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Nature Apr 2022Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be exploited in the...
Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be exploited in the development of vaccines or cancer immunotherapies. STING is a transmembrane dimeric protein that is located in the endoplasmic reticulum or in the Golgi apparatus. STING is activated by the binding of its cytoplasmic ligand-binding domain to cyclic dinucleotides that are produced by the DNA sensor cyclic GMP-AMP (cGAMP) synthase or by invading bacteria. Cyclic dinucleotides induce a conformational change in the STING ligand-binding domain, which leads to a high-order oligomerization of STING that is essential for triggering the downstream signalling pathways. However, the cGAMP-induced STING oligomers tend to dissociate in solution and have not been resolved to high resolution, which limits our understanding of the activation mechanism. Here we show that a small-molecule agonist, compound 53 (C53), promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of cGAMP. We determined a cryo-electron microscopy structure of STING bound to both C53 and cGAMP, revealing a stable oligomer that is formed by side-by-side packing and has a curled overall shape. Notably, C53 binds to a cryptic pocket in the STING transmembrane domain, between the two subunits of the STING dimer. This binding triggers outward shifts of transmembrane helices in the dimer, and induces inter-dimer interactions between these helices to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING than either ligand alone.
Topics: Cell Cycle Proteins; Cryoelectron Microscopy; Dinucleoside Phosphates; Humans; Immunity, Innate; Ligands; Membrane Proteins; Nucleotides, Cyclic; Tumor Suppressor Proteins
PubMed: 35388221
DOI: 10.1038/s41586-022-04559-7 -
Science (New York, N.Y.) May 2017The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. However, active gene regulatory elements are generally hypomethylated relative to...
The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. However, active gene regulatory elements are generally hypomethylated relative to their flanking regions, and the binding of some transcription factors (TFs) is diminished by methylation of their target sequences. By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences. Most of these are in the extended homeodomain family. Structural analysis showed that homeodomain specificity for methylcytosine depends on direct hydrophobic interactions with the methylcytosine 5-methyl group. This study provides a systematic examination of the effect of an epigenetic DNA modification on human TF binding specificity and reveals that many developmentally important proteins display preference for mCpG-containing sequences.
Topics: CpG Islands; Cytosine; DNA; DNA Methylation; Dinucleoside Phosphates; Epigenesis, Genetic; Genome, Human; Humans; Protein Binding; Protein Domains; SELEX Aptamer Technique; Transcription Factors
PubMed: 28473536
DOI: 10.1126/science.aaj2239 -
Molecules (Basel, Switzerland) Nov 2019Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell... (Review)
Review
Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell proliferation, regulation of enzymes, neurotransmission, platelet disaggregation and modulation of vascular tone. Various methodologies have been developed over the past fifty years to access these compounds, involving enzymatic processes or chemical procedures based either on P(III) or P(V) chemistry. Both solution-phase and solid-support strategies have been developed and are reported here. Recently, green chemistry approaches have emerged, offering attracting alternatives. This review outlines the main synthetic pathways for the preparation of dinucleoside 5',5'-polyphosphates, focusing on pharmacologically relevant compounds, and highlighting recent advances.
Topics: Deoxycytosine Nucleotides; Dinucleoside Phosphates; Dry Eye Syndromes; Green Chemistry Technology; Humans; Ophthalmic Solutions; Phosphorylation; Polyphosphates; Purinergic P2Y Receptor Agonists; Receptors, Purinergic; Uracil Nucleotides; Uridine
PubMed: 31783537
DOI: 10.3390/molecules24234334 -
Microbiology (Reading, England) Nov 2019Antibiotic producing sense and respond to environmental signals by using nucleotide second messengers, including (p)ppGpp, cAMP, c-di-GMP and c-di-AMP. As summarized in... (Review)
Review
Antibiotic producing sense and respond to environmental signals by using nucleotide second messengers, including (p)ppGpp, cAMP, c-di-GMP and c-di-AMP. As summarized in this review, these molecules are important message carriers that coordinate the complex morphological transition from filamentous growth to sporulation along with the secondary metabolite production. Here, we provide an overview of the enzymes that make and break these second messengers and suggest candidates for (p)ppGpp and cAMP enzymes to be studied. We highlight the target molecules that bind these signalling molecules and elaborate individual functions that they control in the context of development. Finally, we discuss open questions in the field, which may guide future studies in this exciting research area.
