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[PMID]:27325740
[Au] Autor:Kozel C; Thompson B; Hustak S; Moore C; Nakashima A; Singh CR; Reid M; Cox C; Papadopoulos E; Luna RE; Anderson A; Tagami H; Hiraishi H; Slone EA; Yoshino KI; Asano M; Gillaspie S; Nietfeld J; Perchellet JP; Rothenburg S; Masai H; Wagner G; Beeser A; Kikkawa U; Fleming SD; Asano K
[Ad] Endereço:Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
[Ti] Título:Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.
[So] Source:Nucleic Acids Res;44(18):8704-8713, 2016 Oct 14.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/metabolismo
Proteínas de Ligação a DNA/metabolismo
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/metabolismo
Iniciação Traducional da Cadeia Peptídica
[Mh] Termos MeSH secundário: Animais
Carcinogênese/patologia
Linhagem Celular Tumoral
Drosophila melanogaster/metabolismo
Fator de Iniciação 3 em Eucariotos
Fibrossarcoma/patologia
Técnicas de Silenciamento de Genes
Células HEK293
Células HeLa
Seres Humanos
Masculino
Espectrometria de Massas
Camundongos Nus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BZW2 protein, human); 0 (DNA-Binding Proteins); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-3); 0 (Eukaryotic Initiation Factor-5); 145891-90-3 (Activating Transcription Factor 4)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160622
[St] Status:MEDLINE


  2 / 100 MEDLINE  
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[PMID]:25417541
[Au] Autor:Bavli-Kertselli I; Melamed D; Bar-Ziv L; Volf H; Arava Y
[Ad] Endereço:Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel.
[Ti] Título:Overexpression of eukaryotic initiation factor 5 rescues the translational defect of tpk1w in a manner that necessitates a novel phosphorylation site.
[So] Source:FEBS J;282(3):504-20, 2015 Feb.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cells respond to changes in their environment through mechanisms that often necessitate reprogramming of the translation machinery. The fastest and strongest of all tested responses is the translation inhibition observed following abrupt depletion of glucose from the media of yeast cells. The speed of the response suggests a post-translational modification of a key component of the translation machinery. This translation factor is as yet unknown. A cAMP-dependent protein kinase mutant yeast strain (tpk1(w)) that does not respond properly to glucose depletion and maintains translation was described previously. We hypothesized that the inability of tpk1(w) to arrest translation results from abnormal expression of key translation mediators. Genome-wide analysis of steady-state mRNA levels in tpk1(w) revealed underexpression of several candidates. Elevating the cellular levels of eukaryotic initiation factor (eIF) 5 by overexpression rescued the translational defect of tpk1(w). Restoring ribosomal dissociation by eIF5 necessitated an active GAP domain and multiple regions throughout this protein. Phosphoproteomics analysis of wild-type cells overexpressing eIF5 revealed increased phosphorylation in a novel site (Thr191) upon glucose depletion. Mutating this residue and introducing it into tpk1(w) abolished the ability of eIF5 to rescue the translational defect. Intriguingly, introducing this mutation into the wild-type strain did not hamper its translational response. We further show that Thr191 is phosphorylated in vitro by Casein Kinase II (CKII), and yeast cells with a mutated CKII have a reduced response to glucose depletion. These results implicate phosphorylation of eIF5 at Thr191 by CKII as one of the pathways for regulating translation upon glucose depletion.
[Mh] Termos MeSH primário: Fator de Iniciação 5 em Eucariotos/metabolismo
Polirribossomos/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Fator de Iniciação 5 em Eucariotos/genética
Fosfoproteínas/metabolismo
Fosforilação
Proteômica
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-5); 0 (Phosphoproteins); 0 (Saccharomyces cerevisiae Proteins)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:150128
[Lr] Data última revisão:
150128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141125
[St] Status:MEDLINE
[do] DOI:10.1111/febs.13158


  3 / 100 MEDLINE  
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[PMID]:25486352
[Au] Autor:Jennings MD; Pavitt GD
[Ad] Endereço:a Faculty of Life Sciences ; The University of Manchester ; Manchester , UK.
