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  1. Article ; Online: 4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation.

    Igreja, Cátia / Peter, Daniel / Weiler, Catrin / Izaurralde, Elisa

    Nature communications

    2014  Volume 5, Page(s) 4790

    Abstract: eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit ... ...

    Abstract eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit translation initiation. Some 4E-BPs contain non-canonical 4E-BMs (NC 4E-BMs), but the contribution of these motifs to the repressive mechanism--and whether these motifs are present in all 4E-BPs--remains unknown. Here, we show that the three annotated Drosophila melanogaster 4E-BPs contain NC 4E-BMs. These motifs bind to a lateral surface on eIF4E that is not used by eIF4G. This distinct molecular recognition mode is exploited by 4E-BPs to dock onto eIF4E-eIF4G complexes and effectively displace eIF4G from the dorsal surface of eIF4E. Our data reveal a hitherto unrecognized role for the NC4E-BMs and the lateral surface of eIF4E in 4E-BP-mediated translational repression, and suggest that bipartite 4E-BP mimics might represent efficient therapeutic tools to dampen translation during oncogenic transformation.
    MeSH term(s) Amino Acid Motifs ; Animals ; Binding Sites ; Binding, Competitive ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Eukaryotic Initiation Factor-4E/chemistry ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/chemistry ; Eukaryotic Initiation Factor-4G/genetics ; Eukaryotic Initiation Factor-4G/metabolism ; Gene Expression Regulation ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
    Chemical Substances Drosophila Proteins ; Eukaryotic Initiation Factor-4E ; Eukaryotic Initiation Factor-4G ; Recombinant Proteins ; cup protein, Drosophila
    Language English
    Publishing date 2014-09-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/ncomms5790
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Molecular architecture of 4E-BP translational inhibitors bound to eIF4E.

    Peter, Daniel / Igreja, Cátia / Weber, Ramona / Wohlbold, Lara / Weiler, Catrin / Ebertsch, Linda / Weichenrieder, Oliver / Izaurralde, Elisa

    Molecular cell

    2015  Volume 57, Issue 6, Page(s) 1074–1087

    Abstract: The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical ... ...

    Abstract The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and fly eIF4E bound to Thor, 4E-T, and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation.
    MeSH term(s) Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Motifs ; Animals ; Binding Sites ; Binding, Competitive ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Crystallography, X-Ray ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Eukaryotic Initiation Factor-4E/chemistry ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/chemistry ; Eukaryotic Initiation Factor-4G/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/chemistry ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Models, Molecular ; Molecular Mimicry ; Peptide Initiation Factors/chemistry ; Peptide Initiation Factors/genetics ; Peptide Initiation Factors/metabolism ; Phosphoproteins/chemistry ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Conformation ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Drosophila Proteins ; EIF4EBP1 protein, human ; EIF4EBP3 protein, human ; Eukaryotic Initiation Factor-4E ; Eukaryotic Initiation Factor-4G ; Intracellular Signaling Peptides and Proteins ; Peptide Initiation Factors ; Phosphoproteins ; Recombinant Proteins ; Thor protein, Drosophila ; eIF4G2 protein, Drosophila
    Language English
    Publishing date 2015-02-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2015.01.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5055: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Nonsense-mediated mRNA decay effectors are essential for zebrafish embryonic development and survival.

    Wittkopp, Nadine / Huntzinger, Eric / Weiler, Catrin / Saulière, Jérôme / Schmidt, Steffen / Sonawane, Mahendra / Izaurralde, Elisa

    Molecular and cellular biology

    2009  Volume 29, Issue 13, Page(s) 3517–3528

    Abstract: The nonsense-mediated mRNA decay (NMD) pathway promotes rapid degradation of mRNAs containing premature translation termination codons (PTCs or nonsense codons), preventing accumulation of potentially detrimental truncated proteins. In metazoa, seven ... ...

    Abstract The nonsense-mediated mRNA decay (NMD) pathway promotes rapid degradation of mRNAs containing premature translation termination codons (PTCs or nonsense codons), preventing accumulation of potentially detrimental truncated proteins. In metazoa, seven genes (upf1, upf2, upf3, smg1, smg5, smg6, and smg7) have been identified as essential for NMD; here we show that the zebrafish genome encodes orthologs of upf1, upf2, smg1, and smg5 to smg7 and two upf3 paralogs. We also show that Upf1 is required for degradation of PTC-containing mRNAs in zebrafish embryos. Moreover, its depletion has a severe impact on embryonic development, early patterning, and viability. Similar phenotypes are observed in Upf2-, Smg5-, or Smg6-depleted embryos, suggesting that zebrafish embryogenesis requires an active NMD pathway. Using cultured cells, we demonstrate that the ability of a PTC to trigger NMD is strongly stimulated by downstream exon-exon boundaries. Thus, as in mammals and plants but in contrast to invertebrates and fungi, NMD is coupled to splicing in zebrafish. Our results together with previous studies show that NMD effectors are essential for vertebrate embryogenesis and suggest that the coupling of splicing and NMD has been maintained in vertebrates but lost in fungi and invertebrates.
    MeSH term(s) Animals ; Cells, Cultured ; Exons ; Humans ; Introns ; Molecular Sequence Data ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/metabolism ; Phenotype ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/physiology ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Oligonucleotides, Antisense ; RNA, Messenger ; Zebrafish Proteins
    Language English
    Publishing date 2009-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00177-09
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1666: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Identification of recessive maternal-effect mutations in the zebrafish using a gynogenesis-based method.

    Pelegri, Francisco / Dekens, Marcus P S / Schulte-Merker, Stefan / Maischein, Hans-Martin / Weiler, Catrin / Nüsslein-Volhard, Christiane

    Developmental dynamics : an official publication of the American Association of Anatomists

    2004  Volume 231, Issue 2, Page(s) 324–335

    Abstract: In animal species, early developmental processes are driven by maternally derived factors. Here, we describe a forward genetics approach to identify recessive mutations in genes encoding such maternal factors in the zebrafish. We used a gynogenesis-based ...

    Abstract In animal species, early developmental processes are driven by maternally derived factors. Here, we describe a forward genetics approach to identify recessive mutations in genes encoding such maternal factors in the zebrafish. We used a gynogenesis-based approach to identify 14 recessive maternal-effect mutations. Homozygosity for these mutations in adult females leads to the inviability of their offspring. Confocal microscopy of embryos labeled with a DNA dye and a membrane marker allowed us to further analyze mutant embryos for defects in nuclear and cellular divisions. The mutations result in a range of defects in early developmental processes, including egg activation, early nuclear events, mitosis, cytokinesis, axial patterning, and gastrulation. Our effort constitutes a systematic attempt to identify maternal-effect genes in a vertebrate species. The sample of mutations that we have identified reflects the diversity of maternally driven functions in early development and underscores the importance of maternal factors in this process.
    MeSH term(s) Animals ; Body Patterning ; Embryo, Nonmammalian/anatomy & histology ; Embryo, Nonmammalian/drug effects ; Embryo, Nonmammalian/physiology ; Female ; Genes, Recessive ; Male ; Morphogenesis ; Mutagens/pharmacology ; Mutation ; Phenotype ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/physiology
    Chemical Substances Mutagens
    Language English
    Publishing date 2004-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.20145
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ub I Zs.60: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 64: Show issues

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