Littérature scientifique sur le sujet « Macrodomains »
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Articles de revues sur le sujet "Macrodomains"
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Haikarainen, Teemu, Mirko M. Maksimainen, Ezeogo Obaji, and Lari Lehtiö. "Development of an Inhibitor Screening Assay for Mono-ADP-Ribosyl Hydrolyzing Macrodomains Using AlphaScreen Technology." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 3 (2017): 255–63. http://dx.doi.org/10.1177/2472555217737006.
Texte intégralRésumé :
Protein mono-ADP-ribosylation is a posttranslational modification involved in the regulation of several cellular signaling pathways. Cellular ADP-ribosylation is regulated by ADP-ribose hydrolases via a hydrolysis of the protein-linked ADP-ribose. Most of the ADP-ribose hydrolases share a macrodomain fold. Macrodomains have been linked to several diseases, such as cancer, but their cellular roles are mostly unknown. Currently, there are no inhibitors available targeting the mono-ADP-ribose hydrolyzing macrodomains. We have developed a robust AlphaScreen assay for the screening of inhibitors against macrodomains having mono-ADP-ribose hydrolysis activity. We utilized this assay for validatory screening against human MacroD1 and identified five compounds inhibiting the macrodomain. Dose–response measurements and an orthogonal assay further validated four of these compounds as MacroD1 inhibitors. The developed assay is homogenous, easy to execute, and suitable for the screening of large compound libraries. The assay principle can also be adapted for other ADP-ribose hydrolyzing macrodomains, which can utilize a biotin-mono-ADP-ribosylated protein as a substrate.
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Hammond, Robert G., Norbert Schormann, Robert Lyle McPherson, Anthony K. L. Leung, Champion C. S. Deivanayagam, and Margaret A. Johnson. "ADP-ribose and analogues bound to the deMARylating macrodomain from the bat coronavirus HKU4." Proceedings of the National Academy of Sciences 118, no. 2 (2021): e2004500118. http://dx.doi.org/10.1073/pnas.2004500118.
Texte intégralRésumé :
Macrodomains are proteins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins. Macrodomains are implicated in viral genome replication and interference with host cell immune responses. They are important to the infectious cycle of Coronaviridae and Togaviridae viruses. We describe crystal structures of the conserved macrodomain from the bat coronavirus (CoV) HKU4 in complex with ligands. The structures reveal a binding cavity that accommodates ADPR and analogs via local structural changes within the pocket. Using a radioactive assay, we present evidence of mono-ADPR (MAR) hydrolase activity. In silico analysis presents further evidence on recognition of the ADPR modification for hydrolysis. Mutational analysis of residues within the binding pocket resulted in diminished enzymatic activity and binding affinity. We conclude that the common structural features observed in the macrodomain in a bat CoV contribute to a conserved function that can be extended to other known macrodomains.
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Rack, Johannes Gregor Matthias, Valentina Zorzini, Zihan Zhu, Marion Schuller, Dragana Ahel, and Ivan Ahel. "Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential." Open Biology 10, no. 11 (2020): 200237. http://dx.doi.org/10.1098/rsob.200237.
Texte intégralRésumé :
Viral macrodomains possess the ability to counteract host ADP-ribosylation, a post-translational modification implicated in the creation of an antiviral environment via immune response regulation. This brought them into focus as promising therapeutic targets, albeit the close homology to some of the human macrodomains raised concerns regarding potential cross-reactivity and adverse effects for the host. Here, we evaluate the structure and function of the macrodomain of SARS-CoV-2, the causative agent of COVID-19. We show that it can antagonize ADP-ribosylation by PARP14, a cellular (ADP-ribosyl)transferase necessary for the restriction of coronaviral infections. Furthermore, our structural studies together with ligand modelling revealed the structural basis for poly(ADP-ribose) binding and hydrolysis, an emerging new aspect of viral macrodomain biology. These new insights were used in an extensive evolutionary analysis aimed at evaluating the druggability of viral macrodomains not only from the Coronaviridae but also Togaviridae and Iridoviridae genera (causing diseases such as Chikungunya and infectious spleen and kidney necrosis virus disease, respectively). We found that they contain conserved features, distinct from their human counterparts, which may be exploited during drug design.
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Ekblad, Torun, Patricia Verheugd, Anders E. Lindgren, Tomas Nyman, Mikael Elofsson, and Herwig Schüler. "Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 4 (2018): 353–62. http://dx.doi.org/10.1177/2472555217750870.
