title: Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations.
abstract: Alpha-synuclein is a presynaptic protein of poorly understood function that is linked to both genetic and sporadic forms of Parkinson's disease. We have proposed that alpha-synuclein may function specifically at synaptic vesicles docked at the plasma membrane, and that the broken-helix state of the protein, comprising two antiparallel membrane-bound helices connected by a nonhelical linker, may target the protein to such docked vesicles by spanning between the vesicle and the plasma membrane. Here, we demonstrate that phosphorylation of alpha-synuclein at tyrosine 39, carried out by c-Abl in vivo, may facilitate interconversion of synuclein from the vesicle-bound extended-helix state to the broken-helix state. Specifically, in the presence of lipid vesicles, Y39 phosphorylation leads to decreased binding of a region corresponding to helix-2 of the broken-helix state, potentially freeing this region of the protein to interact with other membrane surfaces. This effect is largely recapitulated by the phosphomimetic mutation Y39E, and expression of this mutant in yeast results in decreased membrane localization. Intriguingly, the effects of Y39 phosphorylation on membrane binding closely resemble those of the recently reported disease linked mutation G51D. These findings suggest that Y39 phosphorylation could modulate functional aspects of alpha-synuclein and perhaps influence pathological aggregation of the protein as well.
authors.affiliation: Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College , New York, New York 10065, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Dikiy
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne , Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fauvet
authors.affiliation: Department of Genetics, Stanford University School of Medicine , Stanford, California 94305, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Jovičić
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne , Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne , Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Desobry
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne , Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Farah
authors.initials: F
authors.lastname: El-Turk
authors.affiliation: Department of Genetics, Stanford University School of Medicine , Stanford, California 94305, United States.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne , Station 19, CH-1015 Lausanne, Switzerland.|Qatar Biomedical Research Institute (QBRI) , Doha, Qatar.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.affiliation: Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College , New York, New York 10065, United States.
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D009154:Mutation; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008055:Lipids; D008823:Micelles; D051844:alpha-Synuclein; D012967:Sodium Dodecyl Sulfate