scholarly journals PathwayMatcher: proteoform-centric network construction enables fine-granularity multi-omics pathway mapping

2018 ◽  
Author(s):  
Luis Francisco Hernández Sánchez ◽  
Bram Burger ◽  
Carlos Horro ◽  
Antonio Fabregat ◽  
Stefan Johansson ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Biomedical Data ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Network Construction ◽  
Gene Sets ◽  
Functional Knowledge ◽  
Pathway Analyses ◽  
Different Levels

AbstractBackgroundMapping biomedical data to functional knowledge is an essential task in bioinformatics and can be achieved by querying identifiers, e.g. gene sets, in pathway knowledgebases. However, the isoform and post-translational modification states of proteins are lost when converting input and pathways into gene-centric lists.FindingsBased on the Reactome knowledgebase, we built a network of protein-protein interactions accounting for the documented isoform and modification statuses of proteins. We then implemented a command line application called PathwayMatcher (github.com/PathwayAnalysisPlatform/PathwayMatcher) to query this network. PathwayMatcher supports multiple types of omics data as input, and outputs the possibly affected biochemical reactions, subnetworks, and pathways.ConclusionsPathwayMatcher enables refining the network-representation of pathways by including isoform and post-translational modifications. The specificity of pathway analyses is hence adapted to different levels of granularity and it becomes possible to distinguish interactions between different forms of the same protein.

scholarly journals PathwayMatcher: proteoform-centric network construction enables fine-granularity multiomics pathway mapping

GigaScience ◽  
2019 ◽  
Vol 8 (8) ◽  
Author(s):  
Luis Francisco Hernández Sánchez ◽  
Bram Burger ◽  
Carlos Horro ◽  
Antonio Fabregat ◽  
Stefan Johansson ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Knowledge Bases ◽  
Protein Isoforms ◽  
Biomedical Data ◽  
Protein Protein Interactions ◽  
Gene Sets ◽  
Functional Knowledge ◽  
Pathway Analyses ◽  
Different Levels

Abstract Background Mapping biomedical data to functional knowledge is an essential task in bioinformatics and can be achieved by querying identifiers (e.g., gene sets) in pathway knowledge bases. However, the isoform and posttranslational modification states of proteins are lost when converting input and pathways into gene-centric lists. Findings Based on the Reactome knowledge base, we built a network of protein-protein interactions accounting for the documented isoform and modification statuses of proteins. We then implemented a command line application called PathwayMatcher (github.com/PathwayAnalysisPlatform/PathwayMatcher) to query this network. PathwayMatcher supports multiple types of omics data as input and outputs the possibly affected biochemical reactions, subnetworks, and pathways. Conclusions PathwayMatcher enables refining the network representation of pathways by including proteoforms defined as protein isoforms with posttranslational modifications. The specificity of pathway analyses is hence adapted to different levels of granularity, and it becomes possible to distinguish interactions between different forms of the same protein.

scholarly journals Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

2021 ◽  
Vol 11 ◽  
Author(s):  
Carolina Alquezar ◽  
Shruti Arya ◽  
Aimee W. Kao
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Protein Localization ◽  
Critical Role ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Tau Function ◽  
Potential Impact ◽  
Important Position

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.

scholarly journals The Function of FEN1 is Regulated by Post-Translational Modification

2021 ◽  
Author(s):  
Zhenxing Wu ◽  
Xiaofen Mo ◽  
Chengbo Lang ◽  
Jinjing Luo
Keyword(s):  
Protein Interactions ◽  
Cellular Localization ◽  
Genome Instability ◽  
Nuclease Activity ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Dna Structures ◽  
Effective Role ◽  
Regulate Protein

Flap endonuclease 1 (FEN1) is a multifunctional DNA branching nuclease. Post-translational modifications (PTMs) exist in this protein widely, including phosphorylation, methylation, acetylation, ubiquitination and small ubiquitination modification (SUMO). Here, we make a summary for those PTMs studies on FEN1, to illustrate relationships between mutations of those amino acids and their functions alteration of FEN1. Numerous evidences have confirmed that dysfunction of FEN1 would lead to genome instability, and then induce a variety of chromosome-related diseases ultimately, including tumors. On one hand, interaction partner also stimulates FEN1 nuclease activity, to further ensure an effective role in the processing of different DNA structures; on the other hand, PTMs may regulate protein-protein interactions and FEN1’s cellular localization.

scholarly journals Regulation of Protein Post-Translational Modifications on Metabolism of Actinomycetes

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1122
Author(s):  
Chen-Fan Sun ◽  
Yong-Quan Li ◽  
Xu-Ming Mao
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Structure Activity ◽  
Variable Environments ◽  
Metabolic States ◽  
Metabolite Synthesis ◽  
External Stimuli