Texte intégralRésumé :
Macrodomains recognize intracellular adenosine diphosphate (ADP)-ribosylation resulting in either removal of the modification or a protein interaction event. Research into compounds that modulate macrodomain functions could make important contributions. We investigated the interactions of all seven individual macrodomains of the human poly(ADP-ribose) polymerase (PARP) family members PARP9, PARP14, and PARP15 with five mono-ADP-ribosylated (automodified) ADP-ribosyltransferase domains using an AlphaScreen assay. Several mono-ADP-ribosylation-dependent interactions were identified, and they were found to be in the micromolar affinity range using surface plasmon resonance (SPR). We then focused on the interaction between PARP14 macrodomain-2 and the mono-ADP-ribosylated PARP10 catalytic domain, and probed a ~1500-compound diverse library for inhibitors of this interaction using AlphaScreen. Initial hit compounds were verified by concentration–response experiments using AlphaScreen and SPR, and they were tested against PARP14 macrodomain-2 and -3. Two initial hit compounds and one chemical analog each were further characterized using SPR and microscale thermophoresis. In conclusion, our results reveal novel macrodomain interactions and establish protocols for identification of inhibitors of such interactions.
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Kuri, Thomas, Klara K. Eriksson, Akos Putics, et al. "The ADP-ribose-1″-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses." Journal of General Virology 92, no. 8 (2011): 1899–905. http://dx.doi.org/10.1099/vir.0.031856-0.
Texte intégralRésumé :
Several plus-strand RNA viruses encode proteins containing macrodomains. These domains possess ADP-ribose-1″-phosphatase (ADRP) activity and/or bind poly(ADP-ribose), poly(A) or poly(G). The relevance of these activities in the viral life cycle has not yet been resolved. Here, we report that genetically engineered mutants of severe acute respiratory syndrome coronavirus (SARS-CoV) and human coronavirus 229E (HCoV-229E) expressing ADRP-deficient macrodomains displayed an increased sensitivity to the antiviral effect of alpha interferon compared with their wild-type counterparts. The data suggest that macrodomain-associated ADRP activities may have a role in viral escape from the innate immune responses of the host.
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Hussain, Irfan, Nashaiman Pervaiz, Abbas Khan, et al. "Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity." Genes & Immunity 21, no. 6-8 (2020): 409–19. http://dx.doi.org/10.1038/s41435-020-00120-6.
Texte intégralRésumé :
AbstractThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition the secondary structural elements to create new intra-protein contacts and, thereby, may enhance the ability of SARS-CoV-2 to inhibit host immunity. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. Our findings warrant further characterization of macrodomain-specific evolutionary substitutions in in vitro and in vivo models to determine their inhibitory effects on the host immune system.
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Leung, Anthony K. L., Diane E. Griffin, Jürgen Bosch, and Anthony R. Fehr. "The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses." Pathogens 11, no. 1 (2022): 94. http://dx.doi.org/10.3390/pathogens11010094.
Texte intégralRésumé :
Emerging and re-emerging viral diseases pose continuous public health threats, and effective control requires a combination of non-pharmacologic interventions, treatment with antivirals, and prevention with vaccines. The COVID-19 pandemic has demonstrated that the world was least prepared to provide effective treatments. This lack of preparedness has been due, in large part, to a lack of investment in developing a diverse portfolio of antiviral agents, particularly those ready to combat viruses of pandemic potential. Here, we focus on a drug target called macrodomain that is critical for the replication and pathogenesis of alphaviruses and coronaviruses. Some mutations in alphavirus and coronaviral macrodomains are not tolerated for virus replication. In addition, the coronavirus macrodomain suppresses host interferon responses. Therefore, macrodomain inhibitors have the potential to block virus replication and restore the host’s protective interferon response. Viral macrodomains offer an attractive antiviral target for developing direct acting antivirals because they are highly conserved and have a structurally well-defined (druggable) binding pocket. Given that this target is distinct from the existing RNA polymerase and protease targets, a macrodomain inhibitor may complement current approaches, pre-empt the threat of resistance and offer opportunities to develop combination therapies for combating COVID-19 and future viral threats.
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Zapata-Pérez, Rubén, Fernando Gil-Ortiz, Ana Belén Martínez-Moñino, Antonio Ginés García-Saura, Jordi Juanhuix, and Álvaro Sánchez-Ferrer. "Structural and functional analysis of Oceanobacillus iheyensis macrodomain reveals a network of waters involved in substrate binding and catalysis." Open Biology 7, no. 4 (2017): 160327. http://dx.doi.org/10.1098/rsob.160327.