[Ti] Título:A new function and complexity for protein translation initiation factor eIF2B.
[So] Source:Cell Cycle;13(17):2660-5, 2014.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:eIF2B is a multisubunit protein that is critical for protein synthesis initiation and its control. It is a guanine nucleotide exchange factor (GEF) for its GTP-binding protein partner eIF2. eIF2 binds initiator tRNA to ribosomes and promotes mRNA AUG codon recognition. eIF2B is critical for regulation of protein synthesis via a conserved mechanism of phosphorylation of eIF2, which converts eIF2 from a substrate to an inhibitor of eIF2B GEF. In addition, inherited mutations affecting eIF2B subunits cause the fatal disorder leukoencephalopathy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central nervous system Hypomyelination (CACH). Here we review findings which reveal that eIF2B is a decameric protein and also define a new function for the eIF2B. Our results demonstrate that the eIF2Bγ subunit is required for eIF2B to gain access to eIF2•GDP. Specifically it displaces a third translation factor eIF5 (a dual function GAP and GDI) from eIF2•GDP/eIF5 complexes. Thus eIF2B is a GDI displacement factor (or GDF) in addition to its role as a GEF, prompting the redrawing of the eIF2 cycling pathway to incorporate the new steps. In structural studies using mass spectrometry and cross-linking it is shown that eIF2B is a dimer of pentamers and so is twice as large as previously thought. A binding site for GTP on eIF2B was also found, raising further questions concerning the mechanism of nucleotide exchange. The implications of these findings for eIF2B function and for VWM/CACH disease are discussed.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/metabolismo
Iniciação Traducional da Cadeia Peptídica
[Mh] Termos MeSH secundário: Animais
Fator de Iniciação 5 em Eucariotos/metabolismo
Guanosina Difosfato/metabolismo
Seres Humanos
Modelos Biológicos
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B); 0 (Eukaryotic Initiation Factor-5); 146-91-8 (Guanosine Diphosphate)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141209
[St] Status:MEDLINE
[do] DOI:10.4161/15384101.2014.948797


  4 / 100 MEDLINE  
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[PMID]:25260592
[Au] Autor:Pisareva VP; Pisarev AV
[Ad] Endereço:Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA andrey.pisarev@downstate.edu.
[Ti] Título:eIF5 and eIF5B together stimulate 48S initiation complex formation during ribosomal scanning.
[So] Source:Nucleic Acids Res;42(19):12052-69, 2014 Oct 29.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:48S initiation complex (48S IC) formation is the first stage in the eukaryotic translation process. According to the canonical mechanism, 40S ribosomal subunit binds to the 5'-end of messenger RNA (mRNA) and scans its 5'-untranslated region (5'-UTR) to the initiation codon where it forms the 48S IC. Entire process is mediated by initiation factors. Here we show that eIF5 and eIF5B together stimulate 48S IC formation influencing initiation codon selection during ribosomal scanning. Initiation on non-optimal start codons--following structured 5'-UTRs, in bad AUG context, within few nucleotides from 5'-end of mRNA and CUG start codon--is the most affected. eIF5-induced hydrolysis of eIF2-bound GTP is essential for stimulation. GTP hydrolysis increases the probability that scanning ribosomal complexes will recognize and arrest scanning at a non-optimal initiation codon. Such 48S ICs are less stable owing to dissociation of eIF2*GDP from initiator tRNA, and eIF5B is then required to stabilize the initiator tRNA in the P site of 40S subunit. Alternative model that eIF5 and eIF5B cause 43S pre-initiation complex rearrangement favoring more efficient initiation codon recognition during ribosomal scanning is equally possible. Mutational analysis of eIF1A and eIF5B revealed distinct functions of eIF5B in 48S IC formation and subunit joining.
