Structural characterization of α-synuclein in an aggregation prone state

The relation of alpha-synuclein (alpha S) aggregation to Parkinson's disease has long been recognized, but the pathogenic species and its molecular properties have yet to be identified. To obtain insight into the properties of as in an aggregation-prone state, we studied the structural properties of alpha S at acidic pH using NMR spectroscopy and computation. NMR demonstrated that as remains natively unfolded at lower pH, but secondary structure propensities were changed in proximity to acidic residues. The ensemble of conformations of alpha S at acidic pH is characterized by a rigidification and compaction of the Asp and Glu-rich C-terminal region, an increased probability for proximity between the NAC-region and the C-terminal region and a lower probability for interactions between the N- and C-terminal regions.