scholarly journals STALLION: a stacking-based ensemble learning framework for prokaryotic lysine acetylation site prediction

2021 ◽  
Author(s):  
Shaherin Basith ◽  
Gwang Lee ◽  
Balachandran Manavalan
Keyword(s):  
Critical Role ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Disease States ◽  
Regulatory Processes ◽  
Prokaryotic Species ◽  
Lysine Residues ◽  
Predicted Values ◽  
Feature Selection Approach ◽  
Species Specific

Abstract Protein post-translational modification (PTM) is an important regulatory mechanism that plays a key role in both normal and disease states. Acetylation on lysine residues is one of the most potent PTMs owing to its critical role in cellular metabolism and regulatory processes. Identifying protein lysine acetylation (Kace) sites is a challenging task in bioinformatics. To date, several machine learning-based methods for the in silico identification of Kace sites have been developed. Of those, a few are prokaryotic species-specific. Despite their attractive advantages and performances, these methods have certain limitations. Therefore, this study proposes a novel predictor STALLION (STacking-based Predictor for ProkAryotic Lysine AcetyLatION), containing six prokaryotic species-specific models to identify Kace sites accurately. To extract crucial patterns around Kace sites, we employed 11 different encodings representing three different characteristics. Subsequently, a systematic and rigorous feature selection approach was employed to identify the optimal feature set independently for five tree-based ensemble algorithms and built their respective baseline model for each species. Finally, the predicted values from baseline models were utilized and trained with an appropriate classifier using the stacking strategy to develop STALLION. Comparative benchmarking experiments showed that STALLION significantly outperformed existing predictor on independent tests. To expedite direct accessibility to the STALLION models, a user-friendly online predictor was implemented, which is available at: http://thegleelab.org/STALLION.

scholarly journals Structural analysis of GNAT acetyltransferases and protein acetylation

2014 ◽  
Vol 70 (a1) ◽  
pp. C299-C299
Author(s):  
Misty Kuhn ◽  
Karolina Majorek ◽  
Ekaterina Filippova ◽  
George Minasov ◽  
Alan Wolfe ◽  
...  
Keyword(s):  
Infectious Diseases ◽  
High Throughput ◽  
Structural Genomics ◽  
Bacterial Species ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Human Pathogens ◽  
Active Site Residues ◽  
Post Translational Modification ◽  
Lysine Residues

The Center for Structural Genomics for Infectious Diseases (CSGID) applies structural genomics approaches to biomedically relevant proteins from human pathogens and provides the infectious disease community with a high throughput pipeline for structure determination. Target proteins include drug targets, essential enzymes, virulence factors and vaccine candidates. Bacterial species generally have many acetyl-coenzyme A dependent GCN5-like Acetyl Transferases (GNATs), however, the substrates of most of them are unknown. Proteomic analysis has also revealed extensive post-translational modification of bacterial proteins, especially acetylation of lysine Nε. These observations led the CSGID to develop a high throughput substrate screen and initiate characterization of bacterial GNATs. One of the bacterial GNATs that acetylates lysine residues, is the Pseudomonas aeruginosa protein PA4794, that acetylates both peptides having a C-terminal lysine and the drug, chloramphenicol. Surprisingly, the acetylation of these two substrates by PA4794 is catalyzed by the enzyme using different active site residues and different kinetic mechanisms. Although it was expected that the GNATs would play a major role in protein acetylation, much of the lysine acetylation observed in bacteria is actually due to the metabolite acetylphosphate (1,2). Crystal structures and proteomics experiments revealed what makes some lysine residues particularly sensitive to acetylphosphate dependent lysine acetylation and what is required for subsequent enzymatic deacetylation. CSGID is funded with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contracts No. HHSN272200700058C and HHSN272201200026C and Midwest Center for Structural Genomics by grant GM094585

scholarly journals Regulation of Cidea protein stability by the ubiquitin-mediated proteasomal degradation pathway