[Mh] Termos MeSH primário: Fator de Iniciação 5 em Eucariotos/metabolismo
Fatores de Iniciação em Eucariotos/metabolismo
Iniciação Traducional da Cadeia Peptídica
Ribossomos/metabolismo
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas
Códon de Iniciação
Fator de Iniciação 1 em Eucariotos/metabolismo
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/genética
Fatores de Iniciação em Eucariotos/genética
Guanosina Trifosfato/metabolismo
Mutação
RNA de Transferência de Metionina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-1); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-5); 0 (Eukaryotic Initiation Factors); 0 (RNA, Transfer, Met); 0 (eukaryotic initiation factor-5B); 0 (eukaryotic peptide initiation factor-1A); 86-01-1 (Guanosine Triphosphate)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140928
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gku877


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[PMID]:25147208
[Au] Autor:Hiraishi H; Oatman J; Haller SL; Blunk L; McGivern B; Morris J; Papadopoulos E; Gutierrez W; Gordon M; Bokhari W; Ikeda Y; Miles D; Fellers J; Asano M; Wagner G; Tazi L; Rothenburg S; Brown SJ; Asano K
[Ad] Endereço:Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
[Ti] Título:Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression.
[So] Source:Nucleic Acids Res;42(16):10321-30, 2014.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Translational control of transcription factor ATF4 through paired upstream ORFs (uORFs) plays an important role in eukaryotic gene regulation. While it is typically induced by phosphorylation of eIF2α, ATF4 translation can be also induced by expression of a translational inhibitor protein, eIF5-mimic protein 1 (5MP1, also known as BZW2) in mammals. Here we show that the 5MP gene is maintained in eukaryotes under strong purifying selection, but is uniquely missing in two major phyla, nematoda and ascomycota. The common function of 5MP from protozoa, plants, fungi and insects is to control translation by inhibiting eIF2. The affinity of human 5MP1 to eIF2ß was measured as being equivalent to the published value of human eIF5 to eIF2ß, in agreement with effective competition of 5MP with eIF5 for the main substrate, eIF2. In the red flour beetle, Tribolium castaneum, RNA interference studies indicate that 5MP facilitates expression of GADD34, a downstream target of ATF4. Furthermore, both 5MP and ATF4 are essential for larval development. Finally, 5MP and the paired uORFs allowing ATF4 control are conserved in the entire metazoa except nematoda. Based on these findings, we discuss the phylogenetic and functional linkage between ATF4 regulation and 5MP expression in this group of eukaryotes.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/genética
Proteínas de Ligação a DNA/metabolismo
Regulação da Expressão Gênica
Biossíntese de Proteínas
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/biossíntese
Animais
Proteínas de Ligação a DNA/classificação
Proteínas de Ligação a DNA/fisiologia
Fator de Iniciação 2 em Eucariotos/antagonistas & inibidores
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/metabolismo
Seres Humanos
Proteínas de Insetos/metabolismo
Fases de Leitura Aberta
Filogenia
Proteína Fosfatase 1/metabolismo
Saccharomyces cerevisiae/metabolismo
Tribolium/enzimologia
Tribolium/genética
Tribolium/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BZW2 protein, human); 0 (DNA-Binding Proteins); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-5); 0 (Insect Proteins); 145891-90-3 (Activating Transcription Factor 4); EC 3.1.3.16 (Protein Phosphatase 1)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140823
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gku670


  6 / 100 MEDLINE  
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[PMID]:25114053
[Au] Autor:Saini AK; Nanda JS; Martin-Marcos P; Dong J; Zhang F; Bhardwaj M; Lorsch JR; Hinnebusch AG
[Ad] Endereço:Laboratory of Gene Regulation and Development, Eunice K. Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA Laboratory on the Mechanism and Regulation of Protein Synthesis, Eunice K. Shriver National Institute of Child Healt
[Ti] Título:Eukaryotic translation initiation factor eIF5 promotes the accuracy of start codon recognition by regulating Pi release and conformational transitions of the preinitiation complex.
