Alpha-Synuclein Disease Mutations Are Structurally Defective and Locally Affect Membrane Binding

The intrinsically disordered human protein alpha-Synuclein (αS) has a prominent role in Parkinson's disease (PD) pathology. Several familial variants of αS are correlated with inherited PD. Disease mutations have been shown to have an impact on lipid membrane binding. Here, using electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling, we show that familial PD-associated variants are structurally defective in membrane binding and alter the local binding properties of the protein.