Structural Ensembles of Membrane-bound α-Synuclein Reveal the Molecular Determinants of Synaptic Vesicle Affinity

A detailed characterisation of the molecular determinants of membrane binding by alpha-synuclein (alpha S), a 140-residue protein whose aggregation is associated with Parkinson's disease, is of fundamental significance to clarify the manner in which the balance between functional and dysfunctional processes are regulated for this protein. Despite its biological relevance, the structural nature of the membrane-bound state alpha S remains elusive, in part because of the intrinsically dynamic nature of the protein and also because of the difficulties in studying this state in a physiologically relevant environment. In the present study we have used solid-state NMR and restrained MD simulations to refine structure and topology of the N-terminal region of alpha S bound to the surface of synaptic-like membranes. This region has fundamental importance in the binding mechanism of alpha S as it acts as to anchor the protein to lipid bilayers. The results enabled the identification of the key elements for the biological properties of alpha S in its membrane-bound state.