title: Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling.
abstract: Many of the proposed physiological functions of alpha-synuclein, a protein involved in the pathogenesis of Parkinson's disease, are related to its ability to interact with phospholipids. To better understand the conformational changes that occur upon membrane binding of monomeric alpha-synuclein, we performed EPR analysis of 47 singly labeled alpha-synuclein derivatives. We show that membrane interaction is mediated by major conformational changes within seven N-terminal 11-aa repeats, which reorganize from a highly dynamic structure into an elongated helical structure devoid of significant tertiary packing. Furthermore, we find that analogous positions from different repeats are in equivalent locations with respect to membrane proximity. These and other findings suggest a curved membrane-dependent alpha-helical structure, wherein each 11-aa repeat takes up three helical turns. Similar helical structures could also apply to apolipoproteins and other lipid-interacting proteins with related 11-aa repeats.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Jao
authors.forename: Ani
authors.initials: A
authors.lastname: Der-Sarkissian
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D017433:Protein Structure, Secondary; D013113:Spin Labels; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D013113:Spin Labels; D051843:Synucleins; D051844:alpha-Synuclein; D003545:Cysteine