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Pesquisa : D12.776.664 [Categoria DeCS]
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  1 / 7771 MEDLINE  
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[PMID]:29377916
[Au] Autor:Tutykhina I; Esmagambetov I; Bagaev A; Pichugin A; Lysenko A; Shcherbinin D; Sedova E; Logunov D; Shmarov M; Ataullakhanov R; Naroditsky B; Gintsburg A
[Ad] Endereço:Federal Research Centre of Epidemiology and Microbiology named after Honorary Academician N. F. Gamaleya, Ministry of Health, Moscow, Russia.
[Ti] Título:Vaccination potential of B and T epitope-enriched NP and M2 against Influenza A viruses from different clades and hosts.
[So] Source:PLoS One;13(1):e0191574, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To avoid outbreaks of influenza virus epidemics and pandemics among human populations, modern medicine requires the development of new universal vaccines that are able to provide protection from a wide range of influenza A virus strains. In the course of development of a universal vaccine, it is necessary to consider that immunity must be generated even against viruses from different hosts because new human epidemic virus strains have their origins in viruses of birds and other animals. We have enriched conserved viral proteins-nucleoprotein (NP) and matrix protein 2 (M2)-by B and T-cell epitopes not only human origin but also swine and avian origin. For this purpose, we analyzed M2 and NP sequences with respect to changes in the sequences of known T and B-cell epitopes and chose conserved and evolutionarily significant epitopes. Eventually, we found consensus sequences of M2 and NP that have the maximum quantity of epitopes that are 100% coincident with them. Consensus epitope-enriched amino acid sequences of M2 and NP proteins were included in a recombinant adenoviral vector. Immunization with Ad5-tet-M2NP induced strong CD8 and CD4 T cells responses, specific to each of the encoded antigens, i.e. M2 and NP. Eight months after immunization with Ad5-tet-M2NP, high numbers of M2- and NP-responding "effector memory" CD44posCD62neg T cells were found in the mouse spleens, which revealed a long-term T cell immune memory conferred by the immunization. In all, the challenge experiments showed an extraordinarily wide-ranging efficacy of protection by the Ad5-tet-M2NP vaccine, covering 5 different heterosubtypes of influenza A virus (2 human, 2 avian and 1 swine).
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Epitopos/imunologia
Vírus da Influenza A/imunologia
Nucleoproteínas/imunologia
Linfócitos T/imunologia
Vacinação
Proteínas da Matriz Viral/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Antivirais/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Viral); 0 (Epitopes); 0 (Nucleoproteins); 0 (Viral Matrix Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191574


  2 / 7771 MEDLINE  
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[PMID]:29261651
[Au] Autor:Goedhals D; Paweska JT; Burt FJ
[Ad] Endereço:Division of Virology, National Health Laboratory Service/University of the Free State, Bloemfontein, South Africa.
[Ti] Título:Long-lived CD8+ T cell responses following Crimean-Congo haemorrhagic fever virus infection.
[So] Source:PLoS Negl Trop Dis;11(12):e0006149, 2017 12.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Crimean-Congo haemorrhagic fever virus (CCHFV) is a member of the Orthonairovirus genus of the Nairoviridae family and is associated with haemorrhagic fever in humans. Although T lymphocyte responses are known to play a role in protection from and clearance of viral infections, specific T cell epitopes have yet to be identified for CCHFV following infection. A panel of overlapping peptides covering the CCHFV nucleoprotein and the structural glycoproteins, GN and GC, were screened by ELISpot assay to detect interferon gamma (IFN-γ) production in vitro by peripheral blood mononuclear cells from eleven survivors with previous laboratory confirmed CCHFV infection. Reactive peptides were located predominantly on the nucleoprotein, with only one survivor reacting to two peptides from the glycoprotein GC. No single epitope was immunodominant, however all but one survivor showed reactivity to at least one T cell epitope. The responses were present at high frequency and detectable several years after the acute infection despite the absence of continued antigenic stimulation. T cell depletion studies confirmed that IFN-γ production as detected using the ELISpot assay was mediated chiefly by CD8+ T cells. This is the first description of CD8+ T cell epitopic regions for CCHFV and provides confirmation of long-lived T cell responses in survivors of CCHFV infection.