2007 ◽  
Vol 408 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Siu Chiu Chan ◽  
Sheng-Cai Lin ◽  
Peng Li
Keyword(s):  
Protein Stability ◽  
Mutational Analysis ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
Degradation Pathway ◽  
Post Translational Modification ◽  
Brown Adipocytes ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Lysine Residues

Cidea, one of three members of the CIDE (cell-death-inducing DNA-fragmentation-factor-45-like effector) family of proteins, is highly enriched in brown adipose tissue, in which it plays a critical role in adaptive thermogenesis and fat accumulation. Cidea-null mice have increased energy expenditure with resistance to high-fat-diet-induced obesity and diabetes. However, little is known as to how the Cidea protein is regulated. In the present study we show that Cidea is a short-lived protein as measured by cycloheximide-based protein chase experiments in different cell lines or in differentiated brown adipocytes. Proteasome inhibitors specifically increased the stability of both transfected and endogenous Cidea protein. Furthermore, Cidea protein was found to be polyubiquitinated when overexpressed in different culture cells as well as in differentiated mature brown adipocytes. Extensive mutational analysis of individual lysine residues revealed that ubiquitinated lysine residues are located in the N-terminal region of Cidea, as alteration of these lysine residues to alanine (N-5KA mutant) renders Cidea much more stable when compared with wild-type or C-terminal lysine-less mutant (C-5KA). Furthermore, K23 (Lys23) within the N-terminus of the Cidea was identified as the major contributor to its polyubiquitination signal and the protein instability. Taken together, the results of our study demonstrated that the ubiquitin–proteasome system confers an important post-translational modification that controls the protein stability of Cidea.

Abstract O-2: The Role of Post-translational Modifications in SERCA2a-related Cardiac Dysfunction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Dongtak Jeong ◽  
Ahyoung Lee ◽  
Shinichi Mitsuyama ◽  
Jae Gyun Oh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Post Translational Modification ◽  
Mice Model ◽  
Down Regulation ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Post Translational Modifications ◽  
Lysine Residues ◽  
Interfering Rna

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) has become a validated target for the treatment of heart failure (HF). The relationship between reduced SERCA2a activity and decreases in protein expression in the setting of HF has been found to be non-linear and the toxic intracellular milieu in HF contributes to SERCA2a’s dysfunction. Post-translational modification (PTM) of SERCA2a has been recently described to as an important mechanism that can explain a reduction in SERCA2a activity in HF. Based on a comprehensive proteomic analysis, we found that the levels and activity of SERCA2a in cardiomyocytes are modulated in parallel with the levels of small ubiquitin-like modifier type 1 (SUMO-1). Moreover, our work has shown that SUMO-1 plays a critical role in protecting SERCA2a from pathological conditions (Kho et al, Nature, 2011). More recently, we demonstrated that SUMO-1 gene transfer and its combination with SERCA2a led to a reversal of HF in a porcine model of ischemic induced HF (Tilemann et al, Sci Transl Med, 2013). In our analysis of SERCA2a PTM in animal models of HF, we observed that SERCA2a is acetylated, and that this acetylation is more prominent in failing hearts. The acetylation of SERCA2a was validated by acetylation assays with acetyltransferase and HDAC inhibitors. We identified several lysine residues on SERCA2a for susceptible to acetylation. In addition, we found that Sirt1 enzyme deacetylates SERCA2a. Sirt1 down-regulation in HL-1 cells using small interfering RNA increased SERCA2a acetylation and thereby decreased its activity. Moreover, SERCA2a acetylation was increased when Sirt1 was depleted by recombinant adeno-associated virus carrying short hairpin RNA for Sirt1 in mice model, which reflected a decrease in intensity of interaction between Sirt1 and SERCA2a. Reduced acetylation was accompanied by an increase in SERCA2a SUMOylation in the heart. Decreased acetylation, combined with increased SUMOylation, of SERCA2a may contribute to the cardioprotective effects of Sirt1. Our results show that SERCA2a acetylation increases during HF and negatively impacts SERCA2a’s function, suggesting that the down-regulation of SERCA2a acetylation may afford a novel intervention in the setting of heart failure.