Topics: Bacterial Proteins; Cyclic AMP; Dinucleoside Phosphates; Gene Expression Regulation, Bacterial; Guanine Nucleotides; Protein Binding; Second Messenger Systems; Spores, Bacterial; Streptomyces
PubMed: 31535967
DOI: 10.1099/mic.0.000846 -
FEMS Microbiology Reviews Nov 2020Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is an emerging second messenger in bacteria and archaea that is synthesized from two molecules of ATP by... (Review)
Review
Cyclic dimeric adenosine 3',5'-monophosphate (c-di-AMP) is an emerging second messenger in bacteria and archaea that is synthesized from two molecules of ATP by diadenylate cyclases and degraded to pApA or two AMP molecules by c-di-AMP-specific phosphodiesterases. Through binding to specific protein- and riboswitch-type receptors, c-di-AMP regulates a wide variety of prokaryotic physiological functions, including maintaining the osmotic pressure, balancing central metabolism, monitoring DNA damage and controlling biofilm formation and sporulation. It mediates bacterial adaptation to a variety of environmental parameters and can also induce an immune response in host animal cells. In this review, we discuss the phylogenetic distribution of c-di-AMP-related enzymes and receptors and provide some insights into the various aspects of c-di-AMP signaling pathways based on more than a decade of research. We emphasize the key role of c-di-AMP in maintaining bacterial osmotic balance, especially in Gram-positive bacteria. In addition, we discuss the future direction and trends of c-di-AMP regulatory network, such as the likely existence of potential c-di-AMP transporter(s), the possibility of crosstalk between c-di-AMP signaling with other regulatory systems, and the effects of c-di-AMP compartmentalization. This review aims to cover the broad spectrum of research on the regulatory functions of c-di-AMP and c-di-AMP signaling pathways.
Topics: Bacteria; Bacterial Physiological Phenomena; Dinucleoside Phosphates; Phylogeny; Research; Signal Transduction
PubMed: 32472931
DOI: 10.1093/femsre/fuaa019 -
Mediators of Inflammation 2014Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly "tuned," can lead to disease. When... (Review)
Review
Inflammation is a complex process that implies the interaction between cells and molecular mediators, which, when not properly "tuned," can lead to disease. When inflammation affects the eye, it can produce severe disorders affecting the superficial and internal parts of the visual organ. The nucleoside adenosine and nucleotides including adenine mononucleotides like ADP and ATP and dinucleotides such as P(1),P(4)-diadenosine tetraphosphate (Ap4A), and P(1),P(5)-diadenosine pentaphosphate (Ap5A) are present in different ocular locations and therefore they may contribute/modulate inflammatory processes. Adenosine receptors, in particular A2A adenosine receptors, present anti-inflammatory action in acute and chronic retinal inflammation. Regarding the A3 receptor, selective agonists like N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (CF101) have been used for the treatment of inflammatory ophthalmic diseases such as dry eye and uveoretinitis. Sideways, diverse stimuli (sensory stimulation, large intraocular pressure increases) can produce a release of ATP from ocular sensory innervation or after injury to ocular tissues. Then, ATP will activate purinergic P2 receptors present in sensory nerve endings, the iris, the ciliary body, or other tissues surrounding the anterior chamber of the eye to produce uveitis/endophthalmitis. In summary, adenosine and nucleotides can activate receptors in ocular structures susceptible to suffer from inflammatory processes. This involvement suggests the possible use of purinergic agonists and antagonists as therapeutic targets for ocular inflammation.
Topics: Adenosine; Animals; Dinucleoside Phosphates; Eye; Humans; Inflammation; Receptors, Purinergic
PubMed: 25132732
DOI: 10.1155/2014/320906 -
Current Opinion in Microbiology Apr 2021Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the... (Review)
Review
Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the identification of 3'-5', 3'-5' cyclic di-GMP (c-di-GMP) in 1987, a second messenger that is now known to be the linchpin signaling pathway modulating bacterial motility and biofilm formation. In the past 15 years, three more cdNs were uncovered: 3'-5', 3'-5' cyclic di-AMP (c-di-AMP) and 3'-5', 3'-5' cyclic GMP-AMP (3',3' cGAMP) in bacteria and 2'-5', 3'-5' cyclic GMP-AMP (2',3' cGAMP) in eukaryotes. We now appreciate that bacteria can synthesize many varieties of cdNs from every ribonucleotide, and even cyclic trinucleotide (ctN) second messengers have been discovered. Here we highlight our current understanding of c-di-GMP and c-di-AMP in bacterial physiology and focus on recent advances in 3',3' cGAMP signaling effectors, its role in bacterial phage response, and the diversity of its synthase family.
