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Experimental & Molecular Medicine Apr 2017Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and... (Review)
Review
Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and globular domains of histones and their levels are precisely balanced by the action of methyltransferases ('writers') and demethylases ('erasers'). In addition, distinct effector proteins ('readers') recognize specific methyl-lysines in a manner that depends on the neighboring amino-acid sequence and methylation state. Misregulation of histone lysine methylation has been implicated in several cancers and developmental defects. Therefore, histone lysine methylation has been considered a potential therapeutic target, and clinical trials of several inhibitors of this process have shown promising results. A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments. This review summarizes enzymes responsible for histone lysine methylation and demethylation and how histone lysine methylation contributes to various biological processes.
Topics: Animals; Histone Code; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Protein Processing, Post-Translational
PubMed: 28450737
DOI: 10.1038/emm.2017.11 -
International Journal of Biological... 2023Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes... (Review)
Review
Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.
Topics: Humans; Arginine; Methylation; Histones; Gene Expression Regulation; Virus Diseases
PubMed: 37928266
DOI: 10.7150/ijbs.89498 -
The Journal of Biological Chemistry Apr 2022Many proteins are modified by posttranslational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in... (Review)
Review
Many proteins are modified by posttranslational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in modulating protein function and thus in optimizing and regulating cellular and physiological processes. Research has mainly focused on nuclear and cytosolic protein methylation, but it has been known for many years that also mitochondrial proteins are methylated. During the last decade, significant progress has been made on identifying the MTases responsible for mitochondrial protein methylation and addressing its functional significance. In particular, several novel human MTases have been uncovered that methylate lysine, arginine, histidine, and glutamine residues in various mitochondrial substrates. Several of these substrates are key components of the bioenergetics machinery, e.g., respiratory Complex I, citrate synthase, and the ATP synthase. In the present review, we report the status of the field of mitochondrial protein methylation, with a particular emphasis on recently discovered human MTases. We also discuss evolutionary aspects and functional significance of mitochondrial protein methylation and present an outlook for this emergent research field.
Topics: Humans; Methylation; Methyltransferases; Mitochondria; Mitochondrial Proteins; Protein Processing, Post-Translational
PubMed: 35247388
DOI: 10.1016/j.jbc.2022.101791 -
American Journal of Physiology. Cell... Oct 2019Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. -methyladenosine (mA) methylation is the most abundant epigenetic...
Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. -methyladenosine (mA) methylation is the most abundant epigenetic modification of mammalian mRNA, but its role in macrophage polarization is still completely unknown. Here, we show that the mA-catalytic enzyme methyltransferase like 3 (METTL3) is specifically upregulated following the M1 polarization of mouse macrophages. Furthermore, METTL3 knockdown through siRNA transfection markedly inhibited M1, but enhanced M2, macrophage polarization. Conversely, its overexpression via plasmid transfection greatly facilitated M1, but attenuated M2, macrophage polarization. Further methylated RNA immunoprecipitation and in vitro mA methylation assays suggested that METTL3 directly methylates mRNA encoding signal transducer and activator of transcription 1 (STAT1), a master transcription factor controlling M1 macrophage polarization, at its coding sequence and 3'-untranslated regions. In addition, METTL3-mediated mRNA methylation significantly increased mRNA stability and subsequently upregulated STAT1 expression. In conclusion, METTL3 drives M1 macrophage polarization by directly methylating mRNA, potentially serving as an anti-inflammatory target.
Topics: Adenosine; Animals; Anti-Inflammatory Agents; Gene Expression Regulation; Macrophage Activation; Macrophages; Male; Methylation; Methyltransferases; Mice, Inbred C57BL; RNA, Messenger; STAT1 Transcription Factor
PubMed: 31365297
DOI: 10.1152/ajpcell.00212.2019 -
Current Opinion in Chemical Biology Jun 2023Reader domains that recognize methylated lysine and arginine residues on histones play a role in the recruitment, stabilization, and regulation of chromatin regulatory... (Review)
Review
Reader domains that recognize methylated lysine and arginine residues on histones play a role in the recruitment, stabilization, and regulation of chromatin regulatory proteins. Targeting reader proteins with small molecule and peptidomimetic inhibitors has enabled the elucidation of the structure and function of specific domains and uncovered their role in diseases. Recent progress towards chemical probes that target readers of lysine methylation, including the Royal family and plant homeodomains (PHD), is discussed here. We highlight recently developed covalent cyclic peptide inhibitors of a plant homeodomain. Additionally, inhibitors targeting previously untargeted Tudor domains and chromodomains are discussed.