scholarly journals Acetylproteomics analyses reveal critical features of lysine-ε-acetylation in Arabidopsis and a role of 14-3-3 protein acetylation in alkaline response

2022 ◽  
Vol 2 (1) ◽  
Author(s):  
Jianfei Guo ◽  
Xiaoqiang Chai ◽  
Yuchao Mei ◽  
Jiamu Du ◽  
Haining Du ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Alkaline Stress ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Evolutionarily Conserved ◽  
Lysine Residues ◽  
Protein Lysine Acetylation ◽  
Subsequent Activation

AbstractLysine-ε-acetylation (Kac) is a post-translational modification (PTM) that is critical for metabolic regulation and cell signaling in mammals. However, its prevalence and importance in plants remain to be determined. Employing high-resolution tandem mass spectrometry, we analyzed protein lysine acetylation in five representative Arabidopsis organs with 2 ~ 3 biological replicates per organ. A total of 2887 Kac proteins and 5929 Kac sites were identified. This comprehensive catalog allows us to analyze proteome-wide features of lysine acetylation. We found that Kac proteins tend to be more uniformly expressed in different organs, and the acetylation status exhibits little correlation with the gene expression level, indicating that acetylation is unlikely caused by stochastic processes. Kac preferentially targets evolutionarily conserved proteins and lysine residues, but only a small percentage of Kac proteins are orthologous between rat and Arabidopsis. A large portion of Kac proteins overlap with proteins modified by other PTMs including ubiquitination, SUMOylation and phosphorylation. Although acetylation, ubiquitination and SUMOylation all modify lysine residues, our analyses show that they rarely target the same sites. In addition, we found that “reader” proteins for acetylation and phosphorylation, i.e., bromodomain-containing proteins and GRF (General Regulatory Factor)/14-3-3 proteins, are intensively modified by the two PTMs, suggesting that they are main crosstalk nodes between acetylation and phosphorylation signaling. Analyses of GRF6/14-3-3λ reveal that the Kac level of GRF6 is decreased under alkaline stress, suggesting that acetylation represses plant alkaline response. Indeed, K56ac of GRF6 inhibits its binding to and subsequent activation of the plasma membrane H+-ATPase AHA2, leading to hypersensitivity to alkaline stress. These results provide valuable resources for protein acetylation studies in plants and reveal that protein acetylation suppresses phosphorylation output by acetylating GRF/14-3-3 proteins.

Recent trends on the development of machine learning approaches for the prediction of lysine acetylation sites

2021 ◽  
Vol 28 ◽  
Author(s):  
Shaherin Basith ◽  
Hye Jin Chang ◽  
Saraswathy Nithiyanandam ◽  
Tae Hwan Shin ◽  
Balachandran Manavalan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Process Time ◽  
Great Promise ◽  
Lysine Acetylation ◽  
Learning Approaches ◽  
Regulatory Processes ◽  
Acetylation Site ◽  
Lysine Residues ◽  
Software Utility ◽  
Key Aspects

: Acetylation on lysine residues is considered as one of the most potent protein post-translational modifications owing to its crucial role in cellular metabolism and regulatory processes. Recent advances in experimental techniques has unraveled several lysine acetylation substrates and sites. However, towing to its cost-ineffectiveness, cumbersome process, time-consumption, and labor-intensiveness, several efforts have geared towards the development of computational tools. In particular, machine learning (ML)-based approaches hold great promise in the rapid discovery of lysine acetylation modification sites, which could be witnessed by the growing number of prediction tools. Recently, several ML methods have been developed for the prediction of lysine acetylation sites owing to their time- and cost-effectiveness. In this review, we present a complete survey of the state-of-the-art ML predictors for lysine acetylation. We discuss about a variety of key aspects for developing a successful predictor, including operating ML algorithms, feature selection methods, validation techniques, and software utility. Initially, we review about lysine acetylation site databases, current ML approaches, working principles, and their performances. Lastly, we discuss the shortcomings and future directions of ML approaches in the prediction of lysine acetylation sites. This review may act as a useful guide for the experimentalists in choosing a right ML tool for their research. Moreover, it may help bioinformaticians in the development of more accurate and advanced ML-based predictors in protein research.