Topics: Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Cyclic GMP; Dinucleoside Phosphates; Nucleotides, Cyclic; Oligonucleotides; Second Messenger Systems
PubMed: 33640793
DOI: 10.1016/j.mib.2021.01.017 -
Purinergic Signalling Mar 2021Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged... (Review)
Review
Development of science needs the cooperation of many creative brains. Sometimes, ideas on a specific area get suddenly exhausted and then it is the time for a privileged mind to think in a different way and reach the turning point to introduce a new paradigm. This happened to Geoffrey Burnstock, a heterodox thinker and nonconformist scientist that has been the paladin of purinergic signalling since 1972, opening neuroscience to the understanding of organs and tissues functioning and development of a new pharmacology. This review summarizes the contribution of our group to the understanding of the role of the diadenosine polyphosphates, ApA, as signalling molecules, describing their tissue and organ distribution, their transport and storage in secretory vesicles and their release and interaction with purinergic receptors. We also have to acknowledge the friendly and kindly support of Professor Burnstock that showed a great interest in the field from our initial findings and actively stimulated our efforts to establish the extracellular roles and biological significance of these dinucleotides.
Topics: Animals; Dinucleoside Phosphates; Humans; Receptors, Purinergic; Secretory Vesicles; Synapses
PubMed: 33025428
DOI: 10.1007/s11302-020-09736-9 -
British Journal of Pharmacology Aug 2009The purinergic system is composed of mononucleosides, mononucleoside polyphosphates and dinucleoside polyphosphates as agonists, as well as the respective purinergic... (Review)
Review
The purinergic system is composed of mononucleosides, mononucleoside polyphosphates and dinucleoside polyphosphates as agonists, as well as the respective purinergic receptors. Interest in the role of the purinergic system in cardiovascular physiology and pathophysiology is on the rise. This review focuses on the overall impact of dinucleoside polyphosphates in the purinergic system. Platelets, adrenal glands, endothelial cells, cardiomyocytes and tubular cells release dinucleoside polyphosphates. Plasma concentrations of dinucleoside polyphosphates are sufficient to cause direct vasoregulatory effects and to induce proliferative effects on vascular smooth muscle cells and mesangial cells. In addition, increased plasma concentrations of a dinucleoside polyphosphate were recently demonstrated in juvenile hypertensive patients. In conclusion, the current literature accentuates the strong physiological and pathophysiological impact of dinucleoside polyphosphates on the cardiovascular system.
Topics: Animals; Antihypertensive Agents; Cell Proliferation; Cystic Fibrosis; Dinucleoside Phosphates; Eye Diseases; Fibrinolytic Agents; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Multimerization; Purinergic Agonists; Receptors, Purinergic; Respiratory Tract Diseases; Vasodilation
PubMed: 19563527
DOI: 10.1111/j.1476-5381.2009.00337.x -
Sheng Wu Gong Cheng Xue Bao = Chinese... Sep 2017Bacterial biofilm plays an important role in persistent microbial infection. Delineation of the formation and development of bacterial biofilm would provide a promising... (Review)
Review
Bacterial biofilm plays an important role in persistent microbial infection. Delineation of the formation and development of bacterial biofilm would provide a promising strategy to treat recalcitrant infection. c-di-AMP (Cyclic diadenosine monophosphate) is a recently identified second messenger of bacteria and involved in plethora of bacterial activities, including cell growth, cell wall homeostasis, biofilm formation and microbial pathogenicity. Here we review the recent literature pertinent to the role and molecular mechanisms of c-di-AMP in regulating biofilm formation of bacteria. The potential application of c-di-AMP and its related proteins in the development of novel antimicrobial therapeutics has also been discussed.
Topics: Bacteria; Biofilms; Dinucleoside Phosphates; Second Messenger Systems
PubMed: 28956388
DOI: 10.13345/j.cjb.170078