Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

The protein alpha-Synuclein (alpha S) is linked to Parkinson's disease through its abnormal aggregation, which is thought to involve cytosolic and membrane-bound forms of alpha S. Following previous studies using micelles and vesicles, we present a comprehensive study of alpha S interaction with phospholipid bilayer nanodiscs. Using a combination of NMR-spectroscopic, biophysical, and computational methods, we structurally and kinetically characterize alpha S interaction with different membrane discs in a quantitative and site-resolved way. We obtain global and residue-specific alpha S membrane affinities, and determine modulations of alpha S membrane binding due to alpha S acetylation, membrane plasticity, lipid charge density, and accessible membrane surface area, as well as the consequences of the different binding modes for alpha S amyloid fibril formation. Our results establish a structural and kinetic link between the observed dissimilar binding modes and either aggregation-inhibiting properties, largely unperturbed aggregation, or accelerated aggregation due to membrane-assisted fibril nucleation.