Texte intégralRésumé :
Macrodomains are ubiquitous conserved domains that bind or transform ADP-ribose (ADPr) metabolites. In humans, they are involved in transcription, X-chromosome inactivation, neurodegeneration and modulating PARP1 signalling, making them potential targets for therapeutic agents. Unfortunately, some aspects related to the substrate binding and catalysis of MacroD-like macrodomains still remain unclear, since mutation of the proposed catalytic aspartate does not completely abolish enzyme activity. Here, we present a functional and structural characterization of a macrodomain from the extremely halotolerant and alkaliphilic bacterium Oceanobacillus iheyensis (OiMacroD), related to hMacroD1/hMacroD2, shedding light on substrate binding and catalysis. The crystal structures of D40A, N30A and G37V mutants, and those with MES, ADPr and ADP bound, allowed us to identify five fixed water molecules that play a significant role in substrate binding. Closure of the β6–α4 loop is revealed as essential not only for pyrophosphate recognition, but also for distal ribose orientation. In addition, a novel structural role for residue D40 is identified. Furthermore, it is revealed that OiMacroD not only catalyses the hydrolysis of O -acetyl-ADP-ribose but also reverses protein mono-ADP-ribosylation. Finally, mutant G37V supports the participation of a substrate-coordinated water molecule in catalysis that helps to select the proper substrate conformation.
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Alhammad, Yousef M. O., and Anthony R. Fehr. "The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation." Viruses 12, no. 4 (2020): 384. http://dx.doi.org/10.3390/v12040384.
Texte intégralRésumé :
Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein–protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.
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McPherson, Robert Lyle, Rachy Abraham, Easwaran Sreekumar, et al. "ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence." Proceedings of the National Academy of Sciences 114, no. 7 (2017): 1666–71. http://dx.doi.org/10.1073/pnas.1621485114.
Texte intégralRésumé :
Chikungunya virus (CHIKV), an Old World alphavirus, is transmitted to humans by infected mosquitoes and causes acute rash and arthritis, occasionally complicated by neurologic disease and chronic arthritis. One determinant of alphavirus virulence is nonstructural protein 3 (nsP3) that contains a highly conserved MacroD-type macrodomain at the N terminus, but the roles of nsP3 and the macrodomain in virulence have not been defined. Macrodomain is a conserved protein fold found in several plus-strand RNA viruses that binds to the small molecule ADP-ribose. Prototype MacroD-type macrodomains also hydrolyze derivative linkages on the distal ribose ring. Here, we demonstrated that the CHIKV nsP3 macrodomain is able to hydrolyze ADP-ribose groups from mono(ADP-ribosyl)ated proteins. Using mass spectrometry, we unambiguously defined its substrate specificity as mono(ADP-ribosyl)ated aspartate and glutamate but not lysine residues. Mutant viruses lacking hydrolase activity were unable to replicate in mammalian BHK-21 cells or mosquitoAedes albopictuscells and rapidly reverted catalytically inactivating mutations. Mutants with reduced enzymatic activity had slower replication in mammalian neuronal cells and reduced virulence in 2-day-old mice. Therefore, nsP3 mono(ADP-ribosyl)hydrolase activity is critical for CHIKV replication in both vertebrate hosts and insect vectors, and for virulence in mice.
Thèses sur le sujet "Macrodomains"
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Russo, Alessandra. "Design, synthesis and biological activity of new target selective antitumoral agents." Doctoral thesis, Universita degli studi di Salerno, 2018. http://hdl.handle.net/10556/3037.
Texte intégralRésumé :
2016 - 2017<br>Cancer development is a complex pathological process that exploits a variety of biological actors. The identification of new molecular entities able to interfere with new biological targets, involved in tumorigenesis, is strongly needed, both for the development of new promising drug candidates, and, as chemical probes useful to further investigate less understood biological aspects. Two main targets, involved at different levels, in cancer development, have been thoroughly investigated: Macrodomain proteins, MacroD1 and MacroD2, and the Bcl-2 associated athanogene 3, BAG3 protein... [edited by Author]<br>XXX ciclo
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Forst, Alexandra [Verfasser]. "Recognition of mono-ADP-ribosylated ARTD10 substrates by ARTD8 macrodomains and acetylation of ARTD10 / Alexandra Forst." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2014. http://d-nb.info/105148779X/34.
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Thiel, Axel. "Organisation du chromosome d' Escherichia coli en macrodomaines et régions non-structurées." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112143.
