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Pesquisa : D12.776.835.725.868.249 [Categoria DeCS]
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[PMID]:29241036
[Au] Autor:Rea E; Holder AA; Tewari R
[Ad] Endereço:School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.
[Ti] Título:Plasmodium Peekaboo: PK4 Mediates Parasite Latency.
[So] Source:Cell Host Microbe;22(6):724-725, 2017 12 13.
[Is] ISSN:1934-6069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this issue of Cell Host & Microbe, Zhang et al. (2017) show that translational repression through eIF2α phosphorylation mediated by PK4 kinase activity plays a key role in artemisinin resistance in recrudescent malaria infections. Targeting this druggable process could extend the lifespan of current frontline treatments.
[Mh] Termos MeSH primário: Parasitos
Plasmodium
[Mh] Termos MeSH secundário: Animais
Antimaláricos
Resistência a Medicamentos/efeitos dos fármacos
Fator de Iniciação 2 em Eucariotos
Malária
Malária Falciparum
Fosforilação
Plasmodium falciparum
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Antimalarials); 0 (Eukaryotic Initiation Factor-2)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE


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[PMID]:28743963
[Au] Autor:Yao Y; Lu Q; Hu Z; Yu Y; Chen Q; Wang QK
[Ad] Endereço:Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430074, China.
[Ti] Título:A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure.
[So] Source:Nat Commun;8(1):133, 2017 07 25.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Endoplasmic reticulum stress is an evolutionarily conserved cell stress response associated with numerous diseases, including cardiac hypertrophy and heart failure. The major endoplasmic reticulum stress signaling pathway causing cardiac hypertrophy involves endoplasmic reticulum stress sensor PERK (protein kinase-like kinase) and eIF2α-ATF4-CHOP signaling. Here, we describe a non-canonical, AGGF1-mediated regulatory system for endoplasmic reticulum stress signaling associated with increased p-eIF2α and ATF4 and decreased sXBP1 and CHOP. Specifically, we see a reduced AGGF1 level consistently associated with induction of endoplasmic reticulum stress signaling in mouse models and human patients with heart failure. Mechanistically, AGGF1 regulates endoplasmic reticulum stress signaling by inhibiting ERK1/2 activation, which reduces the level of transcriptional repressor ZEB1, leading to induced expression of miR-183-5p. miR-183-5p post-transcriptionally downregulates CHOP and inhibits endoplasmic reticulum stress-induced apoptosis. AGGF1 protein therapy and miR-183-5p regulate endoplasmic reticulum stress signaling and block endoplasmic reticulum stress-induced apoptosis, cardiac hypertrophy, and heart failure, providing an attractive paradigm for treatment of cardiac hypertrophy and heart failure.Endoplasmic reticulum (ER) stress promotes cardiac dysfunction. Here the authors uncover a pathway whereby AGGF1 blocks ER stress by inhibiting ERK1/2 activation and the transcriptional repressor ZEB1, leading to induction of miR-183-5p and down-regulation of CHOP, and show that AGGF1 can effectively treat cardiac hypertrophy and heart failure.
[Mh] Termos MeSH primário: Apoptose/genética
Estresse do Retículo Endoplasmático/genética
Insuficiência Cardíaca/genética
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/genética
Fator 4 Ativador da Transcrição/metabolismo
Proteínas Angiogênicas/genética
Proteínas Angiogênicas/metabolismo
Animais
Western Blotting
Linhagem Celular
Fator de Iniciação 2 em Eucariotos/genética
Fator de Iniciação 2 em Eucariotos/metabolismo
Expressão Gênica
Insuficiência Cardíaca/metabolismo
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
MicroRNAs/genética
Ratos
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Fator de Transcrição CHOP/genética
Fator de Transcrição CHOP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aggf1 protein, mouse); 0 (Angiogenic Proteins); 0 (Eukaryotic Initiation Factor-2); 0 (MicroRNAs); 145891-90-3 (Activating Transcription Factor 4); 147336-12-7 (Transcription Factor CHOP)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00171-w


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[PMID]:28926611
[Au] Autor:Briggs JW; Ren L; Chakrabarti KR; Tsai YC; Weissman AM; Hansen RJ; Gustafson DL; Khan YA; Dinman JD; Khanna C
[Ad] Endereço:Tumor Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
[Ti] Título:Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus.
