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J Biol Chem. 2013 Jun 14;288(24):17620-30. doi: 10.1074/jbc.M113.476697. Epub 2013 Apr 22.

α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles.

Author information

1
Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.

Abstract

α-Synuclein (αS) is a membrane-binding protein with sequence similarity to apolipoproteins and other lipid-carrying proteins, which are capable of forming lipid-containing nanoparticles, sometimes referred to as "discs." Previously, it has been unclear whether αS also possesses this property. Using cryo-electron microscopy and light scattering, we found that αS can remodel phosphatidylglycerol vesicles into nanoparticles whose shape (ellipsoidal) and dimensions (in the 7-10-nm range) resemble those formed by apolipoproteins. The molar ratio of αS to lipid in nanoparticles is ∼1:20, and αS is oligomeric (including trimers and tetramers). Similar nanoparticles form when αS is added to vesicles of mitochondrial lipids. This observation suggests a mechanism for the previously reported disruption of mitochondrial membranes by αS. Circular dichroism and four-pulse double electron electron resonance experiments revealed that in nanoparticles αS assumes a broken helical conformation distinct from the extended helical conformation adopted when αS is bound to intact vesicles or membrane tubules. We also observed αS-dependent tubule and nanoparticle formation in the presence of oleic acid, implying that αS can interact with fatty acids and lipids in a similar manner. αS-related nanoparticles might play a role in lipid and fatty acid transport functions previously attributed to this protein.

KEYWORDS:

Electron Microscopy (EM); Electron Paramagnetic Resonance (EPR); Membrane Proteins; Nanoparticles; Neurodegenerative Diseases; α-Synuclein

PMID:
23609437
PMCID:
PMC3682563
DOI:
10.1074/jbc.M113.476697
[Indexed for MEDLINE]
Free PMC Article

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