Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour

alpha- synuclein (alpha S) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson's disease. In dopaminergic neurons, alpha S exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of alpha S bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study shows three alpha S regions possessing distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane anchor, an unstructured C-terminal region that is weakly associated with the membrane and a central region acting as a sensor of the lipid properties and determining the affinity of alpha S membrane binding. Taken together, our data define the nature of the interactions of alpha S with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.