alpha-synuclein and dioleoylphosphatidic-acid

α-Synuclein (α-syn), which causally links to Parkinson's disease, binds to vesicles containing phosphatidic acid (PA). However, the effects of the fatty acyl chains of PA on its ability to bind to α-syn protein remain unclear. Intriguingly, we reveal that among several PA species, 18:1/18:1-PA is the most strongly bound PA to the α-syn protein. Moreover, 18:1/18:1-PA more strongly enhances secondary structural changes from the random coil form to the α-helical form than 16:0/18:1-PA. Furthermore, 18:1/18:1-PA more markedly accelerates generation of multimeric and proteinase K-resistant α-syn protein compared to 16:0/18:1-PA. These results indicate that among phospholipids examined so far, 18:1/18:1-PA demonstrates the strongest binding to α-syn, as well as the most effective enhancement of its secondary structural changes and aggregation formation.

Topics: alpha-Synuclein; Animals; Brain Chemistry; Endopeptidase K; Escherichia coli; Female; Gene Expression; Humans; Liposomes; Mice; Phosphatidic Acids; Protein Aggregates; Protein Binding; Protein Multimerization; Protein Stability; Protein Structure, Secondary; Proteolysis; Recombinant Proteins

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