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia
Vírus da Febre Hemorrágica da Crimeia-Congo/imunologia
Febre Hemorrágica da Crimeia/imunologia
Imunidade Inata
[Mh] Termos MeSH secundário: Adulto
Idoso
Sequência de Aminoácidos
Estudos de Coortes
ELISPOT
Epitopos/imunologia
Feminino
Glicoproteínas/imunologia
Febre Hemorrágica da Crimeia/virologia
Seres Humanos
Leucócitos Mononucleares/imunologia
Masculino
Meia-Idade
Nucleoproteínas/imunologia
Biblioteca de Peptídeos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Epitopes); 0 (Glycoproteins); 0 (Nucleoproteins); 0 (Peptide Library)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0006149


  3 / 7771 MEDLINE  
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[PMID]:29262365
[Au] Autor:Bénarouche A; Habchi J; Cagna A; Maniti O; Girard-Egrot A; Cavalier JF; Longhi S; Carrière F
[Ad] Endereço:Aix-Marseille University, CNRS, Enzymologie Interfaciale et Physiologie de la Lipolyse UMR 7282, Marseille, France; TECLIS Scientific, Tassin, France.
[Ti] Título:Interfacial Properties of N , an Intrinsically Disordered Protein.
[So] Source:Biophys J;113(12):2723-2735, 2017 Dec 19.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Intrinsically disordered proteins (IDPs) lack stable secondary and tertiary structure under physiological conditions in the absence of their biological partners and thus exist as dynamic ensembles of interconverting conformers, often highly soluble in water. However, in some cases, IDPs such as the ones involved in neurodegenerative diseases can form protein aggregates and their aggregation process may be triggered by the interaction with membranes. Although the interfacial behavior of globular proteins has been extensively studied, experimental data on IDPs at the air/water (A/W) and water/lipid interfaces are scarce. We studied here the intrinsically disordered C-terminal domain of the Hendra virus nucleoprotein (N ) and compared its interfacial properties to those of lysozyme that is taken as a model globular protein of similar molecular mass. Adsorption of N at the A/W interface was studied in the absence and presence of phospholipids using Langmuir films, polarization modulated-infrared reflection-absorption spectroscopy, and an automated drop tensiometer for interfacial tension and elastic modulus determination with oscillating bubbles. N showed a significant surface activity, with a higher adsorption capacity at the A/W interface and penetration into egg phosphatidylcholine monolayer compared to lysozyme. Whereas lysozyme remains folded upon compression of the protein layer at the A/W interface and shows a quasi-pure elastic behavior, N shows a much higher molecular area and forms a highly viscoelastic film with a high dilational modulus. To our knowledge, a new disorder-to-order transition is thus observed for the N protein that folds into an antiparallel ß-sheet at the A/W interface and presents strong intermolecular interactions.
[Mh] Termos MeSH primário: Proteínas Intrinsicamente Desordenadas/química
Proteínas Intrinsicamente Desordenadas/metabolismo
Nucleoproteínas/química
Nucleoproteínas/metabolismo
Proteínas Virais/química
Proteínas Virais/metabolismo
[Mh] Termos MeSH secundário: Adsorção
Ar
Muramidase/química
Fosfatidilcolinas/química
Conformação Proteica
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intrinsically Disordered Proteins); 0 (Nucleoproteins); 0 (Phosphatidylcholines); 0 (Viral Proteins); 0 (nucleoprotein, Hendra virus); 059QF0KO0R (Water); EC 3.2.1.17 (Muramidase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


  4 / 7771 MEDLINE  
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[PMID]:29040311
[Au] Autor:Kondoh T; Manzoor R; Nao N; Maruyama J; Furuyama W; Miyamoto H; Shigeno A; Kuroda M; Matsuno K; Fujikura D; Kajihara M; Yoshida R; Igarashi M; Takada A
[Ad] Endereço:Division of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
[Ti] Título:Putative endogenous filovirus VP35-like protein potentially functions as an IFN antagonist but not a polymerase cofactor.