[So] Source:Nucleic Acids Res;42(15):9623-40, 2014 Sep.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:eIF5 is the GTPase activating protein (GAP) for the eIF2 · GTP · Met-tRNAi (Met) ternary complex with a critical role in initiation codon selection. Previous work suggested that the eIF5 mutation G31R/SUI5 elevates initiation at UUG codons by increasing GAP function. Subsequent work implicated eIF5 in rearrangement of the preinitiation complex (PIC) from an open, scanning conformation to a closed state at AUG codons, from which Pi is released from eIF2 · GDP · Pi. To identify eIF5 functions crucial for accurate initiation, we investigated the consequences of G31R on GTP hydrolysis and Pi release, and the effects of intragenic G31R suppressors on these reactions, and on the partitioning of PICs between open and closed states. eIF5-G31R altered regulation of Pi release, accelerating it at UUG while decreasing it at AUG codons, consistent with its ability to stabilize the closed complex at UUG. Suppressor G62S mitigates both defects of G31R, accounting for its efficient suppression of UUG initiation in G31R,G62S cells; however suppressor M18V impairs GTP hydrolysis with little effect on PIC conformation. The strong defect in GTP hydrolysis conferred by M18V likely explains its broad suppression of Sui(-) mutations in numerous factors. We conclude that both of eIF5's functions, regulating Pi release and stabilizing the closed PIC conformation, contribute to stringent AUG selection in vivo.
[Mh] Termos MeSH primário: Códon de Iniciação
Fator de Iniciação 5 em Eucariotos/metabolismo
Guanosina Trifosfato/metabolismo
Iniciação Traducional da Cadeia Peptídica
[Mh] Termos MeSH secundário: Fator de Iniciação 1 em Eucariotos/genética
Fator de Iniciação 2 em Eucariotos/genética
Fator de Iniciação 5 em Eucariotos/química
Fator de Iniciação 5 em Eucariotos/genética
Mutação
Fosfatos/metabolismo
Supressão Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-1); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-5); 0 (Phosphates); 0 (eukaryotic peptide initiation factor-1A); 86-01-1 (Guanosine Triphosphate)
[Em] Mês de entrada:1412
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140813
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gku653


  7 / 100 MEDLINE  
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[PMID]:24499181
[Au] Autor:Hinnebusch AG
[Ad] Endereço:Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; email: ahinnebusch@nih.gov.
[Ti] Título:The scanning mechanism of eukaryotic translation initiation.
[So] Source:Annu Rev Biochem;83:779-812, 2014.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In eukaryotes, the translation initiation codon is generally identified by the scanning mechanism, wherein every triplet in the messenger RNA leader is inspected for complementarity to the anticodon of methionyl initiator transfer RNA (Met-tRNAi). Binding of Met-tRNAi to the small (40S) ribosomal subunit, in a ternary complex (TC) with eIF2-GTP, is stimulated by eukaryotic initiation factor 1 (eIF1), eIF1A, eIF3, and eIF5, and the resulting preinitiation complex (PIC) joins the 5' end of mRNA preactivated by eIF4F and poly(A)-binding protein. RNA helicases remove secondary structures that impede ribosome attachment and subsequent scanning. Hydrolysis of eIF2-bound GTP is stimulated by eIF5 in the scanning PIC, but completion of the reaction is impeded at non-AUG triplets. Although eIF1 and eIF1A promote scanning, eIF1 and possibly the C-terminal tail of eIF1A must be displaced from the P decoding site to permit base-pairing between Met-tRNAi and the AUG codon, as well as to allow subsequent phosphate release from eIF2-GDP. A second GTPase, eIF5B, catalyzes the joining of the 60S subunit to produce an 80S initiation complex that is competent for elongation.
