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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour

Author

Listed:
  • Giuliana Fusco

    (University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK)

  • Alfonso De Simone

    (Imperial College London, South Kensington, London SW7 2AZ, UK)

  • Tata Gopinath

    (Molecular Biology and Biophysics, University of Minnesota)

  • Vitaly Vostrikov

    (Molecular Biology and Biophysics, University of Minnesota)

  • Michele Vendruscolo

    (University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK)

  • Christopher M. Dobson

    (University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK)

  • Gianluigi Veglia

    (Molecular Biology and Biophysics, University of Minnesota
    University of Minnesota)

Abstract

α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson’s disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of αS bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study shows three αS regions possessing distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane anchor, an unstructured C-terminal region that is weakly associated with the membrane and a central region acting as a sensor of the lipid properties and determining the affinity of αS membrane binding. Taken together, our data define the nature of the interactions of αS with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.

Suggested Citation

  • Giuliana Fusco & Alfonso De Simone & Tata Gopinath & Vitaly Vostrikov & Michele Vendruscolo & Christopher M. Dobson & Gianluigi Veglia, 2014. "Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour," Nature Communications, Nature, vol. 5(1), pages 1-8, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4827
    DOI: 10.1038/ncomms4827
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    Cited by:

    1. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Steven J. Roeters & Kris Strunge & Kasper B. Pedersen & Thaddeus W. Golbek & Mikkel Bregnhøj & Yuge Zhang & Yin Wang & Mingdong Dong & Janni Nielsen & Daniel E. Otzen & Birgit Schiøtt & Tobias Weidner, 2023. "Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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