[So] Source:PLoS One;12(9):e0185089, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.
[Mh] Termos MeSH primário: Sirolimo/análogos & derivados
Sirolimo/farmacologia
Resposta a Proteínas não Dobradas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Fator de Iniciação 2 em Eucariotos/metabolismo
Seres Humanos
Fosforilação/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-akt/metabolismo
Processamento de RNA/efeitos dos fármacos
RNA Mensageiro/metabolismo
RNA Ribossômico 28S/metabolismo
Sarcoma/metabolismo
Sarcoma/patologia
Solventes/química
Solventes/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteína 1 de Ligação a X-Box/genética
Proteína 1 de Ligação a X-Box/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (RNA, Messenger); 0 (RNA, Ribosomal, 28S); 0 (Solvents); 0 (X-Box Binding Protein 1); 0 (XBP1 protein, human); 624KN6GM2T (temsirolimus); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185089


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[PMID]:28918745
[Au] Autor:Sogorin EA; Selikhanov GK; Agalarov SC
[Ad] Endereço:Institute of Protein Research, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. sultan@vega.protres.ru.
[Ti] Título:Coupling of Translation Initiation and Termination Does Not Depend on the Mode of Initiation.
[So] Source:Biochemistry (Mosc);82(7):816-820, 2017 Jul.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently we described a novel phenomenon observed during eukaryotic translation in a cell-free system: the coupling of initiation and termination on different mRNA molecules. Here we show that the phenomenon does not depend on a special mode of initiation. The mRNAs with certain leader sequences known to require different determinants for successful initiation were examined. Even in a case of using the intergenic internal ribosome entry site (IRES) of cricket paralysis virus RNA as the leader sequence, while no initiation factors are required, the effect of coupling is well expressed, including trials in the presence of hippuristanol as an inhibitor of eIF4A. Thus, the effect persists in the absence of scanning and does not depend on initiator tRNA and eIF2. The results suggest that the initiation factors are not involved in the coupling mechanism.
[Mh] Termos MeSH primário: RNA Mensageiro/metabolismo
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas
Sistema Livre de Células/metabolismo
Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores
Fator de Iniciação 4A em Eucariotos/metabolismo
Genes Reporter
Sítios Internos de Entrada Ribossomal/genética
Iniciação Traducional da Cadeia Peptídica
Terminação Traducional da Cadeia Peptídica
Plasmídeos/metabolismo
Esteróis/química
Esteróis/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (Eukaryotic Initiation Factor-2); 0 (Internal Ribosome Entry Sites); 0 (RNA, Messenger); 0 (Sterols); 0 (hippuristanol); EC 2.7.7.- (Eukaryotic Initiation Factor-4A)
[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:170919
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917070069


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[PMID]:28844859
[Au] Autor:Liu Y; Pan X; Li S; Yu Y; Chen J; Yin J; Li G
[Ad] Endereço:Department of Liver Surgery, Huai'an First Hospital Affiliated to Nanjing Medical University, Huai'an, Jiangsu Province, 223300, China; Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210009, China. Electronic address: 195804981@qq
[Ti] Título:Endoplasmic reticulum stress restrains hepatocyte growth factor expression in hepatic stellate cells and rat acute liver failure model.
[So] Source:Chem Biol Interact;277:43-54, 2017 Nov 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to test whether endoplasmic reticulum (ER) stress suppresses hepatocyte growth factor (HGF) expression in hepatic stellate cells (HSCs) and whether ER stress plays a role in alleviating d-Galactosamine and Lipopolysaccharide (D-GalN/LPS)-induced acute liver failure (ALF) by regulating HGF expression. Rat HSCs line HSC-T6 were treated with the ER stress inducers tunicamycin or thapsigargin, and ER stress inhibitors sodium 4-phenylbutyrate (4-PBA) or salubrinal, respectively. Recombinant lentivirus containing eukaryotic translation initiation factor 2α (eIf2α), named LV-eIf2α-shRNA-GFP was produced to block eIf2α activated by ER stress. A rat ALF model was created by intraperitoneal injection of D-GalN/LPS, and 100 mg/kg 4-PBA was injected 6 h before injection as an inhibitor of ER stress. Levels of HGF, c-Met, vascular endothelial growth factor (VEGF), GRP78, eIf2α, phospho-eIF2α, ATF4 and CHOP in vitro and in vivo were measured. Our results demonstrated that ER stress stimulated VEGF but inhibited HGF expression in HSC-T6 cells. Both the stimulation of VEGF and the inhibition of HGF could be partly prevented by 4-PBA or Salubrinal. eIf2α expression was upregulated during ERS and interfering eIf2α expression proportionately down-regulated HGF expression. Inhibition of HGF and c-Met expression was also observed in the ALF rat. Treatment with 4-PBA prevented the reduction of HGF in ALF rats. ER stress regulates HGF expression in vitro and in vivo, which depends on eIf2α pathway. Reduction in liver damage of ALF by 4-PBA is associated with attenuation of ER stress and maintaining HGF production.
