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Biochemical Society Transactions Dec 2021The dynamic processes of mitochondrial fusion and fission determine the shape of mitochondria, which can range from individual fragments to a hyperfused network, and... (Review)
Review
The dynamic processes of mitochondrial fusion and fission determine the shape of mitochondria, which can range from individual fragments to a hyperfused network, and influence mitochondrial function. Changes in mitochondrial shape can occur rapidly, allowing mitochondria to adapt to specific cues and changing cellular demands. Here, we will review what is known about how key proteins required for mitochondrial fusion and fission are regulated by their acetylation status, with acetylation promoting fission and deacetylation enhancing fusion. In particular, we will examine the roles of NAD+ dependant sirtuin deacetylases, which mediate mitochondrial acetylation, and how this post-translational modification provides an exquisite regulatory mechanism to co-ordinate mitochondrial function with metabolic demands of the cell.
Topics: Acetylation; Mitochondria; Mitochondrial Dynamics; Proteins
PubMed: 34812890
DOI: 10.1042/BST20210798 -
Cells Nov 2022The tumor suppressor p53 is a transcription factor that regulates the expression of dozens of target genes and diverse physiological processes. To precisely regulate the... (Review)
Review
The tumor suppressor p53 is a transcription factor that regulates the expression of dozens of target genes and diverse physiological processes. To precisely regulate the p53 network, p53 undergoes various post-translational modifications and alters the selectivity of target genes. Acetylation plays an essential role in cell fate determination through the activation of p53. Although the acetylation of p53 has been examined, the underlying regulatory mechanisms remain unclear and, thus, have attracted the interest of researchers. We herein discuss the role of acetylation in the p53 pathway, with a focus on p53 acetyltransferases and deacetylases. We also review recent findings on the regulators of these enzymes to understand the mode of p53 acetylation from a broader perspective.
Topics: Tumor Suppressor Protein p53; Acetylation; Protein Processing, Post-Translational; Acetyltransferases; Transcription Factors
PubMed: 36497084
DOI: 10.3390/cells11233825 -
Biochimica Et Biophysica Acta. Gene... Feb 2021GCN5, conserved from yeast to humans, and the vertebrate specific PCAF, are lysine acetyltransferase enzymes found in large protein complexes. Both enzymes have well... (Review)
Review
GCN5, conserved from yeast to humans, and the vertebrate specific PCAF, are lysine acetyltransferase enzymes found in large protein complexes. Both enzymes have well documented roles in the histone acetylation and the concomitant regulation of transcription. However, these enzymes also acetylate non-histone substrates to impact diverse aspects of cell physiology. Here, I review our current understanding of non-histone acetylation by GCN5 and PCAF across eukaryotes, from target identification to molecular mechanism and regulation. I focus mainly on budding yeast, where Gcn5 was first discovered, and mammalian systems, where the bulk of non-histone substrates have been characterized. I end the review by defining critical caveats and open questions that apply to all models.
Topics: Acetylation; Amino Acid Sequence; Conserved Sequence; Eukaryota; Histone Acetyltransferases; Protein Processing, Post-Translational; Saccharomyces cerevisiae Proteins; p300-CBP Transcription Factors
PubMed: 32711095
DOI: 10.1016/j.bbagrm.2020.194608 -
Essays in Biochemistry Feb 2020Post-translational modifications (PTMs) are integral to the regulation of protein function, characterising their role in this process is vital to understanding how cells... (Review)
Review
Post-translational modifications (PTMs) are integral to the regulation of protein function, characterising their role in this process is vital to understanding how cells work in both healthy and diseased states. Mass spectrometry (MS) facilitates the mass determination and sequencing of peptides, and thereby also the detection of site-specific PTMs. However, numerous challenges in this field continue to persist. The diverse chemical properties, low abundance, labile nature and instability of many PTMs, in combination with the more practical issues of compatibility with MS and bioinformatics challenges, contribute to the arduous nature of their analysis. In this review, we present an overview of the established MS-based approaches for analysing PTMs and the common complications associated with their investigation, including examples of specific challenges focusing on phosphorylation, lysine acetylation and redox modifications.
Topics: Acetylation; Computational Biology; Humans; Mass Spectrometry; Oxidation-Reduction; Phosphorylation; Protein Processing, Post-Translational; Proteins
PubMed: 31957791
DOI: 10.1042/EBC20190055 -
Nature Structural & Molecular Biology Oct 2019The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine... (Review)
Review
The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine residues. This basic activity endows BrD proteins with versatile functions in the regulation of protein-protein interactions mediating chromatin-templated gene transcription, DNA recombination, replication and repair. Consequently, BrD proteins are involved in the pathogenesis of numerous human diseases. In this Review, we highlight our current understanding of BrD biology, and discuss the latest development of small-molecule inhibitors targeting BrDs as emerging epigenetic therapies for cancer and inflammatory disorders.
Topics: Acetylation; Animals; Drug Discovery; Epigenesis, Genetic; Histone Code; Histones; Humans; Inflammation; Models, Molecular; Neoplasms; Protein Domains; Small Molecule Libraries; Transcription Factors
PubMed: 31582847
DOI: 10.1038/s41594-019-0309-8 -
Journal of the American Chemical Society Mar 2023The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and...
The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.