[So] Source:PLoS One;12(10):e0186450, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It has been proposed that some non-retroviral RNA virus genes are integrated into vertebrate genomes. Endogenous filovirus-like elements (EFLs) have been discovered in some mammalian genomes. However, their potential roles in ebolavirus infection are unclear. A filovirus VP35-like element (mlEFL35) is found in the little brown bat (Myotis lucifugus) genome. Putative mlEFL35-derived protein (mlEFL35p) contains nearly full-length amino acid sequences corresponding to ebolavirus VP35. Ebola virus VP35 has been shown to bind double-stranded RNA, leading to inhibition of type I interferon (IFN) production, and is also known as a viral polymerase cofactor that is essential for viral RNA transcription/replication. In this study, we transiently expressed mlEFL35p in human kidney cells and investigated its biological functions. We first found that mlEFL35p was coimmunoprecipitated with itself and ebolavirus VP35s but not with the viral nucleoprotein. Then the biological functions of mlEFL35p were analyzed by comparing it to ebolavirus VP35s. We found that the expression of mlEFL35p significantly inhibited human IFN-ß promoter activity as well as VP35s. By contrast, expression of mlEFL35p did not support viral RNA transcription/replication and indeed slightly decrease the reporter gene expression in a minigenome assay. These results suggest that mlEFL35p potentially acts as an IFN antagonist but not a polymerase cofactor.
[Mh] Termos MeSH primário: Ebolavirus/genética
Interações Hospedeiro-Patógeno
Interferon beta/antagonistas & inibidores
Nucleoproteínas/genética
RNA de Cadeia Dupla/genética
Proteínas do Core Viral/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Quirópteros/virologia
Ebolavirus/isolamento & purificação
Ebolavirus/metabolismo
Expressão Gênica
Genes Reporter
Células HEK293
Seres Humanos
Interferon beta/genética
Interferon beta/imunologia
Luciferases/genética
Luciferases/metabolismo
Nucleoproteínas/metabolismo
Regiões Promotoras Genéticas
Ligação Proteica
RNA de Cadeia Dupla/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Proteínas do Core Viral/metabolismo
Replicação Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleoproteins); 0 (RNA, Double-Stranded); 0 (Recombinant Proteins); 0 (Viral Core Proteins); 0 (nucleoprotein VP35, Ebola virus); 77238-31-4 (Interferon-beta); EC 1.13.12.- (Luciferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186450


  5 / 7771 MEDLINE  
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[PMID]:28917841
[Au] Autor:Gc JB; Pokhrel R; Bhattarai N; Johnson KA; Gerstman BS; Stahelin RV; Chapagain PP
[Ad] Endereço:Department of Physics, Florida International University, Miami, FL 33199, United States.
[Ti] Título:Graphene-VP40 interactions and potential disruption of the Ebola virus matrix filaments.
[So] Source:Biochem Biophys Res Commun;493(1):176-181, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ebola virus infections cause hemorrhagic fever that often results in very high fatality rates. In addition to exploring vaccines, development of drugs is also essential for treating the disease and preventing the spread of the infection. The Ebola virus matrix protein VP40 exists in various conformational and oligomeric forms and is a potential pharmacological target for disrupting the virus life-cycle. Here we explored graphene-VP40 interactions using molecular dynamics simulations and graphene pelleting assays. We found that graphene sheets associate strongly with VP40 at various interfaces. We also found that the graphene is able to disrupt the C-terminal domain (CTD-CTD) interface of VP40 hexamers. This VP40 hexamer-hexamer interface is crucial in forming the Ebola viral matrix and disruption of this interface may provide a method to use graphene or similar nanoparticle based solutions as a disinfectant that can significantly reduce the spread of the disease and prevent an Ebola epidemic.
