Protein acetylation as a means to regulate protein function in tune with metabolic state

2014 ◽  
Vol 42 (4) ◽  
pp. 1037-1042 ◽  
Author(s):  
Lei Shi ◽  
Benjamin P. Tu
Keyword(s):  
Energy Metabolism ◽  
Present Article ◽  
Protein Function ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Metabolic State ◽  
Acetyl Coa ◽  
Acetyl Group ◽  
Regulate Protein

Protein acetylation has emerged as a prominent post-translational modification that can occur on a wide variety of proteins. The metabolite acetyl-CoA is a key intermediate in energy metabolism that also serves as the acetyl group donor in protein acetylation modifications. Therefore such acetylation modifications might be coupled to the intracellular availability of acetyl-CoA. In the present article, we summarize recent evidence suggesting that the particular protein acetylation modifications enable the regulation of protein function in tune with acetyl-CoA availability and thus the metabolic state of the cell.

scholarly journals Mechanisms, regulation and consequences of protein SUMOylation

2010 ◽  
Vol 428 (2) ◽  
pp. 133-145 ◽  
Author(s):  
Kevin A. Wilkinson ◽  
Jeremy M. Henley
Keyword(s):  
Protein Function ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Wide Range ◽  
Lysine Residues ◽  
Ubiquitination Pathway ◽  
Regulate Protein ◽  
Substrate Proteins ◽  
Protein Sumoylation

The post-translational modification SUMOylation is a major regulator of protein function that plays an important role in a wide range of cellular processes. SUMOylation involves the covalent attachment of a member of the SUMO (small ubiquitin-like modifier) family of proteins to lysine residues in specific target proteins via an enzymatic cascade analogous to, but distinct from, the ubiquitination pathway. There are four SUMO paralogues and an increasing number of proteins are being identified as SUMO substrates. However, in many cases little is known about how SUMOylation of these targets is regulated. Compared with the ubiquitination pathway, relatively few components of the conjugation machinery have been described and the processes that specify individual SUMO paralogue conjugation to defined substrate proteins are an active area of research. In the present review, we briefly describe the SUMOylation pathway and present an overview of the recent findings that are beginning to identify some of the mechanisms that regulate protein SUMOylation.

scholarly journals The roles of O-linked β-N-acetylglucosamine in cardiovascular physiology and disease

2012 ◽  
Vol 302 (10) ◽  
pp. H1905-H1918 ◽  
Author(s):  
Natasha E. Zachara
Keyword(s):  
Protein Function ◽  
Type Ii Diabetes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reciprocal Relationship ◽  
Cellular Stress Response ◽  
Cellular Injury ◽  
Type Ii ◽  
Post Translational Modification ◽  
Regulate Protein

More than 1,000 proteins of the nucleus, cytoplasm, and mitochondria are dynamically modified by O-linked β- N-acetylglucosamine ( O-GlcNAc), an essential post-translational modification of metazoans. O-GlcNAc, which modifies Ser/Thr residues, is thought to regulate protein function in a manner analogous to protein phosphorylation and, on a subset of proteins, appears to have a reciprocal relationship with phosphorylation. Like phosphorylation, O-GlcNAc levels change dynamically in response to numerous signals including hyperglycemia and cellular injury. Recent data suggests that O-GlcNAc appears to be a key regulator of the cellular stress response, the augmentation of which is protective in models of acute vascular injury, trauma hemorrhage, and ischemia-reperfusion injury. In contrast to these studies, O-GlcNAc has also been implicated in the development of hypertension and type II diabetes, leading to vascular and cardiac dysfunction. Here we summarize the current understanding of the roles of O-GlcNAc in the heart and vasculature.

scholarly journals Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael Lammers
Keyword(s):  
Protein Function ◽  
High Energy ◽  
Research Field ◽  
Dimensional Structure ◽  
Special Focus ◽  
Side Chains ◽  
Amino Group ◽  
Acetyl Phosphate ◽  
Post Translational Modification ◽  
Metabolic State

