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Position-Specific Analysis and Prediction for Protein Lysine Acetylation Based on Multiple Features  [PDF]
Sheng-Bao Suo, Jian-Ding Qiu, Shao-Ping Shi, Xing-Yu Sun, Shu-Yun Huang, Xiang Chen, Ru-Ping Liang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049108
Abstract: Protein lysine acetylation is a type of reversible post-translational modification that plays a vital role in many cellular processes, such as transcriptional regulation, apoptosis and cytokine signaling. To fully decipher the molecular mechanisms of acetylation-related biological processes, an initial but crucial step is the recognition of acetylated substrates and the corresponding acetylation sites. In this study, we developed a position-specific method named PSKAcePred for lysine acetylation prediction based on support vector machines. The residues around the acetylation sites were selected or excluded based on their entropy values. We incorporated features of amino acid composition information, evolutionary similarity and physicochemical properties to predict lysine acetylation sites. The prediction model achieved an accuracy of 79.84% and a Matthews correlation coefficient of 59.72% using the 10-fold cross-validation on balanced positive and negative samples. A feature analysis showed that all features applied in this method contributed to the acetylation process. A position-specific analysis showed that the features derived from the critical neighboring residues contributed profoundly to the acetylation site determination. The detailed analysis in this paper can help us to understand more of the acetylation mechanism and can provide guidance for the related experimental validation.
The Tale of Protein Lysine Acetylation in the Cytoplasm
Karin Sadoul,Jin Wang,Boubou Diagouraga,Saadi Khochbin
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/970382
Abstract: Reversible posttranslational modification of internal lysines in many cellular or viral proteins is now emerging as part of critical signalling processes controlling a variety of cellular functions beyond chromatin and transcription. This paper aims at demonstrating the role of lysine acetylation in the cytoplasm driving and coordinating key events such as cytoskeleton dynamics, intracellular trafficking, vesicle fusion, metabolism, and stress response.
LAceP: Lysine Acetylation Site Prediction Using Logistic Regression Classifiers  [PDF]
Ting Hou, Guangyong Zheng, Pingyu Zhang, Jia Jia, Jing Li, Lu Xie, Chaochun Wei, Yixue Li
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089575
Abstract: Background Lysine acetylation is a crucial type of protein post-translational modification, which is involved in many important cellular processes and serious diseases. However, identification of protein acetylated sites through traditional experiment methods is time-consuming and laborious. Those methods are not suitable to identify a large number of acetylated sites quickly. Therefore, computational methods are still very valuable to accelerate lysine acetylated site finding. Result In this study, many biological characteristics of acetylated sites have been investigated, such as the amino acid sequence around the acetylated sites, the physicochemical property of the amino acids and the transition probability of adjacent amino acids. A logistic regression method was then utilized to integrate these information for generating a novel lysine acetylation prediction system named LAceP. When compared with existing methods, LAceP overwhelms most of state-of-the-art methods. Especially, LAceP has a more balanced prediction capability for positive and negative datasets. Conclusion LAceP can integrate different biological features to predict lysine acetylation with high accuracy. An online web server is freely available at http://www.scbit.org/iPTM/.
The biology of lysine acetylation integrates transcriptional programming and metabolism
Jigneshkumar Patel, Ravi R Pathak, Shiraz Mujtaba
Nutrition & Metabolism , 2011, DOI: 10.1186/1743-7075-8-12
Abstract: DNA methylation and lysine modifications comprise major epigenetic processes on chromatin, which alter nucleosomal architecture leading to gene activation or repression [1-3]. Dynamic post-translational modifications (PTMs) occurring in the proximity of a gene promoter are one of the hallmarks of epigenetic regulation of gene expression [4]. Although an individual lysine residue may undergo mutually exclusive multiple PTMs, including acetylation, methylation, neddylation, ubiquitynation and sumoylation, multiple lysines of a single protein can undergo diverse modifications [5,6]. Functionally, these site-specific PTMs, which are established during transcriptional programming, impart flexibility to regulate cellular processes in response to diverse physiological and external stimuli. PTMs impact functional capabilities of a protein, thus validating the notion that biological complexities are not restricted only by the number of genes [7]. To elucidate the functional consequences of a single PTM or combinatorial PTMs occurring on chromatin, the histone code hypothesis proposes to integrate the gene regulatory ability of a site-specific histone modification within its biological context [8,9]. In quintessence, a site-specific PTM serves as a mark to recruit a chromatin-associated protein complex(es) that participates in controlling gene activity, thereby, regulating cell fate decisions [10]. For instance, within chromatin, depending on the site and degree of the modification, lysine methylation can cause either gene activation or repression; lysine acetylation on histones is associated with chromatin relaxation contributing to gene activation; and the biochemical outcome of lysine ubiquitynation or sumoylation is dynamic turnover of proteins. In addition, although the role of methylation in modulating non-histone proteins, including transcription factor activity, is only beginning to be understood, acetylation of transcription factors can affect their DNA-binding abili