Texte intégralRésumé :
Le chromosome circulaire de la bactérie Escherichia coli est composé de quatre macrodomaines et deux régions non structurées. Cette organisation influence la ségrégation des chromatides sœurs et la mobilité de l’ADN chromosomique. La structuration de la région terminus (Ter) en macrodomaine est lié à l’interaction de la protéine MatP avec la séquence cible de 13 pb (sic) appelée matS répétée 23 fois dans ce domaine de 800 kb. Le travail réalisé durant ma thèse a permis l’identification et la caractérisation d’un système site-spécifique qui restreint à la région Ter un effet associé à la protéine MatP qui contraint la mobilité de l’ADN et retarde la ségrégation de loci après réplication. Deux séquences spécifiques de 12 pb localisées dans les macrodomaines Right et Left sont requises et suffisantes pour arrêter la propagation du processus de contrainte sur le reste du chromosome. Les changements de propriétés de l’ADN ne sont pas dus à la présence d’un procédé agissant en trans mais probablement à un effet agissant en cis à longue distance et partant des sites matS. De manière remarquable, ces changements de propriétés sont régulés au cours du cycle cellulaire et ne sont présents seulement quand le macrodomaine Ter est associé à la machinerie de division au centre de la cellule. L’insulation de la région Ter requière une protéine nouvellement identifiée comme encrée à la membrane que nous avons nommé TidP et qui a été conservé avec la protéine MatP au cours de l’évolution. Nos résultats indiquent que deux systèmes d’organisation spécifiques sont requis pour l’organisation du macrodomaine Ter au cours du cycle cellulaire. Un second aspect de mon travail a été la caractérisation des mécanismes de contraintes affectant les macrodomaines Right et Left. Nous avons montré, en étudiant le comportement de grands cercles d’ADN excisés, que les propriétés de ces macrodomaines sont conservées dans un contexte extra-chromosomique. Ces résultats suggèrent l’implication d’éléments associés à la molécule d’ADN dans ces macrodomaines et responsable de leur organisation<br>The organization of the Escherichia coli chromosome into a ring composed of four macrodomains and two less-structured region influences the segregation of sister chromatids and the mobility of chromosomal DNA. The structuring of the terminus region (Ter) into a macrodomain relies on the interaction of the protein MatP with a 13 bp target called matS repeated 23 times in the 800-kb long domain. The work performed during my Ph. D. allowed the identification and characterization of a site-specific system that restricts to the Ter region an effect associated to MatP that constrains DNA mobility and delays loci segregation. Two specific 12 bp sequences located in the flanking Left and Right macrodomains are required and sufficient to impede the spreading of the constraining process to the rest of the chromosome. The change of DNA properties does not rely on the presence of a trans-acting process but rather involves a cis-effect acting at a long distance from matS sites. Remarkably, the constraining process is regulated during the cell cycle and occurs only when the Ter MD is associated with the division machinery at mid-cell. Insulation of the Ter region requires a newly identified membrane-anchored protein designated TidP conserved with MatP through evolution. Our results indicate that 2 specific organizational systems are required for the management of the Ter region during the cell cycle. A second aspect of my work, consisted in the characterization of constraining mechanisms affecting the Right and Left macrodomains. I have shown, using excisions of large chromosomal rings, that their macrodomain properties were conserved in an extrachromosomal context, suggesting that a chromatin like structuring was involved in their organization
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Schuller, Marion. "Investigating strategies to modify PARP14 function through macrodomain inhibition." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:51a76ee9-609a-4765-ab55-d95a64e2bb7d.
Texte intégralRésumé :
Macrodomains are conserved protein interaction modules that are present in all domains of life and mediate recognition of sequence motifs harbouring adenosine diphosphate ribose (ADPR) modifications. In addition, some of them are able to control the turnover of ADPR signalling through their catalytic activity removing these modifications. Macrodomains are hence implicated in a variety of cellular processes as well as in diseases including cancer and viral pathogenesis. The polyadenosine-diphosphate-ribose polymerase (PARP) family member PARP14 is one of twelve human macrodomain-containing proteins; it contains three macrodomains in addition to its catalytic PARP domain. PARP14 was shown to be involved in several cellular processes linked to cancer development in for example B-cell lymphoma and hepatocellular carcinoma. Therefore PARP14 including its macrodomains has emerged as a potential therapeutic target. However, the lack of specific small molecule inhibitors has hampered domain-specific target validation studies so far. Current approaches focus on inhibitor development for its PARP domain, yet attaining selectivity of these inhibitors over other PARP enzymes has been challenging. The aim of the work described in this thesis was therefore to evaluate the possibility of targeting PARP14 via inhibition of its macrodomains with small molecule inhibitors as an alternative to PARP domain inhibition. These studies revealed that displacing PARP14 from its target sites requires inhibitor development for both its second and third macrodomain. Druggability of both macrodomains has been demonstrated by the highly selective allosteric macrodomain 2 inhibitor GeA-69 and by several fragment hits targeting the ADPR binding site of macrodomain 3. Finally, PARP14 was confirmed to be implicated in DNA repair mechanisms protecting cells against replication stress, suggesting that a dual PARP14 macrodomain inhibitor may provide the possibility to potentiate genotoxic chemotherapy for cancer treatment.
