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Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations

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    Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations
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    † Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, New York 10065, United States
    ‡ Laboratory of Molecular and Chemical Biology of Neurodegeneration, Ecole Polytechnique Fédérale de Lausanne, Station 19, CH-1015 Lausanne, Switzerland
    § Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, United States
    ∥ Qatar Biomedical Research Institute (QBRI), Doha, Qatar
    *E-mail: [email protected]
    *E-mail: [email protected]
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2016, 11, 9, 2428–2437
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    https://doi.org/10.1021/acschembio.6b00539
    Published June 29, 2016
    Copyright © 2016 American Chemical Society
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    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.6b00539.

    • Description of materials and methods and supplementary data is included. Supporting Figures S1–S9: Membrane-bound states of aSyn; semisynthesis of pY39 aSyn; purity analysis of semisynthetic pY39 aSyn; secondary structure of semisynthetic pY39 aSyn; purity analysis of proteins prepared by in vitro phosphorylation; NMR comparison of WT, pY39, and Y39E aSyn in the free state; PRE of spin labeled aSyn bound to SDS micelles; toxicity of aSyn Y39E in yeast; and characterization of the effect of Y39 phosphorylation on aSyn fibrillization propensity using semisynthetic pY39 aSyn (PDF)

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    Cite this: ACS Chem. Biol. 2016, 11, 9, 2428–2437
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    https://doi.org/10.1021/acschembio.6b00539
    Published June 29, 2016
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