Protein post-translational modification (PTM) is a reversible process, which can dynamically regulate the metabolic state of cells through regulation of protein structure, activity, localization or protein–protein interactions. Actinomycetes are present in the soil, air and water, and their life cycle is strongly determined by environmental conditions. The complexity of variable environments urges Actinomycetes to respond quickly to external stimuli. In recent years, advances in identification and quantification of PTMs have led researchers to deepen their understanding of the functions of PTMs in physiology and metabolism, including vegetative growth, sporulation, metabolite synthesis and infectivity. On the other hand, most donor groups for PTMs come from various metabolites, suggesting a complex association network between metabolic states, PTMs and signaling pathways. Here, we review the mechanisms and functions of PTMs identified in Actinomycetes, focusing on phosphorylation, acylation and protein degradation in an attempt to summarize the recent progress of research on PTMs and their important role in bacterial cellular processes.

Protein Interaction Domains and Post-Translational Modifications: Structural Features and Drug Discovery Applications

2020 ◽  
Vol 27 (37) ◽  
pp. 6306-6355 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia Anna Mercurio ◽  
Marilisa Leone
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Structural Information ◽  
Protein Complexes ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
Modular Architecture ◽  
Post Translational Modifications ◽  
Interaction Domains

Background:: Many pathways regarding healthy cells and/or linked to diseases onset and progression depend on large assemblies including multi-protein complexes. Protein-protein interactions may occur through a vast array of modules known as protein interaction domains (PIDs). Objective:: This review concerns with PIDs recognizing post-translationally modified peptide sequences and intends to provide the scientific community with state of art knowledge on their 3D structures, binding topologies and potential applications in the drug discovery field. Method:: Several databases, such as the Pfam (Protein family), the SMART (Simple Modular Architecture Research Tool) and the PDB (Protein Data Bank), were searched to look for different domain families and gain structural information on protein complexes in which particular PIDs are involved. Recent literature on PIDs and related drug discovery campaigns was retrieved through Pubmed and analyzed. Results and Conclusion:: PIDs are rather versatile as concerning their binding preferences. Many of them recognize specifically only determined amino acid stretches with post-translational modifications, a few others are able to interact with several post-translationally modified sequences or with unmodified ones. Many PIDs can be linked to different diseases including cancer. The tremendous amount of available structural data led to the structure-based design of several molecules targeting protein-protein interactions mediated by PIDs, including peptides, peptidomimetics and small compounds. More studies are needed to fully role out, among different families, PIDs that can be considered reliable therapeutic targets, however, attacking PIDs rather than catalytic domains of a particular protein may represent a route to obtain selective inhibitors.

scholarly journals Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Song Yang ◽  
Kasey Jividen ◽  
Teddy Kamata ◽  
Natalia Dworak ◽  
Luke Oostdyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Prostate Cancer Cells ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Complex Assembly ◽  
Adp Ribosylation ◽  
Signaling Axis ◽  
Regulate Protein ◽  
Protein Complex Assembly

AbstractAndrogen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

scholarly journals The Protein Interactome of Glycolysis in Escherichia coli

Proteomes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 16
Author(s):  
Shomeek Chowdhury ◽  
Stephen Hepper ◽  
Mudassir K. Lodi ◽  
Milton H. Saier ◽  
Peter Uetz
Keyword(s):  
Escherichia Coli ◽  
Protein Interactions ◽  
Allosteric Regulation ◽  
Glycolytic Enzymes ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Interacting Protein ◽  
E Coli ◽  
Protein Interactome ◽  
The Impact

Glycolysis is regulated by numerous mechanisms including allosteric regulation, post-translational modification or protein-protein interactions (PPI). While glycolytic enzymes have been found to interact with hundreds of proteins, the impact of only some of these PPIs on glycolysis is well understood. Here we investigate which of these interactions may affect glycolysis in E. coli and possibly across numerous other bacteria, based on the stoichiometry of interacting protein pairs (from proteomic studies) and their conservation across bacteria. We present a list of 339 protein-protein interactions involving glycolytic enzymes but predict that ~70% of glycolytic interactors are not present in adequate amounts to have a significant impact on glycolysis. Finally, we identify a conserved but uncharacterized subset of interactions that are likely to affect glycolysis and deserve further study.

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

scholarly journals Expanding the potential genes of inborn errors of immunity through protein interactions

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Humza A. Khan ◽  
Manish J. Butte
Keyword(s):  
Genetic Variation ◽  
Protein Interactions ◽  
Immune Cell ◽  
Genetic Disorders ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
New Genes ◽  
Inborn Errors Of Immunity

Abstract Background Inborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity. Results Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types. Conclusions By merging genes derived from protein interactions of known IEI genes with transcriptional data, we offer a new list of candidate genes that may play a role in as-yet undiscovered IEIs.

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