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  1. Article ; Online: DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones

    Meital Abayev-Avraham / Yehuda Salzberg / Dar Gliksberg / Meital Oren-Suissa / Rina Rosenzweig

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 16

    Abstract: Abstract Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a ... ...

    Abstract Abstract Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.
    Keywords Science ; Q
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Sexually dimorphic architecture and function of a mechanosensory circuit in C. elegans

    Hagar Setty / Yehuda Salzberg / Shadi Karimi / Elisheva Berent-Barzel / Michael Krieg / Meital Oren-Suissa

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 15

    Abstract: Mechanosensation is crucial for survival in many organisms. Here, authors reveal that the two sexes of C. elegans show dramatic differences in circuit architecture, neuronal activity and molecular components to drive mechanosensory behavior. ...

    Abstract Mechanosensation is crucial for survival in many organisms. Here, authors reveal that the two sexes of C. elegans show dramatic differences in circuit architecture, neuronal activity and molecular components to drive mechanosensory behavior.
    Keywords Science ; Q
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  3. Article ; Online: Ubiquitin-dependent regulation of a conserved DMRT protein controls sexually dimorphic synaptic connectivity and behavior

    Emily A Bayer / Rebecca C Stecky / Lauren Neal / Phinikoula S Katsamba / Goran Ahlsen / Vishnu Balaji / Thorsten Hoppe / Lawrence Shapiro / Meital Oren-Suissa / Oliver Hobert

    eLife, Vol

    2020  Volume 9

    Abstract: Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system ...

    Abstract Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but previously uncharacterized Doublesex/Mab-3 related transcription factor (DMRT), dmd-4, is expressed in two classes of sex-shared phasmid neurons specifically in hermaphrodites but not in males. We find dmd-4 to promote hermaphrodite-specific synaptic connectivity and neuronal function of phasmid sensory neurons. Sex-specificity of DMD-4 function is conferred by a novel mode of posttranslational regulation that involves sex-specific protein stabilization through ubiquitin binding to a phylogenetically conserved but previously unstudied protein domain, the DMA domain. A human DMRT homolog of DMD-4 is controlled in a similar manner, indicating that our findings may have implications for the control of sexual differentiation in other animals as well.
    Keywords C. elegans ; sexual dimorphism ; transcription factor ; synapse pruning ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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