Deciphering a global network of functionally associated post‐translational modifications

Mínguez, Pablo; Parca, Luca; Diella, Francesca; Mende, Daniel R.; Kumar, Runjun D.; Helmer-Citterich, Manuela; Gavin, Anne‐Claude; Noort, Vera van; Bork, Peer

doi:10.1038/msb.2012.31

Cited by 217 publications

(238 citation statements)

References 84 publications

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“…Sequence motifs, structural proximity, and residue co-evolution were presumed to imply the functional association between PTM sites in previous studies (8,26); here, we systematically tested the effectiveness of these features to predict the PTM cross-talk using by far the largest collection of validated cross-talk data sets. We demonstrated that the crosstalk and control pairs can be distinguished by the sequence and structural distances and co-localization within the same disordered region location, as well as the residue and modification co-evolution measures.…”

Section: Discussionmentioning

confidence: 99%

“…The co-evolution of two PTM sites was measured using the mutual information (MI) method (8,32,33) Referring to the example shown in Fig. 2A again, there are eight known PTM sites in the part of human p53 sequence, and two pairs (S15-T18 and S37-S46) cross-talk to each other: Phosphorylation of T18 depends on the prior phosphorylation of S15 site (35), and phosphorylation level of S46 is regulated by phosphorylation at S37 (36).…”

Section: Methodsmentioning

confidence: 99%

“…phosphate, acetyl, or methyl) to specific amino acid residues (1), which play important roles in regulating gene expression, modifying protein functions, and modulating protein-protein interactions (2)(3)(4)(5)(6). With the development of mass spectrometry (MS) techniques, increasing number of PTM sites have been identified (7,8). Multiple PTMs within one protein can coordinately determine a functional outcome, which is called PTM crosstalk (9).…”

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confidence: 99%

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Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Huang

Xu²,

Zhou

et al. 2015

Molecular & Cellular Proteomics

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Post-translational modification (PTM) 1 plays an important role in regulating the functions of proteins. PTMs of multiple residues on one protein may work together to determine a functional outcome, which is known as PTM crosstalk. Identification of PTM cross-talks is an emerging theme in proteomics and has elicited great interest, but their properties remain to be systematically characterized. To this end, we collected 193 PTM cross-talk pairs in 77 human proteins from the literature and then tested location preference and co-evolution at the residue and modification levels. We found that cross-talk events preferentially occurred among nearby PTM sites, especially in disordered protein regions, and cross-talk pairs tended to co-evolve. Given the properties of PTM cross-talk pairs, a naïve Bayes classifier integrating different features was built to predict cross-talks for pairwise combination of PTM sites. By using a 10-fold cross-validation, the integrated prediction model showed an area under the receiver operating characteristic (ROC) curve of 0.833, superior to using any individual feature alone. The prediction performance was also demonstrated to be robust to the biases in the collected PTM cross-talk pairs. The integrated approach has the potential for large-scale prioritization of PTM cross-talk candidates for functional validation and was implemented as a web server available at

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Huang

Xu²,

Zhou

et al. 2015

Molecular & Cellular Proteomics

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“…Cross-talk between phosphorylation and ubiquitin modification is a significant aspect of intracellular signaling networks (101,174). In a most direct case, the enzymatic activity of OTUD5 (DUBA) is entirely contingent on phosphorylation at a single serine residue, which interacts directly with the COOH-terminal tail of ubiquitin (97).…”

Section: Regulation Of Dub Activitymentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…The post-translational modification (PTM) of proteins is a major mechanism for eukaryotic cells to regulate their complex physiological processes [1,2]. Moreover, the adduction of reactive compounds to proteins is a pivotal triggering event in chemical toxicity [3,4].…”

Section: Introductionmentioning

confidence: 99%

A computational analysis of S-(2-succino)cysteine sites in proteins

Miglio

Sabatino

Veglia

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The adduction of fumaric acid to the sulfhydryl group of certain cysteine (Cys) residues in proteins via a Michaellike reaction leads to the formation of S-(2-succino)cysteine (2SC) sites. Although its role remains to be fully understood, this post-translational Cys modification (protein succination) has been implicated in the pathogenesis of diabetes/obesity and fumarate hydratase-related diseases. In this study, theoretical approaches to address sequence-and 3D-structure-based features possibly underlying the specificity of protein succination have been applied to perform the first analysis of the available data on the succinate proteome. A total of 182 succinated proteins, 205 modifiable, and 1750 non-modifiable sites have been examined. The rate of 2SC sites per protein ranged from 1 to 3, and the overall relative abundance of modifiable sites was 10.8%. Modifiable and nonmodifiable sites were not distinguishable when the hydrophobicity of the Cys-flaking peptides, the acid dissociation constant value of the sulfhydryl groups, and the secondary structure of the Cys-containing segments were compared. By contrast, significant differences were determined when the accessibility of the sulphur atoms and the amino acid composition of the Cys-flaking peptides were analysed. Based on these findings, a sequence-based score function has been evaluated as a descriptor for Cys residues. In conclusion, our results indicate that modifiable and non-modifiable sites form heterogeneous subsets when features often discussed to describe Cys reactivity are examined. However, they also suggest that some differences exist, which may constitute the baseline for further investigations aimed at the development of predictive methods for 2SC sites in proteins.

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Deciphering a global network of functionally associated post‐translational modifications

Abstract: This study is the first large-scale comparative analysis of multiple types of post-translational modifications in different eukaryotic species. The resulting network of co-evolving and functionally associated modifications reveals the global landscape of post-translational regulation.

Cited by 217 publications

References 84 publications

Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Deubiquitylases From Genes to Organism

A computational analysis of S-(2-succino)cysteine sites in proteins

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