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

Igor Dikiy, Bruno Fauvet, Ana Jovičić, Anne Laure Mahul-Mellier, Carole Desobry, Farah El-Turk, Aaron D. Gitler, Hilal A. Lashuel, David Eliezer

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2428-2437
Number of pages10
JournalACS Chemical Biology
Volume11
Issue number9
DOIs
Publication statusPublished - 16 Sep 2016

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alpha-Synuclein
Phosphorylation
Membranes
Mutation
Cell membranes
Proteins
Synucleins
Cell Membrane
Synaptic Vesicles
Parkinson Disease
Tyrosine
Yeasts
Yeast
Lipids
Agglomeration
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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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. / Dikiy, Igor; Fauvet, Bruno; Jovičić, Ana; Mahul-Mellier, Anne Laure; Desobry, Carole; El-Turk, Farah; Gitler, Aaron D.; Lashuel, Hilal A.; Eliezer, David.

In: ACS Chemical Biology, Vol. 11, No. 9, 16.09.2016, p. 2428-2437.

Research output: Contribution to journalArticle

Dikiy, I, Fauvet, B, Jovičić, A, Mahul-Mellier, AL, Desobry, C, El-Turk, F, Gitler, AD, Lashuel, HA & Eliezer, D 2016, 'Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations', ACS Chemical Biology, vol. 11, no. 9, pp. 2428-2437. https://doi.org/10.1021/acschembio.6b00539
Dikiy, Igor ; Fauvet, Bruno ; Jovičić, Ana ; Mahul-Mellier, Anne Laure ; Desobry, Carole ; El-Turk, Farah ; Gitler, Aaron D. ; Lashuel, Hilal A. ; Eliezer, David. / Semisynthetic and in Vitro Phosphorylation of Alpha-Synuclein at Y39 Promotes Functional Partly Helical Membrane-Bound States Resembling Those Induced by PD Mutations. In: ACS Chemical Biology. 2016 ; Vol. 11, No. 9. pp. 2428-2437.
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