Global Analysis of Lysine Acetylation Suggests the Involvement of Protein Acetylation in Diverse Biological Processes in Rice (Oryza sativa)  [PDF]
Babi Ramesh Reddy Nallamilli, Mariola J. Edelmann, Xiaoxian Zhong, Feng Tan, Hana Mujahid, Jian Zhang, Bindu Nanduri, Zhaohua Peng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089283
Abstract: Lysine acetylation is a reversible, dynamic protein modification regulated by lysine acetyltransferases and deacetylases. Recent advances in high-throughput proteomics have greatly contributed to the success of global analysis of lysine acetylation. A large number of proteins of diverse biological functions have been shown to be acetylated in several reports in human cells, E.coli, and dicot plants. However, the extent of lysine acetylation in non-histone proteins remains largely unknown in monocots, particularly in the cereal crops. Here we report the mass spectrometric examination of lysine acetylation in rice (Oryza sativa). We identified 60 lysine acetylated sites on 44 proteins of diverse biological functions. Immunoblot studies further validated the presence of a large number of acetylated non-histone proteins. Examination of the amino acid composition revealed substantial amino acid bias around the acetylation sites and the amino acid preference is conserved among different organisms. Gene ontology analysis demonstrates that lysine acetylation occurs in diverse cytoplasmic, chloroplast and mitochondrial proteins in addition to the histone modifications. Our results suggest that lysine acetylation might constitute a regulatory mechanism for many proteins, including both histones and non-histone proteins of diverse biological functions.
Systematic Analysis of the Functions of Lysine Acetylation in the Regulation of Tat Activity  [PDF]
Minghao He, Linlin Zhang, Xincheng Wang, Lihong Huo, Lei Sun, Chengye Feng, Xutian Jing, Danyao Du, Huabin Liang, Min Liu, Zhangyong Hong, Jun Zhou
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067186
Abstract: The Tat protein of HIV-1 has several well-known properties, such as nucleocytoplasmic trafficking, transactivation of transcription, interaction with tubulin, regulation of mitotic progression, and induction of apoptosis. Previous studies have identified a couple of lysine residues in Tat that are essential for its functions. In order to analyze the functions of all the lysine residues in Tat, we mutated them individually to alanine, glutamine, and arginine. Through systematic analysis of the lysine mutants, we discovered several previously unidentified characteristics of Tat. We found that lysine acetylation could modulate the subcellular localization of Tat, in addition to the regulation of its transactivation activity. Our data also revealed that lysine mutations had distinct effects on microtubule assembly and Tat binding to bromodomain proteins. By correlation analysis, we further found that the effects of Tat on apoptosis and mitotic progression were not entirely attributed to its effect on microtubule assembly. Our findings suggest that Tat may regulate diverse cellular activities through binding to different proteins and that the acetylation of distinct lysine residues in Tat may modulate its interaction with various partners.
Ecdysone Induced Gene Expression Is Associated with Acetylation of Histone H3 Lysine 23 in Drosophila melanogaster  [PDF]
László Bodai, Nóra Zsindely, Renáta Gáspár, Ildikó Kristó, Orbán Komonyi, Imre Miklós Boros
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040565
Abstract: Posttranslational modification of histones regulates transcription but the exact role that acetylation of specific lysine residues plays in biological processes in vivo is still not clearly understood. To assess the contribution of different histone modifications to transcriptional activation in vivo, we determined the acetylation patterns on the ecdysone induced Eip74EF and Eip75B genes in Drosophila melanogaster larvae by chromatin immunoprecipitation. We found that acetylation of histone H3 lysine 23 is localized to promoters and correlates with endogenous ecdysone induced gene activation. In contrast, acetylation of lysines 8, 12 and 16 of histone H4 and lysine 9 of histone H3 showed minor differences in their distribution on the regulatory and transcribed regions tested, and had limited or no correlation with ecdysone induced transcriptional activity. We found that dCBP, which is encoded by the nejire gene, acetylates H3 lysine 23 in vivo, and silencing of nejire leads to reduced expression of the Eip74EF and Eip75B genes. Our results suggest that acetylation of specific lysine residues of histones contribute specifically to the dynamic regulation of transcription. Furthermore, along with previous studies identify CBP dependent H3 lysine 23 acetylation as an evolutionarily conserved chromatin modification involved in steroid induced gene activation.