[Mh] Termos MeSH primário: Regulação para Baixo
Estresse do Retículo Endoplasmático
Células Estreladas do Fígado/patologia
Fator de Crescimento de Hepatócito/genética
Falência Hepática Aguda/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Fator de Iniciação 2 em Eucariotos/genética
Regulação da Expressão Gênica
Células Estreladas do Fígado/metabolismo
Falência Hepática Aguda/patologia
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 67256-21-7 (Hepatocyte Growth Factor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28844332
[Au] Autor:Allen AG; Morgans S; Smith E; Aron MM; Jancovich JK
[Ad] Endereço:Department of Biological Sciences, California State University, San Marcos, CA 92096, USA.
[Ti] Título:The Ambystoma tigrinum virus (ATV) RNase III gene can modulate host PKR activation and interferon production.
[So] Source:Virology;511:300-308, 2017 Nov.
[Is] ISSN:1096-0341
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The iridovirus RNase III gene is one of 26 conserved core genes among the family Iridoviridae. Initial studies suggest this viral protein functions to suppress RNA interference pathways that may attack viral RNA during infection. Therefore, to determine if the Ambystoma tigrinum virus (ATV) RNase III-like gene (ORF 25R) can modulate the host innate immune response fish and human cells ectopically expressing 25R were treated with polyI:C and monitored for interferon synthesis and phosphorylation of eIF2α and PKR. We found a decrease in cellular IFN production and modulation of the PKR pathway. In addition, ATV deleted of the RNase III gene (ATVΔ25R) shows reduced pathogenicity in tiger salamanders. Collectively our data suggest that the ATV 25R protein is a pathogenesis factor that may function to help evade the host's immune response by masking activators of the IFN pathway.
[Mh] Termos MeSH primário: Interferons/antagonistas & inibidores
Inibidores de Proteínas Quinases/metabolismo
Proteínas Recombinantes/metabolismo
Ribonuclease III/metabolismo
Proteínas Virais/metabolismo
Fatores de Virulência/metabolismo
eIF-2 Quinase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Ambystoma/virologia
Animais
Linhagem Celular
Fator de Iniciação 2 em Eucariotos/metabolismo
Peixes
Interações Hospedeiro-Patógeno
Seres Humanos
Evasão da Resposta Imune
Fosfoproteínas/análise
Fosforilação
Processamento de Proteína Pós-Traducional
Proteínas Recombinantes/genética
Proteínas Virais/genética
Fatores de Virulência/genética
eIF-2 Quinase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); 0 (Recombinant Proteins); 0 (Viral Proteins); 0 (Virulence Factors); 9008-11-1 (Interferons); EC 2.7.11.1 (eIF-2 Kinase); EC 3.1.26.3 (Ribonuclease III)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28771613
[Au] Autor:Anda S; Zach R; Grallert B
[Ad] Endereço:Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
[Ti] Título:Activation of Gcn2 in response to different stresses.
[So] Source:PLoS One;12(8):e0182143, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:All organisms have evolved pathways to respond to different forms of cellular stress. The Gcn2 kinase is best known as a regulator of translation initiation in response to starvation for amino acids. Work in budding yeast has showed that the molecular mechanism of GCN2 activation involves the binding of uncharged tRNAs, which results in a conformational change and GCN2 activation. This pathway requires GCN1, which ensures delivery of the uncharged tRNA onto GCN2. However, Gcn2 is activated by a number of other stresses which do not obviously involve accumulation of uncharged tRNAs, raising the question how Gcn2 is activated under these conditions. Here we investigate the requirement for ongoing translation and tRNA binding for Gcn2 activation after different stresses in fission yeast. We find that mutating the tRNA-binding site on Gcn2 or deleting Gcn1 abolishes Gcn2 activation under all the investigated conditions. These results suggest that tRNA binding to Gcn2 is required for Gcn2 activation not only in response to starvation but also after UV irradiation and oxidative stress.