Topics: Chromatin; Histones; Lysine; Methylation; Protein Binding
PubMed: 36948085
DOI: 10.1016/j.cbpa.2023.102286 -
Trends in Biochemical Sciences May 2013Methylated lysine and arginine residues in histones represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction... (Review)
Review
Methylated lysine and arginine residues in histones represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction domains modulates transcription. Although some methylating enzymes appear to be histone specific, many can modify histone and non-histone substrates and an increasing number are specific for non-histone substrates. Some of the non-histone substrates can also be involved in transcription, but a distinct subset of protein methylation reactions occurs at residues buried deeply in ribosomal proteins that may function in protein-RNA interactions rather than protein-protein interactions. Additionally, recent work has identified enzymes that catalyze protein methylation reactions at new sites in ribosomal and other proteins. These reactions include modifications of histidine and cysteine residues as well as the N terminus.
Topics: Animals; Histone-Lysine N-Methyltransferase; Histones; Humans; Methylation; Protein Interaction Domains and Motifs; Proteins; Ribosomal Proteins; Transcription Factors
PubMed: 23490039
DOI: 10.1016/j.tibs.2013.02.004 -
Molecules (Basel, Switzerland) Oct 2018DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and... (Review)
Review
DNA methylation is a prevalent epigenetic modification involved in regulating a number of essential cellular processes, including genomic accessibility and transcriptional outcomes. As such, aberrant alterations in global DNA methylation patterns have been associated with a growing number of disease conditions. Nevertheless, the full mechanisms by which DNA methylation information is interpreted and translated into genomic responses is not yet fully understood. Methyl-CpG binding proteins (MBPs) function as important mediators of this essential process by selectively reading DNA methylation signals and translating this information into down-stream cellular outcomes. The Cys₂His₂ zinc finger scaffold is one of the most abundant DNA binding motifs found within human transcription factors, yet only a few zinc finger containing proteins capable of conferring selectivity for mCpG over CpG sites have been characterized. This review summarizes our current structural understanding for the mechanisms by which the zinc finger MBPs evaluated to date read this essential epigenetic mark. Further, some of the biological implications for mCpG readout elicited by this family of MBPs are discussed.
Topics: CpG Islands; DNA Methylation; DNA-Binding Proteins; Epigenesis, Genetic; Humans; Signal Transduction; Transcription Factors; Zinc Fingers
PubMed: 30301273
DOI: 10.3390/molecules23102555 -
Seminars in Cancer Biology Aug 2022Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the... (Review)
Review
Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.
Topics: Histones; Humans; Lysine; Methylation; Methyltransferases; Neoplasms
PubMed: 33753223
DOI: 10.1016/j.semcancer.2021.03.015 -
Mutation Research May 2007Lysine methylation plays a central role in the "histone code" that regulates chromatin structure, impacts transcription, and responds to DNA damage. A single lysine can... (Review)
Review
Lysine methylation plays a central role in the "histone code" that regulates chromatin structure, impacts transcription, and responds to DNA damage. A single lysine can be mono-, di-, tri-methylated, or unmethylated, with different functional consequences for each of the four forms. This review (written in the early 2006) described structural aspects of methylation of histone lysine residues by two enzyme families with entirely different structural scaffolding (the SET proteins and Dot1p), and the protein motifs that recognize (decode) these methyl-lysine signals. We also discuss the recently discovered protein lysine demethylating enzymes (LSD1 and JmjC domains).
Topics: Animals; Chromatin Assembly and Disassembly; Histones; Humans; Lysine; Methylation; Models, Chemical; Models, Molecular; Molecular Conformation; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Substrate Specificity
PubMed: 17374386
DOI: 10.1016/j.mrfmmm.2006.05.041 -
Journal of Molecular Biology Feb 2021Lysine methylation is a key regulator of protein-protein binding. The amine group of lysine can accept up to three methyl groups, and experiments show that...
Lysine methylation is a key regulator of protein-protein binding. The amine group of lysine can accept up to three methyl groups, and experiments show that protein-protein binding free energies are sensitive to the extent of methylation. These sensitivities have been rationalized in terms of chemical and structural features present in the binding pockets of methyllysine binding domains. However, understanding their specific roles requires an energetic analysis. Here we propose a theoretical framework to combine quantum and molecular mechanics methods, and compute the effect of methylation on protein-protein binding free energies. The advantages of this approach are that it derives contributions from all local non-trivial effects of methylation on induction, polarizability and dispersion directly from self-consistent electron densities, and at the same time determines contributions from well-characterized hydration effects using a computationally efficient classical mean field method. Limitations of the approach are discussed, and we note that predicted free energies of fourteen out of the sixteen cases agree with experiment. Critical assessment of these cases leads to the following overarching principles that drive methylation-state recognition by protein domains. Methylation typically reduces the pairwise interaction between proteins. This biases binding toward lower methylated states. Simultaneously, however, methylation also makes it easier to partially dehydrate proteins and place them in protein-protein complexes. This latter effect biases binding in favor of higher methylated states. The overall effect of methylation on protein-protein binding depends ultimately on the balance between these two effects, which is observed to be tuned via several combinations of local features.
Topics: Binding Sites; Carrier Proteins; Hydrogen Bonding; Lysine; Methylation; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Proteins; Solvents; Structure-Activity Relationship
PubMed: 33307090
DOI: 10.1016/j.jmb.2020.166745