protein-based biomarker discovery, and may be readily applied to studies of pancreatic disease. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine.

Dataset Information

PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications.

Publications

PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications.

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