[Mh] Termos MeSH primário: Grafite/química
Nucleoproteínas/química
Nucleoproteínas/ultraestrutura
Proteínas do Core Viral/química
Proteínas do Core Viral/ultraestrutura
Proteínas da Matriz Viral/química
Proteínas da Matriz Viral/ultraestrutura
[Mh] Termos MeSH secundário: Sítios de Ligação
Simulação de Dinâmica Molecular
Ligação Proteica
Conformação Proteica
Multimerização Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleoproteins); 0 (VP40 protein, virus); 0 (Viral Core Proteins); 0 (Viral Matrix Proteins); 0 (nucleoprotein VP40, Ebola virus); 7782-42-5 (Graphite)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170918
[St] Status:MEDLINE


  6 / 7771 MEDLINE  
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[PMID]:28915404
[Au] Autor:Lier C; Becker S; Biedenkopf N
[Ad] Endereço:Institute of Virology, Philipps-University Marburg, Marburg, Germany; German Center of Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Marburg, Germany.
[Ti] Título:Dynamic phosphorylation of Ebola virus VP30 in NP-induced inclusion bodies.
[So] Source:Virology;512:39-47, 2017 Dec.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Zaire Ebolavirus (EBOV) causes a severe feverish disease with high case fatality rates. Transcription of EBOV is dependent on the activity of the nucleocapsid protein VP30 which represents an essential viral transcription factor. Activity of VP30 is regulated via phosphorylation at six N-terminal serine residues. Recent data demonstrated that dynamic phosphorylation and dephosphorylation of serine residue 29 is essential for transcriptional support activity of VP30. To analyze the spatio/temporal dynamics of VP30 phosphorylation, we generated a peptide antibody recognizing specifically VP30 phosphorylated at serine 29. Using this antibody we could demonstrate that (i) the majority of VP30 molecules in EBOV-infected cells is dephosphorylated at the crucial position serine 29, (ii) both, VP30 phosphorylation and dephosphorylation take place in viral inclusion bodies that are induced by the nucleoprotein NP and (iii) NP influences the phosphorylation state of VP30.
[Mh] Termos MeSH primário: Corpos de Inclusão Viral/fisiologia
Nucleoproteínas/metabolismo
Fatores de Transcrição/metabolismo
Proteínas do Core Viral/metabolismo
Proteínas Virais/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Regulação Viral da Expressão Gênica/fisiologia
Seres Humanos
Fosforilação
Fatores de Transcrição/genética
Proteínas Virais/genética
Replicação Viral/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleoproteins); 0 (Transcription Factors); 0 (VP30 protein, ebola virus); 0 (Viral Core Proteins); 0 (Viral Proteins); 0 (nucleoprotein VP35, Ebola virus)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE


  7 / 7771 MEDLINE  
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[PMID]:28911100
[Au] Autor:Lee N; Le Sage V; Nanni AV; Snyder DJ; Cooper VS; Lakdawala SS
[Ad] Endereço:University of Pittsburgh School of Medicine, Department of Microbiology and Molecular Genetics, 450 Technology Drive, Pittsburgh, PA 15219, USA.
[Ti] Título:Genome-wide analysis of influenza viral RNA and nucleoprotein association.
[So] Source:Nucleic Acids Res;45(15):8968-8977, 2017 Sep 06.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Influenza A virus (IAV) genomes are composed of eight single-stranded RNA segments that are coated by viral nucleoprotein (NP) molecules. Classically, the interaction between NP and viral RNA (vRNA) is depicted as a uniform pattern of 'beads on a string'. Using high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP), we identified the vRNA binding profiles of NP for two H1N1 IAV strains in virions. Contrary to the prevailing model for vRNA packaging, NP does not bind vRNA uniformly in the A/WSN/1933 and A/California/07/2009 strains, but instead each vRNA segment exhibits a unique binding profile, containing sites that are enriched or poor in NP association. Intriguingly, both H1N1 strains have similar yet distinct NP binding profiles despite extensive sequence conservation. Peaks identified by HITS-CLIP were verified as true NP binding sites based on insensitivity to DNA antisense oligonucleotide-mediated RNase H digestion. Moreover, nucleotide content analysis of NP peaks revealed that these sites are relatively G-rich and U-poor compared to the genome-wide nucleotide content, indicating an as-yet unidentified sequence bias for NP association in vivo. Taken together, our genome-wide study of NP-vRNA interaction has implications for the understanding of influenza vRNA architecture and genome packaging.
