title: A stable lipid-induced aggregate of alpha-synuclein.
abstract: 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).
authors.affiliation: Department of Molecular Physics, Leiden University, P.O. Box 9504, 2300 RA Leiden, The Netherlands.
authors.forename: Malte
authors.initials: M
authors.lastname: Drescher
authors.forename: Bart D
authors.initials: BD
authors.lastname: van Rooijen
authors.forename: Gertjan
authors.initials: G
authors.lastname: Veldhuis
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.forename: Martina
authors.initials: M
authors.lastname: Huber
mesh_terms: D019281:Dimerization; D008055:Lipids / Q000737:chemistry*; D008958:Models, Molecular; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
chemical_list: D008055:Lipids; D051844:alpha-Synuclein