Dietary, Metabolic, and Potentially Environmental Modulation of the Lysine Acetylation Machinery  [PDF]
Go-Woon Kim,Goran Gocevski,Chao-Jung Wu,Xiang-Jiao Yang
International Journal of Cell Biology , 2010, DOI: 10.1155/2010/632739
Abstract: Healthy lifestyles and environment produce a good state of health. A number of scientific studies support the notion that external stimuli regulate an individual's epigenomic profile. Epigenetic changes play a key role in defining gene expression patterns under both normal and pathological conditions. As a major posttranslational modification, lysine (K) acetylation has received much attention, owing largely to its significant effects on chromatin dynamics and other cellular processes across species. Lysine acetyltransferases and deacetylases, two opposing families of enzymes governing K-acetylation, have been intimately linked to cancer and other diseases. These enzymes have been pursued by vigorous efforts for therapeutic development in the past 15 years or so. Interestingly, certain dietary components have been found to modulate acetylation levels in vivo. Here we review dietary, metabolic, and environmental modulators of the K-acetylation machinery and discuss how they may be of potential value in the context of disease prevention. 1. Introduction The link of lifestyles, such as dietary patterns and physical activity, to the risk of developing cancer and other diseases has received support from a plethora of epidemiological and biochemical studies. In line with this, a report from the World Health Organization (WHO) states that cancer causes 7.1 million deaths annually (12.5% of the global total) and dietary factors account for about 30% of all cancers in western countries and approximately up to 20% in developing countries (http://www.who.int/dietphysicalactivity/publications/facts/cancer/en/). The report also indicates that diet is second only to tobacco as a preventable cause. As developing countries become urbanized, not only does cancer incidence increase but also the patterns tend to shift towards those in economically developed countries. For example, the westernized diets and lifestyles (characterized by high calorie intake and insufficient physical activity), acquired in Japan in the past 60 years or so, are suspected to be a significant factor for increased incidence of breast, liver, colon, prostate, and pancreatic cancers in the country [1]. An important question is what are the mechanisms underlying the epidemiological shift? There may be multiple answers. One likely is that acquired diet and lifestyles might have altered or reprogrammed the epigenetic makeup of affected individuals, thereby contributing to the onset and development of cancer and other diseases. While a person’s genetic blueprint remains relatively static, his or her
Bioinformatic Analysis and Post-Translational Modification Crosstalk Prediction of Lysine Acetylation  [PDF]
Zhike Lu, Zhongyi Cheng, Yingming Zhao, Samuel L. Volchenboum
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028228
Abstract: Recent proteomics studies suggest high abundance and a much wider role for lysine acetylation (K-Ac) in cellular functions. Nevertheless, cross influence between K-Ac and other post-translational modifications (PTMs) has not been carefully examined. Here, we used a variety of bioinformatics tools to analyze several available K-Ac datasets. Using gene ontology databases, we demonstrate that K-Ac sites are found in all cellular compartments. KEGG analysis indicates that the K-Ac sites are found on proteins responsible for a diverse and wide array of vital cellular functions. Domain structure prediction shows that K-Ac sites are found throughout a wide variety of protein domains, including those in heat shock proteins and those involved in cell cycle functions and DNA repair. Secondary structure prediction proves that K-Ac sites are preferentially found in ordered structures such as alpha helices and beta sheets. Finally, by mutating K-Ac sites in silico and predicting the effect on nearby phosphorylation sites, we demonstrate that the majority of lysine acetylation sites have the potential to impact protein phosphorylation, methylation, and ubiquitination status. Our work validates earlier smaller-scale studies on the acetylome and demonstrates the importance of PTM crosstalk for regulation of cellular function.
FANCJ/BACH1 Acetylation at Lysine 1249 Regulates the DNA Damage Response  [PDF]
Jenny Xie,Min Peng,Shawna Guillemette,Steven Quan,Stephanie Maniatis,Yuliang Wu,Aditya Venkatesh,Scott A. Shaffer,Robert M. Brosh Jr.,Sharon B. Cantor
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002786
Abstract: BRCA1 promotes DNA repair through interactions with multiple proteins, including CtIP and FANCJ (also known as BRIP1/BACH1). While CtIP facilitates DNA end resection when de-acetylated, the function of FANCJ in repair processing is less well defined. Here, we report that FANCJ is also acetylated. Preventing FANCJ acetylation at lysine 1249 does not interfere with the ability of cells to survive DNA interstrand crosslinks (ICLs). However, resistance is achieved with reduced reliance on recombination. Mechanistically, FANCJ acetylation facilitates DNA end processing required for repair and checkpoint signaling. This conclusion was based on the finding that FANCJ and its acetylation were required for robust RPA foci formation, RPA phosphorylation, and Rad51 foci formation in response to camptothecin (CPT). Furthermore, both preventing and mimicking FANCJ acetylation at lysine 1249 disrupts FANCJ function in checkpoint maintenance. Thus, we propose that the dynamic regulation of FANCJ acetylation is critical for robust DNA damage response, recombination-based processing, and ultimately checkpoint maintenance.
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