scholarly journals Ancient Regulatory Role of Lysine Acetylation in Central Metabolism

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Ernesto S. Nakayasu ◽  
Meagan C. Burnet ◽  
Hanna E. Walukiewicz ◽  
Christopher S. Wilkins ◽  
Anil K. Shukla ◽  
...  
Keyword(s):  
Protein Function ◽  
Active Sites ◽  
Metabolic Regulation ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Direct Role ◽  
Data Set ◽  
Evolutionarily Conserved ◽  
Lysine Residues

ABSTRACT Lysine acetylation is a common protein post-translational modification in bacteria and eukaryotes. Unlike phosphorylation, whose functional role in signaling has been established, it is unclear what regulatory mechanism acetylation plays and whether it is conserved across evolution. By performing a proteomic analysis of 48 phylogenetically distant bacteria, we discovered conserved acetylation sites on catalytically essential lysine residues that are invariant throughout evolution. Lysine acetylation removes the residue’s charge and changes the shape of the pocket required for substrate or cofactor binding. Two-thirds of glycolytic and tricarboxylic acid (TCA) cycle enzymes are acetylated at these critical sites. Our data suggest that acetylation may play a direct role in metabolic regulation by switching off enzyme activity. We propose that protein acetylation is an ancient and widespread mechanism of protein activity regulation. IMPORTANCE Post-translational modifications can regulate the activity and localization of proteins inside the cell. Similar to phosphorylation, lysine acetylation is present in both eukaryotes and prokaryotes and modifies hundreds to thousands of proteins in cells. However, how lysine acetylation regulates protein function and whether such a mechanism is evolutionarily conserved is still poorly understood. Here, we investigated evolutionary and functional aspects of lysine acetylation by searching for acetylated lysines in a comprehensive proteomic data set from 48 phylogenetically distant bacteria. We found that lysine acetylation occurs in evolutionarily conserved lysine residues in catalytic sites of enzymes involved in central carbon metabolism. Moreover, this modification inhibits enzymatic activity. Our observations suggest that lysine acetylation is an evolutionarily conserved mechanism of controlling central metabolic activity by directly blocking enzyme active sites.

Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6544-6563
Author(s):  
Victoria Lucia Alonso ◽  
Luis Emilio Tavernelli ◽  
Alejandro Pezza ◽  
Pamela Cribb ◽  
Carla Ritagliati ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Chagas Disease ◽  
Causative Agent ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Lysine Acetylation ◽  
Specific Manner ◽  
Lysine Residues ◽  
Antiparasitic Drugs

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

Review of Progress in Predicting Protein Methylation Sites

2019 ◽  
Vol 23 (15) ◽  
pp. 1663-1670 ◽  
Author(s):  
Chunyan Ao ◽  
Shunshan Jin ◽  
Yuan Lin ◽  
Quan Zou
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcriptional Activity ◽  
Regulation Of Gene Expression ◽  
Protein Methylation ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Regulatory Enzymes ◽  
Lysine Residues ◽  
Arginine Residues

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.

Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Nuclear Cataract ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Ability To Act ◽  
Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

scholarly journals Deacetylation as a receptor-regulated direct activation switch for pannexin channels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Hsin Chiu ◽  
Christopher B. Medina ◽  
Catherine A. Doyle ◽  
Ming Zhou ◽  
Adishesh K. Narahari ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Lysine Acetylation ◽  
Intercellular Signaling ◽  
Histone Deacetylase 6 ◽  
Pannexin 1 ◽  
Lysine Deacetylase ◽  
Channel Opening ◽  
Lysine Residues ◽  
G Protein Coupled

AbstractActivation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia – histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism.

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