α-Synuclein Oligomers with Broken Helical Conformation Form Lipoprotein Nanoparticles

• Published in: The Journal of biological chemistry 2013-06, Vol.288 (24), p.17620-17630
• Main Authors: Varkey, Jobin, Mizuno, Naoko, Hegde, Balachandra G., Cheng, Naiqian, Steven, Alasdair C., Langen, Ralf
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - isolation & purification; alpha-Synuclein - ultrastructure; Cholesterol - chemistry; Chromatography, Gel; Cryoelectron Microscopy; Electron Microscopy (EM); Electron Paramagnetic Resonance (EPR); Fluorescence Resonance Energy Transfer; Humans; Lipoproteins - chemistry; Lipoproteins - isolation & purification; Lipoproteins - ultrastructure; Membrane Proteins; Membranes, Artificial; Mitochondrial Membranes - chemistry; Molecular Biophysics; Nanoparticles; Nanoparticles - analysis; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Neurodegenerative Diseases; Particle Size; Phosphatidylcholines - chemistry; Phosphatidylglycerols - chemistry; Phosphatidylserines - chemistry; Protein Structure, Quaternary; Protein Structure, Secondary; α-Synuclein
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.476697

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. Background: Parkinson disease protein α-synuclein has sequence similarity with apolipoproteins. Results: α-Synuclein can generate nanoparticles from phospholipid membranes and fatty acids by taking up a broken helical structure. Conclusion: These nanoparticles have shapes and dimensions reminiscent of apolipoprotein nanodiscs. Significance: The data suggest apolipoprotein-like roles for α-synuclein as a lipid- or fatty acid-carrying protein.