[Mh] Termos MeSH primário: Genoma Viral
Vírus da Influenza A Subtipo H1N1/genética
Nucleoproteínas/química
RNA Viral/química
Proteínas Virais/química
Vírion/genética
[Mh] Termos MeSH secundário: Sequência de Bases
Sítios de Ligação
Sequência Conservada
Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Vírus da Influenza A Subtipo H1N1/metabolismo
Vírus da Influenza A Subtipo H1N1/ultraestrutura
Modelos Moleculares
Nucleoproteínas/genética
Nucleoproteínas/metabolismo
Oligonucleotídeos Antissenso/química
Ligação Proteica
RNA Viral/genética
RNA Viral/metabolismo
Ribonuclease H/química
Proteínas Virais/genética
Proteínas Virais/metabolismo
Vírion/metabolismo
Vírion/ultraestrutura
Montagem de Vírus/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleoproteins); 0 (Oligonucleotides, Antisense); 0 (RNA, Viral); 0 (Viral Proteins); EC 3.1.26.4 (Ribonuclease H)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx584


  8 / 7771 MEDLINE  
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[PMID]:28777080
[Au] Autor:Baklouti A; Goulet A; Lichière J; Canard B; Charrel RN; Ferron F; Coutard B; Papageorgiou N
[Ad] Endereço:Architecture et Fonction des Macromolécules Biologiques, CNRS, Aix-Marseille Université, 13288 Marseille, France.
[Ti] Título:Toscana virus nucleoprotein oligomer organization observed in solution.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 8):650-659, 2017 Aug 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Toscana virus (TOSV) is an arthropod-borne virus belonging to the Phlebovirus genus within the Bunyaviridae family. As in other bunyaviruses, the genome of TOSV is made up of three RNA segments. They are encapsidated by the nucleoprotein (N), which also plays an essential role in virus replication. To date, crystallographic structures of phlebovirus N have systematically revealed closed-ring organizations which do not fully match the filamentous organization of the ribonucleoprotein (RNP) complex observed by electron microscopy. In order to further bridge the gap between crystallographic data on N and observations of the RNP by electron microscopy, the structural organization of recombinant TOSV N was investigated by an integrative approach combining X-ray diffraction crystallography, transmission electron microscopy, small-angle X-ray scattering, size-exclusion chromatography and multi-angle laser light scattering. It was found that in solution TOSV N forms open oligomers consistent with the encapsidation mechanism of phlebovirus RNA.
[Mh] Termos MeSH primário: Proteínas do Nucleocapsídeo/química
Nucleoproteínas/química
Vírus da Febre do Flebótomo Napolitano/química
[Mh] Termos MeSH secundário: Infecções por Bunyaviridae/virologia
Cristalografia por Raios X
Modelos Moleculares
Proteínas do Nucleocapsídeo/metabolismo
Proteínas do Nucleocapsídeo/ultraestrutura
Nucleoproteínas/metabolismo
Nucleoproteínas/ultraestrutura
Conformação Proteica
Multimerização Proteica
RNA Viral/metabolismo
Vírus da Febre do Flebótomo Napolitano/metabolismo
Espalhamento a Baixo Ângulo
Soluções
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleocapsid Proteins); 0 (Nucleoproteins); 0 (RNA, Viral); 0 (Solutions)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317008774


  9 / 7771 MEDLINE  
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[PMID]:28777079
[Au] Autor:Yekwa E; Khourieh J; Canard B; Papageorgiou N; Ferron F
[Ad] Endereço:CNRS, AFMB UMR 7257, 13288 Marseille, France.
