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  1. Article ; Online: Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein.

    Melissa Birol / Slawomir P Wojcik / Andrew D Miranker / Elizabeth Rhoades

    PLoS Biology, Vol 17, Iss 6, p e

    2019  Volume 3000318

    Abstract: Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively ... ...

    Abstract Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively unexplored. Here, we report that αSacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αSun). We identify complex N-linked glycans as binding partners for αSacetyl and demonstrate that cellular internalization of αSacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αSacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl because αSun does not demonstrate sensitivity for N-linked glycans in any of our assays. Our study identifies extracellular N-linked glycans-and the glycoprotein neurexin 1β specifically-as key modulators of neuronal uptake of αSacetyl, drawing attention to the potential therapeutic value of αSacetyl-glycan interactions.
    Keywords Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

    Melissa Birol / Sunil Kumar / Elizabeth Rhoades / Andrew D. Miranker

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: Toxic gain-of-function by islet amyloid polypeptide (IAPP) is thought to be mediated by membrane poration. Here the authors develop diluted-FRET to show that changes in pore structure correlate with onset of toxicity inside insulin secreting cells. ...

    Abstract Toxic gain-of-function by islet amyloid polypeptide (IAPP) is thought to be mediated by membrane poration. Here the authors develop diluted-FRET to show that changes in pore structure correlate with onset of toxicity inside insulin secreting cells.
    Keywords Science ; Q
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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  3. Article ; Online: Foldamer-mediated manipulation of a pre-amyloid toxin

    Sunil Kumar / Melissa Birol / Diana E. Schlamadinger / Slawomir P. Wojcik / Elizabeth Rhoades / Andrew D. Miranker

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 11

    Abstract: Intrinsically disordered proteins that form amyloid fibrils are hard to target with traditional therapeutic approaches. Here, the authors report on an oligoquinoline derivative that binds the human islet amyloid polypeptide, stabilising an alpha-helical ... ...

    Abstract Intrinsically disordered proteins that form amyloid fibrils are hard to target with traditional therapeutic approaches. Here, the authors report on an oligoquinoline derivative that binds the human islet amyloid polypeptide, stabilising an alpha-helical structure that reduces its cellular toxicity.
    Keywords Science ; Q
    Language English
    Publishing date 2016-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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  4. Article ; Online: Structural and biochemical characterization of the Cop9 signalosome CSN5/CSN6 heterodimer.

    Melissa Birol / Radoslav Ivanov Enchev / André Padilla / Florian Stengel / Ruedi Aebersold / Stéphane Betzi / Yinshan Yang / François Hoh / Matthias Peter / Christian Dumas / Aude Echalier

    PLoS ONE, Vol 9, Iss 8, p e

    2014  Volume 105688

    Abstract: The Cop9 signalosome complex (CSN) regulates the functional cycle of the major E3 ubiquitin ligase family, the cullin RING E3 ubiquitin ligases (CRLs). Activated CRLs are covalently modified by the ubiquitin-like protein Nedd8 (neural precursor cell ... ...

    Abstract The Cop9 signalosome complex (CSN) regulates the functional cycle of the major E3 ubiquitin ligase family, the cullin RING E3 ubiquitin ligases (CRLs). Activated CRLs are covalently modified by the ubiquitin-like protein Nedd8 (neural precursor cell expressed developmentally down-regulated protein 8). CSN serves an essential role in myriad cellular processes by reversing this modification through the isopeptidase activity of its CSN5 subunit. CSN5 alone is inactive due to an auto-inhibited conformation of its catalytic domain. Here we report the molecular basis of CSN5 catalytic domain activation and unravel a molecular hierarchy in CSN deneddylation activity. The association of CSN5 and CSN6 MPN (for Mpr1/Pad1 N-terminal) domains activates its isopeptidase activity. The CSN5/CSN6 module, however, is inefficient in CRL deneddylation, indicating a requirement of further elements in this reaction such as other CSN subunits. A hybrid molecular model of CSN5/CSN6 provides a structural framework to explain these functional observations. Docking this model into a published CSN electron density map and using distance constraints obtained from cross-linking coupled to mass-spectrometry, we find that the C-termini of the CSN subunits could form a helical bundle in the centre of the structure. They likely play a key scaffolding role in the spatial organization of CSN and precise positioning of the dimeric MPN catalytic core.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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