The switches.ELM Resource: A Compendium of Conditional Regulatory Interaction Interfaces

Roey, Kim Van; Dinkel, Holger; Weatheritt, Robert J.; Gibson, Toby J.; Davey, Norman E.

doi:10.1126/scisignal.2003345

Cited by 106 publications

(115 citation statements)

References 95 publications

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“…With the keywords combination "((cross AND (talk OR regulate OR link)) OR interplay) AND post translational modification," 766 articles were extracted from PubMed through April 23, 2014. In addition, PTM sites around experimentally characterized short linear motif-based molecular switches were mined from the switches.ELM database (27). Known PTM associations compiled by the PTMcode database (28) were also included as candidates.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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

Huang

Xu²,

Zhou

et al. 2015

Molecular & Cellular Proteomics

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“…Regulation of degron recognition often involves molecular switches that can turn on or turn off interactions in response to environmental and cellular cues (73). Posttranslational modifications, including phosphorylation, represent the most common mechanism for either promoting or inhibiting substrate recognition by E3 ligases.…”

Section: The Complexity Of Degron Regulationmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…It is now clear that cell regulatory decisions are made by molecular switching events in large but highly dynamic, often coalescing, protein complexes (1,2). Protein complex isolation by affinity purification is a common technique, used for the identification of the protein composition of these molecular machines (3), contributing to the elucidation of spatial and temporal patterns of large protein networks and functional modules within these networks (4).…”

mentioning

confidence: 99%

Elution Profile Analysis of SDS-induced Subcomplexes by Quantitative Mass Spectrometry

Texier

Toedt

Gorza

et al. 2014

Molecular & Cellular Proteomics

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Analyzing the molecular architecture of native multiprotein complexes via biochemical methods has so far been difficult and error prone. Protein complex isolation by affinity purification can define the protein repertoire of a given complex, yet, it remains difficult to gain knowledge of its substructure or modular composition. Here, we introduce SDS concentration gradient induced decomposition of protein complexes coupled to quantitative mass spectrometry and in silico elution profile distance analysis. By applying this new method to a cellular transport module, the IFT/lebercilin complex, we demonstrate its ability to determine modular composition as well as sensitively detect known and novel complex components. We show that the IFT/lebercilin complex can be separated into at least five submodules, the IFT complex A, the IFT complex B, the 14 -3-3 protein complex and the CTLH complex, as well as the dynein light chain complex. Understanding the orchestration and dynamics of cellular function on the molecular level is one of the challenges in biology. It is now clear that cell regulatory decisions are made by molecular switching events in large but highly dynamic, often coalescing, protein complexes (1, 2). Protein complex isolation by affinity purification is a common technique, used for the identification of the protein composition of these molecular machines (3), contributing to the elucidation of spatial and temporal patterns of large protein networks and functional modules within these networks (4). Interaction data derived from different protein complex analyses are the basis for predictions of biological pathways or disease mechanisms concerning those proteins (5). Still, in most cases it is difficult or even impossible to determine how, or even if the copurified proteins assemble as a single module in a cell, limiting the fine-grained description of the complex structure (6, 7). The possibility to integrate module and submodule information in higher order protein networks is extremely valuable for their understanding and opens the route to define pathways of information flow within and between discrete molecular machines. Zooming in on a protein mutated in early childhood blindness, lebercilin, we have previously identified proteins of the intraflagellar transport (IFT) machinery to interact with lebercilin (5). IFT appears as a physical entity driving vesicular trafficking through the connecting cilium that bridges the inner and the outer segment of vertebrate photoreceptors (8). IFT, like many other multiprotein complexes, is an example for a functionally fairly well described molecular machine with yet unknown molecular topology and mechanical properties.To determine composition, as well as protein complex topology of lebercilin and its interaction with IFT components, we developed a novel workflow, which we termed "elution profile analysis of SDS-induced subcomplexes by quantitative From the ‡Division

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The switches.ELM Resource: A Compendium of Conditional Regulatory Interaction Interfaces

Cited by 106 publications

References 95 publications

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

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

Degrons in cancer

Elution Profile Analysis of SDS-induced Subcomplexes by Quantitative Mass Spectrometry

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