title: α-Synuclein oligomers with broken helical conformation form lipoprotein nanoparticles.
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.
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Jobin
authors.initials: J
authors.lastname: Varkey
authors.forename: Naoko
authors.initials: N
authors.lastname: Mizuno
authors.forename: Balachandra G
authors.initials: BG
authors.lastname: Hegde
authors.forename: Naiqian
authors.initials: N
authors.lastname: Cheng
authors.forename: Alasdair C
authors.initials: AC
authors.lastname: Steven
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D002784:Cholesterol / Q000737:chemistry; D002850:Chromatography, Gel; D020285:Cryoelectron Microscopy; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure; D008567:Membranes, Artificial; D051336:Mitochondrial Membranes / Q000737:chemistry; D053758:Nanoparticles / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure
chemical_list: D008074:Lipoproteins; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D010718:Phosphatidylserines; D051844:alpha-Synuclein; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Electron Microscopy (EM); Electron Paramagnetic Resonance (EPR); Membrane Proteins; Nanoparticles; Neurodegenerative Diseases; α-Synuclein