Ac(et)ylation is a post-translational modification present in all domains of life. First identified in mammals in histones to regulate RNA synthesis, today it is known that is regulates fundamental cellular processes also in bacteria: transcription, translation, metabolism, cell motility. Ac(et)ylation can occur at the ε-amino group of lysine side chains or at the α-amino group of a protein. Furthermore small molecules such as polyamines and antibiotics can be acetylated and deacetylated enzymatically at amino groups. While much research focused on N-(ε)-ac(et)ylation of lysine side chains, much less is known about the occurrence, the regulation and the physiological roles on N-(α)-ac(et)ylation of protein amino termini in bacteria. Lysine ac(et)ylation was shown to affect protein function by various mechanisms ranging from quenching of the positive charge, increasing the lysine side chains’ size affecting the protein surface complementarity, increasing the hydrophobicity and by interfering with other post-translational modifications. While N-(ε)-lysine ac(et)ylation was shown to be reversible, dynamically regulated by lysine acetyltransferases and lysine deacetylases, for N-(α)-ac(et)ylation only N-terminal acetyltransferases were identified and so far no deacetylases were discovered neither in bacteria nor in mammals. To this end, N-terminal ac(et)ylation is regarded as being irreversible. Besides enzymatic ac(et)ylation, recent data showed that ac(et)ylation of lysine side chains and of the proteins N-termini can also occur non-enzymatically by the high-energy molecules acetyl-coenzyme A and acetyl-phosphate. Acetyl-phosphate is supposed to be the key molecule that drives non-enzymatic ac(et)ylation in bacteria. Non-enzymatic ac(et)ylation can occur site-specifically with both, the protein primary sequence and the three dimensional structure affecting its efficiency. Ac(et)ylation is tightly controlled by the cellular metabolic state as acetyltransferases use ac(et)yl-CoA as donor molecule for the ac(et)ylation and sirtuin deacetylases use NAD+ as co-substrate for the deac(et)ylation. Moreover, the accumulation of ac(et)yl-CoA and acetyl-phosphate is dependent on the cellular metabolic state. This constitutes a feedback control mechanism as activities of many metabolic enzymes were shown to be regulated by lysine ac(et)ylation. Our knowledge on lysine ac(et)ylation significantly increased in the last decade predominantly due to the huge methodological advances that were made in fields such as mass-spectrometry, structural biology and synthetic biology. This also includes the identification of additional acylations occurring on lysine side chains with supposedly different regulatory potential. This review highlights recent advances in the research field. Our knowledge on enzymatic regulation of lysine ac(et)ylation will be summarized with a special focus on structural and mechanistic characterization of the enzymes, the mechanisms underlying non-enzymatic/chemical ac(et)ylation are explained, recent technological progress in the field are presented and selected examples highlighting the important physiological roles of lysine ac(et)ylation are summarized.

scholarly journals Fungal Induced Protein Hyperacetylation Identified by Acetylome Profiling

2016 ◽  
Author(s):  
Justin W Walley ◽  
Zhouxin Shen ◽  
Maxwell R. McReynolds ◽  
Steven P. Briggs
Keyword(s):  
Immune Response ◽  
Protein Function ◽  
Effector Proteins ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Cochliobolus Carbonum ◽  
Pathogen Virulence ◽  
Pathogen Effector ◽  
Race 1 ◽  
Hc Toxin

ABSTRACTLysine acetylation is a key post-translational modification that regulates diverse proteins involved in a range of biological processes. The role of histone acetylation in plant defense is well established and it is known that pathogen effector proteins encoding acetyltransferses can directly acetylate host proteins to alter immunity. However, it is unclear whether endogenous plant enzymes can modulate protein acetylation during an immune response. Here we investigate how the effector molecule HC-toxin, a histone deacetylase inhibitor, produced by Cochliobolus carbonum race 1 promotes pathogen virulence in maize through altering protein acetylation. Using mass spectrometry we globally quantified the abundance of 3,636 proteins and the levels of acetylation at 2,791 sites in maize plants treated with HC-toxin as well as HC-toxin deficient or producing strains of C. carbonum. Analyses of these data demonstrate that acetylation is a widespread post-translational modification impacting proteins encoded by many intensively studied maize genes. Furthermore, the application of exogenous HC-toxin enabled us to show that the activity of plant-encoded enzymes can be modulated to alter acetylation of non-histone proteins during an immune response. Collectively, these results provide a resource for further mechanistic studies examining the regulation of protein function and offer insight into the complex immune response triggered by virulent C. carbonum.

scholarly journals Improved discrimination of asymmetric and symmetric arginine dimethylation by optimization of the normalized collision energy in LC-MS proteomics

2020 ◽  
Author(s):  
Nicolas G. Hartel ◽  
Christopher Z. Liu ◽  
Nicholas A. Graham
Keyword(s):  
Mass Spectrometry ◽  
Protein Function ◽  
Collision Energy ◽  
Neutral Loss ◽  
Peptide Identification ◽  
Arginine Methylation ◽  
Post Translational Modification ◽  
Peptide Enrichment ◽  
Regulate Protein ◽  
Simple Parameter

ABSTRACTProtein arginine methylation regulates diverse biological processes including signaling, metabolism, splicing, and transcription. Despite its important biological roles, arginine methylation remains an understudied post-translational modification. Partly, this is because the two forms of arginine dimethylation, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), are isobaric and therefore indistinguishable by traditional mass spectrometry techniques. Thus, there exists a need for methods that can differentiate these two modifications. Recently, it has been shown that the ADMA and SDMA can be distinguished by the characteristic neutral loss (NL) of dimethylamine and methylamine, respectively. However, the utility of this method is limited because the vast majority of dimethylarginine peptides do not generate measurable NL ions. Here, we report that increasing the normalized collision energy (NCE) in a higher-energy collisional dissociation (HCD) cell increases the generation of the characteristic NL that distinguish ADMA and SDMA. By analyzing both synthetic and endogenous methyl-peptides, we identify an optimal NCE value that maximizes NL generation and simultaneously improves methyl-peptide identification. Using two orthogonal methyl peptide enrichment strategies, high pH strong cation exchange (SCX) and immunoaffinity purification (IAP), we demonstrate that the optimal NCE increases improves NL-based ADMA and SDMA annotation and methyl peptide identifications by 125% and 17%, respectively, compared to the standard NCE. This simple parameter change will greatly facilitate the identification and annotation of ADMA and SDMA in mass spectrometry-based methyl-proteomics to improve our understanding of how these modifications differentially regulate protein function.