Topics: Nucleosomes; Histones; Chromatin; Sirtuins; Acetylation; Glycosyltransferases; Catalysis
PubMed: 36930461
DOI: 10.1021/jacs.2c13512 -
BioEssays : News and Reviews in... Nov 2019The N-end rule denotes the relationship between the identity of the amino-terminal residue of a protein and its in vivo half-life. Since its discovery in 1986, the N-end... (Review)
Review
The N-end rule denotes the relationship between the identity of the amino-terminal residue of a protein and its in vivo half-life. Since its discovery in 1986, the N-end rule has generally been described by a defined set of rules for determining whether an amino-terminal residue is stabilizing or not. However, recent studies are revealing that this N-end rule (or N-degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N-terminal acetylation of N-terminal residues may create a degradation signal (Ac-degron) that promotes the degradation of target proteins. A recent high-throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino-terminal residues-but not the N-terminal acetylation status-may be the indispensable feature of amino-terminal degrons. Herein, these recent advances in N-terminal acetylation and the complexity of N-terminal degradation signals in the context of the N-degron pathway are analyzed.
Topics: Acetylation; Fungal Proteins; Humans; Proteolysis
PubMed: 31549739
DOI: 10.1002/bies.201800167 -
Journal of Cellular Physiology Dec 2021Cells adjust mitochondrial morphologies to coordinate between the cellular demand for energy and the availability of resources. Mitochondrial morphology is regulated by... (Review)
Review
Cells adjust mitochondrial morphologies to coordinate between the cellular demand for energy and the availability of resources. Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. Fission and fusion are dynamic and reversible processes that depend on the coordination of a number of proteins and are primarily regulated by posttranslational modifications. In the mitochondria, more than 20% of proteins are acetylated in proteomic surveys, partly involved in the dynamic regulation of mitochondrial fusion and fission. This article focuses on the molecular mechanism of the mitochondrial dynamics of fusion and fission, and summarizes the related mechanisms and targets of mitochondrial protein acetylation to regulate the mitochondrial dynamics of fusion and fission in energy metabolism.
Topics: Acetylation; Animals; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Protein Processing, Post-Translational; Proteomics
PubMed: 34101176
DOI: 10.1002/jcp.30461 -
Seminars in Cancer Biology Oct 2022Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue... (Review)
Review
Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue to yield an acetate ester bond, neutralizing its positive charge. Regulation of protein functions by acetylation occurs in multiple ways, such as affecting protein stability, activity, localization, and interaction with other proteins or DNA. It has been well documented that the recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery can modulate histone acetylation status, which is directly involved in the dynamic regulation of genes controlling cell proliferation and division. Dysregulation of gene expression is involved in tumorigenesis and aberrant activation of histone deacetylases has been reported in several types of cancer. Moreover, there is growing body of evidence showing that acetylation is widely involved in non-histone proteins to impact their roles in various cellular processes including tumorigenesis. As such, small molecular compounds inhibiting HAT or HDAC enzymatic activities have been developed and investigated for therapeutic purpose. Here we review the recent progress in our understanding of protein acetylation and discuss the therapeutic potential of targeting the acetylation signaling pathway in cancer.
Topics: Humans; Acetylation; Histone Deacetylase Inhibitors; Histone Deacetylases; Protein Processing, Post-Translational; Neoplasms; Proteins; Signal Transduction; Carcinogenesis
PubMed: 33705871
DOI: 10.1016/j.semcancer.2021.03.001 -
Applied Biochemistry and Biotechnology Oct 2023Non-histone protein acetylation is involved in key cellular processes both in eukaryotes and prokaryotes. Acetylation in bacteria is used to modify proteins involved in...
Non-histone protein acetylation is involved in key cellular processes both in eukaryotes and prokaryotes. Acetylation in bacteria is used to modify proteins involved in metabolism and allow the bacteria to adapt to their environment. TTE (Thermoanaerobacter tengcongensis) is an anaerobic, thermophilic saccharolytic bacterium that grows at extreme temperature range between 50 and 80 ℃. The annotated TTE proteome contains less than 3000 proteins. We analyzed the proteome and acetylome of TTE using 2DLC-MS/MS (2-dimensional liquid chromatography mass spectrum). We evaluated the ability of mass spectrometry technology to cover a relatively small proteome as much as possible. And we also observed wide spread of acetylation in TTE, which changed under different temperatures. A total of 2082 proteins were identified, which accounts for about 82% of the database. A total of 2050 (~ 98%) proteins were quantified in at least one culture condition and 1818 proteins were quantified in all 4 conditions. The result also consisted 3457 acetylation sites corresponding to 827 distinct proteins, which covered 40% of the proteins identified. Bioinformatics analysis reported that proteins related to replication, recombination, repair, and extracellular structure cell wall biogenesis had more than half members acetylated, while energy production, carbohydrate transport, and metabolism related proteins were least acetylated. Our result suggested that acetylation affects the ATP-related energy metabolism and energy-dependent biosynthesis process. Comparing the enzymes related with lysine acetylation and acetyl-CoA (acetyl-coenzyme A) metabolism, we suggested that the acetylation of TTE took a non-enzymatic mechanism and affected by abundance of acetyl-CoA.
Topics: Proteome; Tandem Mass Spectrometry; Acetyl Coenzyme A; Acetylation; Protein Processing, Post-Translational
PubMed: 36809429
DOI: 10.1007/s12010-023-04361-9