The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State

The aggregation of alpha-synuclein (alpha S), a protein abundant at presynaptic terminals, is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Emerging evidence indicates that the interaction of alpha S with lipid membranes defines both its physiological function and pathological effects. The characterisation of the modes of membrane binding by alpha S is therefore crucial to clarify the balance between normal and aberrant behaviour of this protein. Here we used solid-state nuclear magnetic resonance (ssNMR) spectroscopy to probe the nature of the N-terminally acetylated form of alpha S (NTAc-alpha S) bound to synaptic-like lipid vesicles. This post-translational modification is prevalent for the physiological form of alpha S and modulates the binding to lipid bilayers. By probing the structure, dynamics and membrane topology of NTAc-alpha S, we found that N-terminal acetylation does not alter significantly the conformational and topological properties of the membrane-bound state of alpha S, despite increasing its propensity for binding. Taken together, our data and previous characterisations of the cytosolic state of NTAc-alpha S clarify that the role of the N-terminal acetylation is to regulate the binding affinity of alpha S for synaptic vesicles without altering the structural properties of the bound state.