alpha-synuclein and tetramethylrhodamine

Previous studies indicate that binding of alpha-synuclein to membranes is critical for its physiological function and the development of Parkinson's disease (PD). Here, we have investigated the association of fluorescence-labeled alpha-synuclein variants with different types of giant unilamellar vesicles using confocal microscopy. We found that alpha-synuclein binds with high affinity to anionic phospholipids, when they are embedded in a liquid-disordered as opposed to a liquid-ordered environment. This indicates that not only electrostatic forces but also lipid packing and hydrophobic interactions are critical for the association of alpha-synuclein with membranes in vitro. When compared to wild-type alpha-synuclein, the disease-causing alpha-synuclein variant A30P bound less efficiently to anionic phospholipids, while the variant E46K showed enhanced binding. This suggests that the natural association of alpha-synuclein with membranes is altered in the inherited forms of Parkinson's disease.

Topics: alpha-Synuclein; Amino Acid Sequence; Anions; Binding Sites; Cell Membrane; Fatty Acids; Fluorescent Dyes; Hydrophobic and Hydrophilic Interactions; Lipids; Microscopy, Fluorescence; Molecular Sequence Data; Molecular Weight; Mutation; Parkinson Disease; Phosphatidic Acids; Phosphatidylcholines; Phosphatidylglycerols; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylserines; Phospholipids; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Rhodamines; Static Electricity; Surface Properties; Unilamellar Liposomes