[Mh] Termos MeSH primário: Fator de Iniciação 1 em Eucariotos/metabolismo
Fator de Iniciação 3 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/metabolismo
RNA de Transferência de Metionina/genética
Subunidades Ribossômicas Menores de Eucariotos/química
[Mh] Termos MeSH secundário: Animais
Pareamento de Bases
Sítios de Ligação
Códon de Iniciação
Guanosina Trifosfato/química
Seres Humanos
Hidrólise
Metionina/química
Ligação Proteica
RNA Helicases/química
Ribossomos/química
Tetrahymena
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-1); 0 (Eukaryotic Initiation Factor-3); 0 (Eukaryotic Initiation Factor-5); 0 (RNA, Transfer, Met); 86-01-1 (Guanosine Triphosphate); AE28F7PNPL (Methionine); EC 3.6.4.13 (RNA Helicases)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:140609
[Lr] Data última revisão:
140609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140207
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-060713-035802


  8 / 100 MEDLINE  
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[PMID]:24335188
[Au] Autor:Martin-Marcos P; Nanda JS; Luna RE; Zhang F; Saini AK; Cherkasova VA; Wagner G; Lorsch JR; Hinnebusch AG
[Ti] Título:Enhanced eIF1 binding to the 40S ribosome impedes conformational rearrangements of the preinitiation complex and elevates initiation accuracy.
[So] Source:RNA;20(2):150-67, 2014 Feb.
[Is] ISSN:1469-9001
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the current model of translation initiation by the scanning mechanism, eIF1 promotes an open conformation of the 40S subunit competent for rapidly loading the eIF2·GTP·Met-tRNAi ternary complex (TC) in a metastable conformation (POUT) capable of sampling triplets entering the P site while blocking accommodation of Met-tRNAi in the PIN state and preventing completion of GTP hydrolysis (Pi release) by the TC. All of these functions should be reversed by eIF1 dissociation from the preinitiation complex (PIC) on AUG recognition. We tested this model by selecting eIF1 Ssu(-) mutations that suppress the elevated UUG initiation and reduced rate of TC loading in vivo conferred by an eIF1 (Sui(-)) substitution that eliminates a direct contact of eIF1 with the 40S subunit. Importantly, several Ssu(-) substitutions increase eIF1 affinity for 40S subunits in vitro, and the strongest-binding variant (D61G), predicted to eliminate ionic repulsion with 18S rRNA, both reduces the rate of eIF1 dissociation and destabilizes the PIN state of TC binding in reconstituted PICs harboring Sui(-) variants of eIF5 or eIF2. These findings establish that eIF1 dissociation from the 40S subunit is required for the PIN mode of TC binding and AUG recognition and that increasing eIF1 affinity for the 40S subunit increases initiation accuracy in vivo. Our results further demonstrate that the GTPase-activating protein eIF5 and ß-subunit of eIF2 promote accuracy by controlling eIF1 dissociation and the stability of TC binding to the PIC, beyond their roles in regulating GTP hydrolysis by eIF2.
[Mh] Termos MeSH primário: Fator de Iniciação 1 em Eucariotos/metabolismo
Subunidades Ribossômicas Menores de Eucariotos/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
Iniciação da Transcrição Genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Códon de Iniciação
Fator de Iniciação 1 em Eucariotos/química
Fator de Iniciação 1 em Eucariotos/genética
Fator de Iniciação 2 em Eucariotos/genética
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/química
Fator de Iniciação 5 em Eucariotos/metabolismo
Técnicas de Inativação de Genes
Guanosina Trifosfato/química
Guanosina Trifosfato/metabolismo
Hidrólise
Dados de Sequência Molecular
Mutação de Sentido Incorreto
Ligação Proteica
Estabilidade Proteica
Subunidades Ribossômicas Menores de Eucariotos/química
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/química
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-1); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-5); 0 (SUI1 protein, S cerevisiae); 0 (SUI3 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 86-01-1 (Guanosine Triphosphate)
[Em] Mês de entrada:1403
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131217
[St] Status:MEDLINE
[do] DOI:10.1261/rna.042069.113


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[PMID]:23293029
[Au] Autor:Nanda JS; Saini AK; Muñoz AM; Hinnebusch AG; Lorsch JR
[Ad] Endereço:Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
[Ti] Título:Coordinated movements of eukaryotic translation initiation factors eIF1, eIF1A, and eIF5 trigger phosphate release from eIF2 in response to start codon recognition by the ribosomal preinitiation complex.