[Ti] Título:Activity inhibition and crystal polymorphism induced by active-site metal swapping.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 8):641-649, 2017 Aug 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Arenaviridae family is one of the two RNA viral families that encode a 3'-5' exonuclease in their genome. An exonuclease domain is found in the Arenaviridae nucleoprotein and targets dsRNA specifically. This domain is directly involved in suppression of innate immunity in the host cell. Like most phosphate-processing enzymes, it requires a divalent metal ion such as Mg (or Mn ) as a cofactor to catalyse nucleotide-cleavage and nucleotide-transfer reactions. On the other hand, calcium (Ca ) inhibits this enzymatic activity, in spite of the fact that Mg and Ca present comparable binding affinities and biological availabilities. Here, the molecular and structural effects of the replacement of magnesium by calcium and its inhibition mechanism for phosphodiester cleavage, an essential reaction in the viral process of innate immunity suppression, are studied. Biochemical data and high-resolution structures of the Mopeia virus exonuclease domain complexed with each ion are reported for the first time. The consequences of the ion swap for the stability of the protein, the catalytic site and the functional role of a specific metal ion in enabling the catalytic cleavage of a dsRNA substrate are outlined.
[Mh] Termos MeSH primário: Arenavirus/química
Arenavirus/enzimologia
Exonucleases/química
Proteínas do Nucleocapsídeo/química
Nucleoproteínas/química
[Mh] Termos MeSH secundário: Infecções por Arenaviridae/virologia
Arenavirus/metabolismo
Sítios de Ligação
Cálcio/metabolismo
Domínio Catalítico
Cátions Bivalentes/metabolismo
Cristalização
Cristalografia por Raios X
Exonucleases/metabolismo
Magnésio/metabolismo
Manganês/metabolismo
Simulação de Acoplamento Molecular
Proteínas do Nucleocapsídeo/metabolismo
Nucleoproteínas/metabolismo
Domínios Proteicos
RNA Viral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cations, Divalent); 0 (Nucleocapsid Proteins); 0 (Nucleoproteins); 0 (RNA, Viral); 42Z2K6ZL8P (Manganese); EC 3.1.- (Exonucleases); I38ZP9992A (Magnesium); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE
[do] DOI:10.1107/S205979831700866X


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[PMID]:28768865
[Au] Autor:Han Z; Sagum CA; Takizawa F; Ruthel G; Berry CT; Kong J; Sunyer JO; Freedman BD; Bedford MT; Sidhu SS; Sudol M; Harty RN
[Ad] Endereço:Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
[Ti] Título:Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress.
[So] Source:J Virol;91(20), 2017 Oct 15.
[Is] ISSN:1098-5514
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ebola virus (EBOV) is a member of the family and the cause of hemorrhagic fever outbreaks. The EBOV VP40 (eVP40) matrix protein is the main driving force for virion assembly and budding. Indeed, expression of eVP40 alone in mammalian cells results in the formation and budding of virus-like particles (VLPs) which mimic the budding process and morphology of authentic, infectious EBOV. To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs. In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40. We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40. Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since (i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress, (ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress, and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress. Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40. In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress. Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted. Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress.
[Mh] Termos MeSH primário: Ebolavirus/fisiologia
Interações Hospedeiro-Patógeno
Nucleoproteínas/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Proteínas do Core Viral/metabolismo
Liberação de Vírus
[Mh] Termos MeSH secundário: Células HEK293
Seres Humanos
Nucleoproteínas/química
Nucleoproteínas/genética
RNA Interferente Pequeno
Ubiquitina-Proteína Ligases/genética
Ubiquitinação
Proteínas do Core Viral/química
Proteínas do Core Viral/genética
Proteínas da Matriz Viral/metabolismo
Vírion/fisiologia
Montagem de Vírus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleoproteins); 0 (RNA, Small Interfering); 0 (Viral Core Proteins); 0 (Viral Matrix Proteins); 0 (nucleoprotein VP40, Ebola virus); EC 2.3.2.26 (WWP1 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE



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