Proteome-wide prediction of acetylation substrates.
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ABSTRACT:
SUBMITTER: Basu A
PROVIDER: S-EPMC2728972 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Protein acetylation plays a critical role in biological processes by regulating the functions and properties of proteins. Thus, the study of protein acetylation dynamics is critical for understanding of how this modification influences protein stability, localization, and function. Here we performed a comprehensive characterization of protein acetylation dynamics using mass spectrometry (MS) based proteomics through utilization of 13C-glucose or D3-acetate, which are metabolized into acetyl-coA, labeling acetyl groups through subsequent incorporation into proteins. Samples were collected at eight time points to monitor rates and trends of heavy acetyl incorporation. Through this platform, we characterized around 1,000 sites with significantly increasing acetylation trends, which we clustered based on their rates of acetylation. Faster rates were enriched on proteins associated with chromatin and RNA metabolism, while slower rates were more typical on proteins involved with lipid metabolism. Among others, we identified sites catalyzed at faster rates with potential critical roles in protein activation, including the histone acetyltransferase p300 acetylated in its activation loop, which could explain self-acetylation as an important feedback mechanism to regulate acetyltransferases. Overall, our studies highlight the dynamic nature of protein acetylation, and how metabolism plays a central role in this regulation.
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Project description:Lysine acetylation (LysAc) is a conserved and important post-translational modification (PTM) that plays a key role in plant physiological and metabolic processes. Based on advances in Lys-acetylated protein immunoenrichment and mass-spectrometric technology, LysAc proteomics studies have been performed in many species. Such studies have made substantial contributions to our understanding of plant LysAc, revealing that Lys-acetylated histones and nonhistones are involved in a broad spectrum of plant cellular processes. Here, we present an extensive overview of recent research on plant Lys-acetylproteomes. We provide in-depth insights into the characteristics of plant LysAc modifications and the mechanisms by which LysAc participates in cellular processes and regulates metabolism and physiology during plant growth and development. First, we summarize the characteristics of LysAc, including the properties of Lys-acetylated sites, the motifs that flank Lys-acetylated lysines, and the dynamic alterations in LysAc among different tissues and developmental stages. We also outline a map of Lys-acetylated proteins in the Calvin-Benson cycle and central carbon metabolism-related pathways. We then introduce some examples of the regulation of plant growth, development, and biotic and abiotic stress responses by LysAc. We discuss the interaction between LysAc and Nα-terminal acetylation and the crosstalk between LysAc and other PTMs, including phosphorylation and succinylation. Finally, we propose recommendations for future studies in the field. We conclude that LysAc of proteins plays an important role in the regulation of the plant life cycle.
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Project description:Protein lysine acetylation is a prevalent post-translational modification that plays pivotal roles in various biological processes in both prokaryotes and eukaryotes. Aspergillus flavus, as an aflatoxin-producing fungus, has attracted tremendous attention due to its health impact on agricultural commodities. Here, we performed the first lysine-acetylome mapping in this filamentous fungus using immune-affinity-based purification integrated with high-resolution mass spectrometry. Overall, we identified 1383 lysine-acetylation sites in 652 acetylated proteins, which account for 5.18% of the total proteins in A. flavus. According to bioinformatics analysis, the acetylated proteins are involved in various cellular processes involving the ribosome, carbon metabolism, antibiotic biosynthesis, secondary metabolites, and the citrate cycle and are distributed in diverse subcellular locations. Additionally, we demonstrated for the first time the acetylation of fatty acid synthase ? and ? encoded by aflA and aflB involved in the aflatoxin-biosynthesis pathway (cluster 54), as well as backbone enzymes from secondary metabolite clusters 20 and 21 encoded by AFLA_062860 and AFLA_064240, suggesting important roles for acetylation associated with these processes. Our findings illustrating abundant lysine acetylation in A. flavus expand our understanding of the fungal acetylome and provided insight into the regulatory roles of acetylation in secondary metabolism.
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Project description:Lysine acetylation is a dynamic and reversible post-translational modification that plays an important role in diverse cellular processes. Botrytis cinerea is the most thoroughly studied necrotrophic species due to its broad host range and huge economic impact. However, to date, little is known about the functions of lysine acetylation in this plant pathogen. In this study, we determined the lysine acetylome of B. cinerea through the combination of affinity enrichment and high-resolution LC-MS/MS analysis. Overall, 1582 lysine acetylation sites in 954 proteins were identified. Bioinformatics analysis shows that the acetylated proteins are involved in diverse biological functions and show multiple cellular localizations. Several particular amino acids preferred near acetylation sites, including K(ac)Y, K(ac)H, K(ac)***R, K(ac)F, FK(ac) and K(ac)***K, were identified in this organism. Protein interaction network analysis demonstrates that a variety of interactions are modulated by protein acetylation. Interestingly, 6 proteins involved in virulence of B. cinerea, including 3 key components of the high-osmolarity glycerol pathway, were found to be acetylated, suggesting that lysine acetylation plays regulatory roles in pathogenesis. These data provides the first comprehensive view of the acetylome of B. cinerea and serves as a rich resource for functional analysis of lysine acetylation in this plant pathogen.
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Project description:Specific E3 ligases target tumor suppressors for degradation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the β-catenin/Wnt and YAP/Hippo pathways by targeting the degradation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degradation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome analysis. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addition, we validated OTU domain-containing protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide analysis of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.
