title: Interaction of α-synuclein with vesicles that mimic mitochondrial membranes.
abstract: α-Synuclein, an intrinsically-disordered protein associated with Parkinson's disease, interacts with mitochondria, but the details of this interaction are unknown. We probed the interaction of α-synuclein and its A30P variant with lipid vesicles by using fluorescence anisotropy and (19)F nuclear magnetic resonance. Both proteins interact strongly with large unilamellar vesicles whose composition is similar to that of the inner mitochondrial membrane, which contains cardiolipin. However, the proteins have no affinity for vesicles mimicking the outer mitochondrial membrane, which lacks cardiolipin. The (19)F data show that the interaction involves α-synuclein's N-terminal region. These data indicate that the middle of the N-terminal region, which contains the KAKEGVVAAAE repeats, is involved in binding, probably via electrostatic interactions between the lysines and cardiolipin. We also found that the strength of α-synuclein binding depends on the nature of the cardiolipin acyl side chains. Eliminating one double bond increases affinity, while complete saturation dramatically decreases affinity. Increasing the temperature increases the binding of wild-type, but not the A30P variant. The data are interpreted in terms of the properties of the protein, cardiolipin demixing within the vesicles upon binding of α-synuclein, and packing density. The results advance our understanding of α-synuclein's interaction with mitochondrial membranes.
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Imola G
authors.initials: IG
authors.lastname: Zigoneanu
authors.forename: Yoo Jeong
authors.initials: YJ
authors.lastname: Yang
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Krois
authors.forename: Emdadul
authors.initials: E
authors.lastname: Haque
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Pielak
mesh_terms: D002308:Cardiolipins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008567:Membranes, Artificial; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D008567:Membranes, Artificial; D051844:alpha-Synuclein