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Mercier, Romain. "Organisation du chromosome d'Escherichia coli en macrodomaines : identification et rôle du système spécifique de site matS-MatP." Paris 11, 2009. http://www.theses.fr/2009PA112361.
Texte intégralRésumé :
Le génome d’E. Coli est composé d’un chromosome unique et circulaire d’une taille de 4,6Mb. Le chromosome est organisé selon différentes échelles : (i) nucléotidique par les séquences codantes et les motifs d’ADN fonctionnels ; (ii) locale par les domains topologiques ou plectonèmes ; (iii) globale par les réplichores et les macrodomaines. Mon travail de thèse s’est attaché à l’étude de l’organisation globale du chromosome en macrodomaines. Le chromosome d’E. Coli est composé de quatre macrodomaines et de deux régions Non‐Struturées. Les macrodomaines divisent le chromosome en quatre unités structurales séparées les unes des autres. Ce projet de recherche s’articule selon deux axes : la compréhension de la dynamique des macrodomaines au cours du cycle cellulaire et la caractérisation de déterminants moléculaires responsables de la structuration du chromosome en macrodomaines. Le premier axe de recherche a permis de mettre en évidence des proprieties dynamiques du chromosome qui suivent la topographie des macrodomaines : cohésion des chromatides sœurs, confinement fort et isolement spatial. A chaque instant du cycle cellulaire toutes les régions composant un macrodomaine présentent une localisation subcellulaire spécifique dépendante du macrodomaine concerné. Les macrodomaines sont spatialement confinés dans des territoires cellulaires distincts. Ce mode d’organisation est comparable à celui des chromosomes interphasiques eucaryotes en territoires chromosomiques. Le deuxième axe de recherche a permis de caractériser un mécanisme moléculaire responsable de la structuration d’un macrodomaine. Ce mécanisme est composé d’un motif d’ADN répété (matS) dans le macrodomaine Ter reconnu spécifiquement par un facteur protéique (MatP). Le complexe matS/MatP confère toutes ses propriétés de dynamique au macrodomaine Ter : forte cohésion des chromatids soeurs, fort confinement et isolement spatial. De plus, ces propriétés de dynamique sont requises pour le bon déroulement de la fin du cycle cellulaire et la formation de deux cellules filles. Finalement, la co‐conservation de MatP avec un groupe de protéines contenant les protéines Dam, SeqA, MukBEF et plusieurs protéines de fonctions inconnues suggère que le complexe matS/MatP fait partie d’un système général de métabolisme de l’ADN lié à la méthylation<br>The organization of the E. Coli chromosome has been defined genetically as consisting of four insulated macrodomains and two less constrained regions. During my Ph. D. Thesis, we have analyzed the positioning, the segregation pattern and the motility of fluorescent markers in the macrodomains or the Non Structured regions. We have demonstrated that the organization into macrodomains influences the segregation of sister chromatids and the mobility of chromosomal DNA in a radically different way than the NS regions. Moreover we have demonstrated that the organization of the Terminus region into a macrodomain relies on the presence of a 13 bp motif called matS repeated 23 times in the 800 kb-long domain. MatS sites are the main targets in the E. Coli chromosome of a newly identified protein designated MatP. MatP accumulates in the cell as a discrete focus that colocalizes with the Ter macrodomain. The effects of MatP inactivation reveal its role as main organizer of the Ter macrodomain : in the absence of MatP, DNA is less compacted, the mobility of markers is increased, and segregation of Ter macrodomain occurs early in the cell cycle. Our results indicate that a specific organizational system is required in the Terminus region for bacterial chromosome management during the cell cycle
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Smith, Alexandra Kimberly. "A Mutational-Functional Analysis of the Escherichia coli Macrodomain Protein, YmdB." Thesis, Temple University, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=10933701.
