A stable lipid-induced aggregate of alpha-synuclein

Malte Drescher, Bart D van Rooijen, Gertjan Veldhuis, Vinod Subramaniam, Martina Huber

    Research output: Contribution to JournalArticleAcademicpeer-review


    The Parkinson's disease-related protein alpha-Synuclein (alphaS) is a 140 residue intrinsically disordered protein. Its membrane-binding properties are thought to be relevant for its physiological or pathologic activity. Here, the interaction of alphaS with POPG [1-Palmitoyl-2-Oleoyl-sn-Glycero-3-(Phosphorac-(1-glycerol))] small unilamellar vesicles (SUVs) is investigated by spin-label EPR using double electron-electron resonance (DEER). Intermolecular distances between four single mutants reveal that well-defined aggregates are formed. The data suggest a coexistence of two dimer structures with main interactions in the helix 2, encompassing residues 50-100. Previously, the horseshoe conformation was detected by intramolecular restraints obtained by DEER on alphaS double mutants (Drescher et al. J. Am. Chem. Soc. 2008, 130, 7796). The present study suggests that interdigitation of two monomers in the aggregate fills the void between the two helices of each of the monomers thus providing a rationale for the horseshoe structure. This aggregate is lipid induced and affects the structure of the POPG SUVs, which become leaky and diminish in size upon contact with alphaS suggesting a possible origin of conflicting results in the recent literature (Jao et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (50), 19666; Georgieva et al. J. Am. Chem. Soc. 2008, 130 (39), 12856; Bortolus et al. J. Am. Chem. Soc. 2008, 130, 6690).

    Original languageEnglish
    Pages (from-to)4080-2
    Number of pages3
    JournalJournal of the American Chemical Society
    Issue number12
    Publication statusPublished - 31 Mar 2010


    • Dimerization
    • Lipids
    • Models, Molecular
    • alpha-Synuclein
    • Journal Article
    • Research Support, Non-U.S. Gov't


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