We studied the coupled binding and folding of
alpha-synuclein, an
intrinsically disordered protein linked with
Parkinson's disease. Using single-molecule fluorescence resonance energy transfer and correlation methods, we directly probed
protein membrane association, structural distributions, and dynamics. Results revealed an intricate energy landscape on which binding of
alpha-synuclein to amphiphilic small molecules or membrane-like partners modulates conformational transitions between a natively unfolded state and multiple alpha-helical structures.
Alpha-synuclein conformation is not continuously tunable, but instead partitions into 2 main classes of folding landscape structural minima. The switch between a broken and an extended helical structure can be triggered by changing the concentration of binding partners or by varying the curvature of the binding surfaces presented by
micelles or bilayers composed of the
lipid-mimetic SDS. Single-molecule experiments with
lipid vesicles of various composition showed that a low fraction of negatively charged
lipids, similar to that found in
biological membranes, was sufficient to drive
alpha-synuclein binding and folding, resulting here in the induction of an extended helical structure. Overall, our results imply that the 2 folded structures are preencoded by the
alpha-synuclein amino acid sequence, and are tunable by small-molecule supramolecular states and differing membrane properties, suggesting novel control elements for
biological and
amyloid regulation of
alpha-synuclein.