Texte intégralRésumé :
<p> Gene expression pathways exhibit many "twists and turns," with theoretically numerous ways in which the pathways can be regulated by both negative and positive feedback mechanisms. A key step in gene expression is RNA maturation (RNA processing), which in the bacterial cell can be accomplished through RNA binding and enzymatic cleavages. The well-characterized bacterial protein Ribonuclease III (RNase III), is a conserved, double-stranded(ds)-specific ribonuclease. In the gram-negative bacterium <i>Escherichia coli</i>, RNase III catalytic activity is subject to both positive and negative regulation. A recent study has indicated that an <i>E. coli</i> protein, YmdB, may negatively regulate RNase III catalytic activity. It has been proposed that YmdB inhibition of RNase III may be part of an adaptive, post-transcriptional physiological response to cellular stress. </p><p> In <i>E. coli</i>, the model organism in this study, YmdB protein is encoded by the single <i>ymdB</i> gene, and has a predicted molecular mass of ∼18.8 kDa. YmdB has been classified as a macrodomain protein, as it exhibits a characteristic fold that specifically provides an ADP-ribose (ADPR) binding site. While YmdB can bind ADPR with good affinity, there may be additional ligands for the binding site. Thus, YmdB protein may interact with other components in the cell, which in turn could modulate the interaction of YmdB with RNase III. </p><p> In previous research conducted within the Nicholson laboratory at Temple University, affinity-purified <i>Escherchia coli(Ec)</i> YmdB and <i> Aquifex aeolicus (Aa)</i> YmdB were found to exhibit ribonucleolytic activity. This observation initiated the long-term goal of learning how YmdB regulates RNase III, and how the ribonucleolytic activity of YmdB may be involved in this process. The specific goal of this thesis project was to further characterize the ribonucleolytic activity of <i>Ec-</i>YmdB through site-specific mutational analysis. Mutations were introduced into a proposed adenine-binding pocket previously identified by crystallography and by molecular modeling. The adenine-binding pocket is a region within the macrodomain fold where ADP-ribose could bind. The mutations were examined for their effect on <i>Ec-</i>YmdB cleavage of a model RNA, R1.1. The results of this study will contribute to the development of a model describing how the ribonucleolytic activity of YmdB is regulated.</p><p>
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Smith, Alexandra Kimberly. "A MUTATIONAL-FUNCTIONAL ANALYSIS OF THE ESCHERICHIA COLI MACRODOMAIN PROTEIN, YMDB." Master's thesis, Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/539353.
Texte intégralRésumé :
Biology<br>M.S.<br>Gene expression pathways exhibit many “twists and turns,” with theoretically numerous ways in which the pathways can be regulated by both negative and positive feedback mechanisms. A key step in gene expression is RNA maturation (RNA processing), which in the bacterial cell can be accomplished through RNA binding and enzymatic cleavages. The well-characterized bacterial protein Ribonuclease III (RNase III), is a conserved, double-stranded(ds)-specific ribonuclease. In the gram-negative bacterium Escherichia coli, RNase III catalytic activity is subject to both positive and negative regulation. A recent study has indicated that an E. coli protein, YmdB, may negatively regulate RNase III catalytic activity. It has been proposed that YmdB inhibition of RNase III may be part of an adaptive, post-transcriptional physiological response to cellular stress. In E. coli, the model organism in this study, YmdB protein is encoded by the single ymdB gene, and has a predicted molecular mass of ~18.8 kDa. YmdB has been classified as a macrodomain protein, as it exhibits a characteristic fold that specifically provides an ADP-ribose (ADPR) binding site. While YmdB can bind ADPR with good affinity, there may be additional ligands for the binding site. Thus, YmdB protein may interact with other components in the cell, which in turn could modulate the interaction of YmdB with RNase III. In previous research conducted within the Nicholson laboratory at Temple University, affinity-purified Escherchia coli(Ec) YmdB and Aquifex aeolicus (Aa) YmdB were found to exhibit ribonucleolytic activity. This observation initiated the long-term goal of learning how YmdB regulates RNase III, and how the ribonucleolytic activity of YmdB may be involved in this process. The specific goal of this thesis project was to further characterize the ribonucleolytic activity of Ec-YmdB through site-specific mutational analysis. Mutations were introduced into a proposed adenine-binding pocket previously identified by crystallography and by molecular modeling. The adenine-binding pocket is a region within the macrodomain fold where ADP-ribose could bind. The mutations were examined for their effect on Ec-YmdB cleavage of a model RNA, R1.1. The results of this study will contribute to the development of a model describing how the ribonucleolytic activity of YmdB is regulated.<br>Temple University--Theses
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Esnault, Emilie. "Etude de la conformation du chromosome chez la bactérie escherichia coli : plasticité et contraintes." Paris 11, 2008. http://www.theses.fr/2008PA112144.