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Project description:Schistosomiasis is a devastating parasitic disease caused by tremotodes of the genus Schistosoma. Eggs produced by sexually mature schistosomes are the causative agents of for pathogenesis and transmission. Elucidating the molecular mechanism of schistosome development and sexual maturation would facilitate the prevention and control of schistosomiasis. Acetylation of lysine is a dynamic and reversible post-translational modification playing keys role in many biological processes including development in both eukaryotes and prokaryotes. To investigate the impacts of lysine acetylation on Schistosoma japonicum (S. japonicum) development and sexual maturation, we used immunoaffinity-based acetyllysine peptide enrichment combined with mass spectrometry (MS), to perform the first comparative analysis of proteome-wide lysine acetylation in both female and male, juvenile (18 days post infection, 18 dpi) and adult (28 dpi) schistosome samples. In total, we identified 874 unique acetylated sites in 494 acetylated proteins. The four samples shared 47 acetylated sites and 46 proteins. More acetylated sites and proteins shared by both females and males were identified in 28 dpi adults (189 and 143, respectively) than in 18 dpi schistosomula (76 and 59, respectively). More stage-unique acetylated sites and proteins were also identified in 28 dpi adults (494 and 210, respectively) than in 18 dpi schistosomula (73 and 44, respectively). Functional annotation showed that in different developmental stages and genders, a number of proteins involving in muscle movement, glycometabolism, lipid metabolism, energy metabolism, environmental stress resistance, antioxidation, etc., displayed distinct acetylation profiles, which was in accordance with the changes of their biological functions during schistosome development, suggesting that lysine acetylation modification exerted important regulatory roles in schistosome development. Taken together, our data provided the first comparative global survey of lysine acetylation in juvenile and adult S. japonicum, which would deepen our understanding of the molecular mechanism of schistosome development and sexual maturation, and provide clues for the development of new anti-schistosome strategies.
| S-EPMC5715381 | biostudies-literature
Project description:Post-translational modification of proteins by lysine acetylation plays important regulatory roles in living cells. The budding yeast Saccharomyces cerevisiae is a widely used unicellular eukaryotic model organism in biomedical research. S. cerevisiae contains several evolutionary conserved lysine acetyltransferases and deacetylases. However, only a few dozen acetylation sites in S. cerevisiae are known, presenting a major obstacle for further understanding the regulatory roles of acetylation in this organism. Here we use high resolution mass spectrometry to identify about 4000 lysine acetylation sites in S. cerevisiae. Acetylated proteins are implicated in the regulation of diverse cytoplasmic and nuclear processes including chromatin organization, mitochondrial metabolism, and protein synthesis. Bioinformatic analysis of yeast acetylation sites shows that acetylated lysines are significantly more conserved compared with nonacetylated lysines. A large fraction of the conserved acetylation sites are present on proteins involved in cellular metabolism, protein synthesis, and protein folding. Furthermore, quantification of the Rpd3-regulated acetylation sites identified several previously known, as well as new putative substrates of this deacetylase. Rpd3 deficiency increased acetylation of the SAGA (Spt-Ada-Gcn5-Acetyltransferase) complex subunit Sgf73 on K33. This acetylation site is located within a critical regulatory domain in Sgf73 that interacts with Ubp8 and is involved in the activation of the Ubp8-containing histone H2B deubiquitylase complex. Our data provides the first global survey of acetylation in budding yeast, and suggests a wide-ranging regulatory scope of this modification. The provided dataset may serve as an important resource for the functional analysis of lysine acetylation in eukaryotes.
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Project description:To check whether mRNA level change for the changed proteins in protein level.
2020-11-01 | GSE156101 | GEO
Project description:Despite recent progress in proteomics most protein complexes are still unknown. Identification of these complexes will help us understand cellular regulatory mechanisms and support development of new drugs. Therefore it is really important to establish detailed information about the composition and the abundance of protein complexes but existing algorithms can only give qualitative predictions. Herein, we propose a new approach based on stochastic simulations of protein complex formation that integrates multi-source data--such as protein abundances, domain-domain interactions and functional annotations--to predict alternative forms of protein complexes together with their abundances. This method, called SiComPre (Simulation based Complex Prediction), achieves better qualitative prediction of yeast and human protein complexes than existing methods and is the first to predict protein complex abundances. Furthermore, we show that SiComPre can be used to predict complexome changes upon drug treatment with the example of bortezomib. SiComPre is the first method to produce quantitative predictions on the abundance of molecular complexes while performing the best qualitative predictions. With new data on tissue specific protein complexes becoming available SiComPre will be able to predict qualitative and quantitative differences in the complexome in various tissue types and under various conditions.
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Project description:Lysine acetylation is a ubiquitous post-translational modification in many organisms including the malaria parasite Plasmodium falciparum, yet the full extent of acetylation across the parasite proteome remains unresolved. Moreover, the functional significance of acetylation or how specific acetyl-lysine sites are regulated is largely unknown. Here we report a seven-fold expansion of the known parasite 'acetylome', characterizing 2,876 acetylation sites on 1,146 proteins. We observe that lysine acetylation targets a diverse range of protein complexes and is particularly enriched within the Apicomplexan AP2 (ApiAP2) DNA-binding protein family. Using quantitative proteomics we determined that artificial perturbation of the acetate/acetyl-CoA balance alters the acetyl-lysine occupancy of several ApiAP2 DNA-binding proteins and related transcriptional proteins. This metabolic signaling could mediate significant downstream transcriptional responses, as we show that acetylation of an ApiAP2 DNA-binding domain ablates its DNA-binding propensity. Lastly, we investigated the acetyl-lysine targets of each class of lysine deacetylase in order to begin to explore how each class of enzyme contributes to regulating the P. falciparum acetylome.
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