[Mh] Termos MeSH primário: Proteínas Serina-Treonina Quinases/metabolismo
RNA de Transferência/metabolismo
Proteínas de Schizosaccharomyces pombe/metabolismo
Estresse Fisiológico/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Cicloeximida/farmacologia
Fator de Iniciação 2 em Eucariotos/metabolismo
Peróxido de Hidrogênio/toxicidade
Mutagênese
Estresse Oxidativo/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fosforilação/efeitos da radiação
Biossíntese de Proteínas/efeitos da radiação
Inibidores da Síntese de Proteínas/farmacologia
Proteínas Serina-Treonina Quinases/química
Proteínas Serina-Treonina Quinases/genética
Schizosaccharomyces/genética
Schizosaccharomyces/metabolismo
Schizosaccharomyces/efeitos da radiação
Proteínas de Schizosaccharomyces pombe/química
Proteínas de Schizosaccharomyces pombe/genética
Alinhamento de Sequência
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Protein Synthesis Inhibitors); 0 (Schizosaccharomyces pombe Proteins); 9014-25-9 (RNA, Transfer); 98600C0908 (Cycloheximide); BBX060AN9V (Hydrogen Peroxide); EC 2.7.11.1 (Gcn2 protein, S pombe); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182143


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[PMID]:28759048
[Au] Autor:Carrara M; Sigurdardottir A; Bertolotti A
[Ad] Endereço:MRC Laboratory of Molecular Biology, Cambridge, UK.
[Ti] Título:Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors.
[So] Source:Nat Struct Mol Biol;24(9):708-716, 2017 Sep.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The reversible phosphorylation of proteins controls most cellular functions. Protein kinases have been popular drug targets, unlike phosphatases, which remain a drug discovery challenge. Guanabenz and Sephin1 are selective inhibitors of the phosphatase regulatory subunit PPP1R15A (R15A) that prolong the benefit of eIF2α phosphorylation, thereby protecting cells from proteostatic defects. In mice, Sephin1 prevents two neurodegenerative diseases, Charcot-Marie-Tooth 1B (CMT-1B) and SOD1-mediated amyotrophic lateral sclerosis (ALS). However, the molecular basis for R15A inhibition is unknown. Here we reconstituted human recombinant eIF2α holophosphatases, R15A-PP1 and R15B-PP1, whose activity depends on both the catalytic subunit PP1 (protein phosphatase 1) and either R15A or R15B. This system enabled the functional characterization of these holophosphatases and revealed that Guanabenz and Sephin1 induced a selective conformational change in R15A, detected by resistance to limited proteolysis. This altered the recruitment of eIF2α, preventing its dephosphorylation. This work demonstrates that regulatory subunits of phosphatases are valid drug targets and provides the molecular rationale to expand this concept to other phosphatases.
[Mh] Termos MeSH primário: Fator de Iniciação 2 em Eucariotos/química
Fator de Iniciação 2 em Eucariotos/metabolismo
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Proteína Fosfatase 1/química
Proteína Fosfatase 1/metabolismo
[Mh] Termos MeSH secundário: Guanabenzo/análogos & derivados
Guanabenzo/metabolismo
Seres Humanos
Ligação Proteica
Conformação Proteica/efeitos dos fármacos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Membrane Proteins); 0 (PPP1R16B protein, human); 0 (Recombinant Proteins); 0 (sephin1); EC 3.1.3.16 (PPP1R15A protein, human); EC 3.1.3.16 (Protein Phosphatase 1); GGD30112WC (Guanabenz)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3443


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[PMID]:28736176
[Au] Autor:Vaidya AT; Lomakin IB; Joseph NN; Dmitriev SE; Steitz TA
[Ad] Endereço:Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520-8114, USA.