[So] Source:J Biol Chem;288(8):5316-29, 2013 Feb 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Accurate recognition of the start codon in an mRNA by the eukaryotic translation preinitiation complex (PIC) is essential for proper gene expression. The process is mediated by eukaryotic translation initiation factors (eIFs) in conjunction with the 40 S ribosomal subunit and (initiator) tRNA(i). Here, we provide evidence that the C-terminal tail (CTT) of eIF1A, which we previously implicated in start codon recognition, moves closer to the N-terminal domain of eIF5 when the PIC encounters an AUG codon. Importantly, this movement is coupled to dissociation of eIF1 from the PIC, a critical event in start codon recognition, and is dependent on the scanning enhancer elements in the eIF1A CTT. The data further indicate that eIF1 dissociation must be accompanied by the movement of the eIF1A CTT toward eIF5 in order to trigger release of phosphate from eIF2, which converts the latter to its GDP-bound state. Our results also suggest that release of eIF1 from the PIC and movement of the CTT of eIF1A are triggered by the same event, most likely accommodation of tRNA(i) in the P site of the 40 S subunit driven by base pairing between the start codon in the mRNA and the anticodon in tRNA(i). Finally, we show that the C-terminal domain of eIF5 is responsible for the factor's activity in antagonizing eIF1 binding to the PIC. Together, our data provide a more complete picture of the chain of molecular events that is triggered when the scanning PIC encounters an AUG start codon in the mRNA.
[Mh] Termos MeSH primário: Códon de Iniciação
Fator de Iniciação 1 em Eucariotos/metabolismo
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 5 em Eucariotos/metabolismo
Ribossomos/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cisteína/genética
Fluoresceína/farmacologia
Transferência Ressonante de Energia de Fluorescência/métodos
Regulação da Expressão Gênica
Seres Humanos
Cinética
Mutação
Ácidos Nucleicos/química
Biossíntese de Proteínas
Estrutura Terciária de Proteína
Proteínas/química
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (Codon, Initiator); 0 (Eukaryotic Initiation Factor-1); 0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-5); 0 (Nucleic Acids); 0 (Proteins); 0 (RNA, Messenger); 0 (eukaryotic peptide initiation factor-1A); K848JZ4886 (Cysteine); TPY09G7XIR (Fluorescein)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130108
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M112.440693


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[PMID]:23143239
[Au] Autor:Zhao H; Wang H; Liu H; Teng M; Li X
[Ad] Endereço:School of Life Sciences, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, People's Republic of China.
[Ti] Título:Crystallization and preliminary crystallographic studies of the W2 domain of Drosophila melanogaster eukaryotic translation initiation factor 5C domain-containing protein.
[So] Source:Acta Crystallogr Sect F Struct Biol Cryst Commun;68(Pt 11):1315-7, 2012 Nov 01.
[Is] ISSN:1744-3091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Drosophila melanogaster eukaryotic translation initiation factor 5C domain-containing protein (ECP) is composed of two independently folded domains which belong to the basic leucine-zipper and W2 domain-containing protein (BZW) family. Based on the sequence similarity between the C-terminal W2 domain of ECP and some eukaryotic translation initiation factors (such as eIF2Bℇ, eIF4γ, eIF5 etc.), ECP has been speculated to participate in the translation initiation process. Structural information on the C-terminal W2 domain of ECP would be helpful in understanding the specific cellular function of this protein. Here, the W2 domain of ECP was expressed and crystallized. Crystals grown by the hanging-drop vapour-diffusion method diffracted to 2.70 Šresolution and belonged to space group I4, with unit-cell parameters a=b=81.05, c=57.44 Å. The Matthews coefficient suggested that there was one molecule per asymmetric unit in the crystal.
[Mh] Termos MeSH primário: Proteínas de Drosophila/química
Drosophila melanogaster/química
Fator de Iniciação 5 em Eucariotos/química
[Mh] Termos MeSH secundário: Animais
Cristalização
Cristalografia por Raios X
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Eukaryotic Initiation Factor-5)
[Em] Mês de entrada:1305
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121113
[St] Status:MEDLINE
[do] DOI:10.1107/S1744309112036512



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