Texte intégralRésumé :
La connaissance des paramètres contraignant l'organisation des chromosomes est importante pour la compréhension plus générale du fonctionnement de la cellule. La plupart des génomes bactériens sont circulaires. Leur réplication progresse de façon bidirectionnelle à partir d'une origine unique et se termine dans la région opposée. La conformation chromosomique naturelle a été modifiée par des inversions. L'impact de ces réarrangements sur la physiologie de la cellule a été regardé. Les résultats montrent que le positionnement préférentiel des gènes sur le brin direct, la localisation des gènes impliqués dans la transcription, la réplication à proximité de l'origine de réplication sur le brin direct, et le biais de séquence observé le long des réplichores, ont une influence à long terme. Au contraire, la symétrie de réplichore a une influence à court terme. Si la perturbation de l'organisation en macrodomaine est le plus souvent bien tolérée par la cellule, deux types d'inversions affectent sévèrement la physiologie de la cellule : l’une impliquant le macrodomaine Ori et l'autre le macrodomaine Ter. La délocalisation de la fin de la réplication en dehors du macrodomaine Ter est très bien tolérée pas la cellule. Par contre, lorsqu’une petite portion de macrodomaine Ter est présente au niveau du nouveau terminus de réplication, la configuration chromosomique devient instable et nécessite RecA pour la viabilité. Des étapes post-réplicatives seraient affectées. RecA est importante de par son activité de recombinaison et parce qu'elle permet l'activation d'une réponse dite réponse SOS, qui permettrait à la cellule d'éviter de finir la réplication dans la région délocalisée<br>Knowledge of forces limiting genome plasticity could improve the general understanting of cell functioning. Most bacterial genomes are circular molecules, and DNA replication proceeds in two directions from a single origin to an opposite region where replication forks meet. Chromosomes were rearranged by large inversions. The respective effects of the rearrangements were assessed. The results show that the preferential positioning of essential genes on the leading strand, the proximity of genes involved in transcription and translation to the origin of replication on the leading strand, and the presence of biased sequences along the replichores operate only as long-term positive selection determinants. By contrast, selection operates to maintain replication arms of similar lengths. If modifying the macrodomain organization is most ofen well tolerated by the cell, two types of inversions severely affect the cell cycle. One involves the Ori macrodomain and the other involves the Ter macrodomain. In an interesting way, the positioning of the replication terminus outside the Ter macrodomain is well tolerated by the cell. On the contrary, when a portion of Ter macrodomain is present in the new zone where replication terminates, the cell physiology is severely affected. This configuration is unstable and RecA becomes essential for viability. Essential post-replication steps, that remain to be identified, seem to be inhibited. The role of RecA is important because of its recombination activity and its capacity to activate the SOS response. The SOS response probably allows replication to terminate outside the mispositionned terminus of replication
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Paudyal, Samridhdi. "FUNCTIONAL ANALYSIS OF THE BACTERIAL MACRODOMAIN PROTEIN YMDB AND ITS INTERACTION WITH RIBONUCLEASE III." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/271085.
Texte intégralRésumé :
Biology<br>Ph.D.<br>The Escherichia coli ymdB gene encodes a ~19 kDa protein that binds ADP-ribose (ADPR) and metabolites related to NAD+. As such, it has been termed a macrodomain protein, referring to a conserved fold that binds ADPR. YmdB can catalyze the hydrolysis of O-acetyl-ADP-ribose (OAADPR), forming acetate and ADPR. OAADPR is a product of sirtuin action on lysine-acetylated proteins, which involves NAD+ as a cosubstrate. There is evidence that YmdB interacts with other proteins, including the conserved enzyme, ribonuclease III. Ribonuclease III (RNase III) is a double-strand(ds)-specific enzyme that processes diverse RNA precursors in bacterial cells to form the mature, functional forms that participate in protein synthesis and gene regulation. RNase III is involved in the maturation, turnover, and action of small noncoding RNAs (sRNAs), which play key roles in regulating bacterial gene expression in response to environmental inputs and changes in growth conditions. A mass-spectroscopy-based analysis of the E. coli proteome has shown that YmdB and RNase III interact in vivo. However, the functional importance of this interaction is not known. There is preliminary evidence that YmdB regulates RNase III activity during specific stress inputs. Thus, during cellular entry into stationary phase (nutrient limitation), or during the cold shock response, YmdB levels increase, which is correlated with a downregulation of RNase III activity. Inhibition of RNase III may alter the maturation and turnover of sRNAs, as well as other RNAs, during the adaptive response to stress. However, it is unclear whether the inhibition is a direct or indirect effect of YmdB on RNase III activity. Moreover, since YmdB binds ADPR, this (or related) metabolite may influence RNase III activity in an YmdB-dependent manner. If the YmdB-RNase III interaction in fact regulates RNase III, this interaction may connect post-transcriptional regulatory pathways with the cellular metabolic state, as reflected by NAD+ and ADPR levels. The goal of this project is to characterize the YmdB interaction with RNase III, with the long-range goal of understanding the mechanism and role of YmdB regulation of RNase III. Since both YmdB and RNase III are conserved bacterial proteins, characterization of YmdB and its influence on RNase III activity would provide insight on a conserved interaction in bacterial cells in general as well as reveal a potentially novel mechanism of post-transcriptional gene regulation.<br>Temple University--Theses
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Lesterlin, Christian. "Rôles de l'organisation en réplichores et en macrodomaines dans la ségrégation du chromosome d'Escherichia coli." Toulouse 3, 2005. http://www.theses.fr/2005TOU30119.