scholarly journals The interaction of canonical Wnt/β-catenin signaling with protein lysine acetylation

2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Hongjuan You ◽  
Qi Li ◽  
Delong Kong ◽  
Xiangye Liu ◽  
Fanyun Kong ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Protein Function ◽  
Protein Modification ◽  
Epigenetic Modification ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Histone Protein ◽  
Protein Lysine Acetylation ◽  
Canonical Wnt

AbstractCanonical Wnt/β-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a significant protein modification which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classified into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modification, and it can modulate the transcription of important biological molecules in Wnt/β-catenin signaling. Additionally, as a type of post-translational modification, non-histone acetylation directly alters the function of the core molecules in Wnt/β-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/β-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/β-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling.

scholarly journals Regulation, Function, and Detection of Protein Acetylation in Bacteria

2017 ◽  
Vol 199 (16) ◽  
Author(s):  
Valerie J. Carabetta ◽  
Ileana M. Cristea
Keyword(s):  
Mass Spectrometry ◽  
Protein Function ◽  
Current Knowledge ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Future Directions ◽  
Lysine Residues ◽  
Functional Consequences ◽  
Regulation Function ◽  
Regulate Protein

ABSTRACT N ε-Lysine acetylation is now recognized as an abundant posttranslational modification (PTM) that influences many essential biological pathways. Advancements in mass spectrometry-based proteomics have led to the discovery that bacteria contain hundreds of acetylated proteins, contrary to the prior notion of acetylation events being rare in bacteria. Although the mechanisms that regulate protein acetylation are still not fully defined, it is understood that this modification is finely tuned via both enzymatic and nonenzymatic mechanisms. The opposing actions of Gcn5-related N-acetyltransferases (GNATs) and deacetylases, including sirtuins, provide the enzymatic control of lysine acetylation. A nonenzymatic mechanism of acetylation has also been demonstrated and proven to be prominent in bacteria, as well as in mitochondria. The functional consequences of the vast majority of the identified acetylation sites remain unknown. From studies in mammalian systems, acetylation of critical lysine residues was shown to impact protein function by altering its structure, subcellular localization, and interactions. It is becoming apparent that the same diversity of functions can be found in bacteria. Here, we review current knowledge of the mechanisms and the functional consequences of acetylation in bacteria. Additionally, we discuss the methods available for detecting acetylation sites, including quantitative mass spectrometry-based methods, which promise to promote this field of research. We conclude with possible future directions and broader implications of the study of protein acetylation in bacteria.

scholarly journals Malonyl-proteome profiles of Staphylococcus aureus reveal lysine malonylation modification in enzymes involved in energy metabolism

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yanan Shi ◽  
Jingjing Zhu ◽  
Yan Xu ◽  
Xiaozhao Tang ◽  
Zushun Yang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Energy Metabolism ◽  
Active Sites ◽  
Current Knowledge ◽  
Tricarboxylic Acid Cycle ◽  
Protein A ◽  
Pentose Phosphate ◽  
Post Translational Modification ◽  
Bacterial Physiology ◽  
Dihydrolipoyl Dehydrogenase

Abstract Background Protein lysine malonylation, a novel post-translational modification (PTM), has been recently linked with energy metabolism in bacteria. Staphylococcus aureus is the third most important foodborne pathogen worldwide. Nonetheless, substrates and biological roles of malonylation are still poorly understood in this pathogen. Results Using anti-malonyl-lysine antibody enrichment and high-resolution LC-MS/MS analysis, 440 lysine-malonylated sites were identified in 281 proteins of S. aureus strain. The frequency of valine in position − 1 and alanine at + 2 and + 4 positions was high. KEGG pathway analysis showed that six categories were highly enriched, including ribosome, glycolysis/gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), valine, leucine, isoleucine degradation, and aminoacyl-tRNA biosynthesis. In total, 31 malonylated sites in S. aureus shared homology with lysine-malonylated sites previously identified in E. coli, indicating malonylated proteins are highly conserved among bacteria. Key rate-limiting enzymes in central carbon metabolic pathways were also found to be malonylated in S. aureus, namely pyruvate kinase (PYK), 6-phosphofructokinase, phosphoglycerate kinase, dihydrolipoyl dehydrogenase, and F1F0-ATP synthase. Notably, malonylation sites were found at or near protein active sites, including KH domain protein, thioredoxin, alanine dehydrogenase (ALD), dihydrolipoyl dehydrogenase (LpdA), pyruvate oxidase CidC, and catabolite control protein A (CcpA), thus suggesting that lysine malonylation may affect the activity of such enzymes. Conclusions Data presented herein expand the current knowledge on lysine malonylation in prokaryotes and indicate the potential roles of protein malonylation in bacterial physiology and metabolism.

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.

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