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  4. 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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research article

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  
•
Jovicic, Ana
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2016
Acs Chemical Biology

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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Type
research article
DOI
10.1021/acschembio.6b00539
Web of Science ID

WOS:000383639800006

Author(s)
Dikiy, Igor
•
Fauvet, Bruno  
•
Jovicic, Ana
•
Mahul-Mellier, Anne-Laure
•
Desobry, Carole  
•
El-Turk, Farah
•
Gitler, Aaron D.
•
Lashuel, Hilal A.  
•
Eliezer, David
Date Issued

2016

Publisher

Amer Chemical Soc

Published in
Acs Chemical Biology
Volume

11

Issue

9

Start page

2428

End page

2437

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LMNN  
Available on Infoscience
November 21, 2016
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/131514
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