Texte intégralRésumé :
Le génome d'E. Coli est composé d'une molécule d'ADN circulaire de 4,6 Mb, qui, in vivo, est compactée en une structure organisée appelée nucléoïde, qui s'organise selon deux modes, en macrodomaines et en réplichores. Les macrodomaines sont de grandes régions chromosomiques composées de séquences qui montrent la même localisation intracellulaire moyenne au cours du cycle et capables d'entrer en contact entre elles. Les réplichores sont définis comme les bras chromosomiques portant des biais de composition en bases sur toute leur longueur, ils coïncident avec les bras de réplication. Mes travaux de thèse démontrent que FtsK est également impliquée dans le positionnement des sites dif. Nous avons démontré que le site dif n'est actif qu'à la jonction des éléments polarisants, ces derniers étant présents sur l'ensemble du chromosome. Par ailleurs, cette thèse consttue la première mise en évidence de l'importance de l'intégrité du macrodomaine Ter dans la ségrégation du chromosome<br>Recent work has highlighted two main levels of global organisation of the E. Coli chromosomes. Macrodomains are large domains inferred from structural data consisting of loci displaying the same intracellular positioning. Replichores, defined by base composition skews, coincide with the replication arms in normal cells. We used chromosome inversions to show that the dif site, which resolves chromosome dimers, only functions when located at the junction of the replichores, whatever their size. This thesis is the first evidence that replichore polarisation has a role in chromosome segregation. We also show that disruption of the Ter macrodomain provokes a cell cycle defect independent from dimer resolution. This confirms the existence of the Ter macrodomain and suggests a role in chromosome dynamics
Chapitres de livres sur le sujet "Macrodomains"
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Posavec Marjanovic´, Melanija, Gytis Jankevicius, and Ivan Ahel. "Hydrolysis of ADP-Ribosylation by Macrodomains." In Methods in Molecular Biology. Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8588-3_14.
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Garab, Gyozo. "Chirally Organized Macrodomains in Thylakoid Membranes. Possible Structural and Regulatory Roles." In Light as an Energy Source and Information Carrier in Plant Physiology. Springer US, 1996. http://dx.doi.org/10.1007/978-1-4613-0409-8_10.
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Smith, Rebecca, and Gyula Timinszky. "Monitoring Poly(ADP-Ribosyl)ation in Response to DNA Damage in Live Cells Using Fluorescently Tagged Macrodomains." In Methods in Molecular Biology. Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8588-3_2.
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Bütepage, Mareike, Sarah Krieg, Laura Eckei, et al. "Assessment of Intracellular Auto-Modification Levels of ARTD10 Using Mono-ADP-Ribose-Specific Macrodomains 2 and 3 of Murine Artd8." In Methods in Molecular Biology. Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-8588-3_4.
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Kamata, Teddy, Chun-Song Yang, Kasey Jividen, et al. "Detection of ADP-Ribosylation of the Androgen Receptor Using the Recombinant Macrodomain AF1521 from Archaeoglobus fulgidus." In Methods in Molecular Biology. Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9195-2_9.
Texte intégralActes de conférences sur le sujet "Macrodomains"
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Antypenko, Lyudmyla, Oleksii Antypenko, and Sergiy Kovalenko. "MOLECULAR DOCKING OF [1,2,4]TRIAZOLO [1,5-c]QUINAZOLINES TO SARS-CoV-2 NON-STRUCTURAL PROTEIN 3 MACRODOMAIN (6YWM)." In RICERCHE SCIENTIFICHE E METODI DELLA LORO REALIZZAZIONE: ESPERIENZA MONDIALE E REALTÀ DOMESTICHE. European Scientific Platform, 2021. http://dx.doi.org/10.36074/logos-26.11.2021.v3.41.
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