Probing the interaction between α-synuclein and lipid membranes by NMR Spectroscopy

α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson’s disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Using a combination of solid-state (Figures 1-3) and solution-state NMR spectroscopy (Figure 4), we characterised the conformations of αS bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study evidences key regions of the protein possessing distinct structural and dynamical properties and having specific roles in determining the way the protein partitions between membrane-bound and unbound states. The N-terminal segment of ca 25 residues adopts a well-defined, motionally restricted helical conformation and acts as a membrane-anchor. This region appears conserved using lipid mixtures having significantly different affinity (Figures 1, 3). The C-terminal residues remain in an unstructured state (Figure 1) and exhibits weak and transient interactions with the membrane surface (Figure 2). A key role has, however, been identified for th