[Ti] Título:Crystal Structure of the C-terminal Domain of Human eIF2D and Its Implications on Eukaryotic Translation Initiation.
[So] Source:J Mol Biol;429(18):2765-2771, 2017 Sep 01.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein synthesis is a key process in all living organisms. In eukaryotes, initiation factor 2 (eIF2) plays an important role in translation initiation as it selects and delivers the initiator tRNA to the small ribosomal subunit. Under stress conditions, phosphorylation of the α-subunit of eIF2 downregulates cellular protein synthesis. However, translation of certain mRNAs continues via the eIF2D-dependent non-canonical initiation pathway. The molecular mechanism of this process remains elusive. In addition, eIF2D plays a role in translation re-initiation and ribosome recycling. Currently, there has been no structural information of eIF2D. We have now determined the crystal structure of the C-terminal domains of eIF2D at 1.4-Å resolution. One domain has the fold similar to that of eIF1, which is crucial for the scanning and initiation codon selection. The second domain has a known SWIB/MDM2 fold, which was not observed before in other translation initiation factors. Our structure reveals atomic details of inter-domain interactions in the C-terminal part of eIF2D and sheds light on the possible role of these domains in eIF2D during translation.
[Mh] Termos MeSH primário: Fator de Iniciação 2 em Eucariotos/química
Iniciação Traducional da Cadeia Peptídica
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Fator de Iniciação 2 em Eucariotos/metabolismo
Seres Humanos
Modelos Moleculares
Conformação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (eIF2D protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


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[PMID]:28732596
[Au] Autor:Weisser M; Schäfer T; Leibundgut M; Böhringer D; Aylett CHS; Ban N
[Ad] Endereço:Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland.
[Ti] Título:Structural and Functional Insights into Human Re-initiation Complexes.
[So] Source:Mol Cell;67(3):447-456.e7, 2017 Aug 03.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:After having translated short upstream open reading frames, ribosomes can re-initiate translation on the same mRNA. This process, referred to as re-initiation, controls the translation of a large fraction of mammalian cellular mRNAs, many of which are important in cancer. Key ribosomal binding proteins involved in re-initiation are the eukaryotic translation initiation factor 2D (eIF2D) or the homologous complex of MCT-1/DENR. We determined the structures of these factors bound to the human 40S ribosomal subunit in complex with initiator tRNA positioned on an mRNA start codon in the P-site using a combination of cryoelectron microscopy and X-ray crystallography. The structures, supported by biochemical experiments, reveal how eIF2D emulates the function of several canonical translation initiation factors by using three independent, flexibly connected RNA binding domains to simultaneously monitor codon-anticodon interactions in the ribosomal P-site and position the initiator tRNA.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Fator de Iniciação 2 em Eucariotos/metabolismo
Fatores de Iniciação em Eucariotos/metabolismo
Proteínas Oncogênicas/metabolismo
RNA Mensageiro/metabolismo
RNA de Transferência/metabolismo
Subunidades Ribossômicas Menores de Eucariotos/metabolismo
Sítio de Iniciação de Transcrição
Iniciação da Transcrição Genética
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteínas de Ciclo Celular/química
Proteínas de Ciclo Celular/genética
Microscopia Crioeletrônica
Cristalografia por Raios X
Fator de Iniciação 2 em Eucariotos/química
Fator de Iniciação 2 em Eucariotos/genética
Fatores de Iniciação em Eucariotos/química
Fatores de Iniciação em Eucariotos/genética
Células HEK293
Seres Humanos
Simulação de Acoplamento Molecular
Complexos Multiproteicos
Mutação
Conformação de Ácido Nucleico
Proteínas Oncogênicas/química
Proteínas Oncogênicas/genética
Ligação Proteica
Conformação Proteica
RNA Mensageiro/química
RNA Mensageiro/genética
RNA de Transferência/química
RNA de Transferência/genética
Subunidades Ribossômicas Menores de Eucariotos/química
Subunidades Ribossômicas Menores de Eucariotos/genética
Relação Estrutura-Atividade
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (DENR protein, human); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factors); 0 (MCTS1 protein, human); 0 (Multiprotein Complexes); 0 (Oncogene Proteins); 0 (RNA, Messenger); 0 (eIF2D protein, human); 9014-25-9 (RNA, Transfer)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE



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