Single-Molecule FRET Reveals Alternative Ligand and Osmolyte-Dependent α-Synuclein Folding

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Intrinsically disordered proteins are involved in diverse cellular functions and linked to numerous diseases. Many of these proteins can interact with multiple binding partners and undergo binding-induced disorder-to-order transitions to fold into alternative ligand-specific functional folds. To test the origin of multiple functional folds, here we compared results of ligand-induced and osmolyte-forced folding of α-synuclein, a Parkinson's disease linked disordered protein that adopts multiple folded conformations upon interaction with its lipid/ lipid mimic binding partners. Employing a combination of single-molecule and ensemble spectroscopic techniques, we directly probed changes in the protein's structures using different folding perturbations. Results from our experiments reveal context-dependent modulation of α-synuclein folding landscapes, suggesting the folding code for the protein's native folds is partially encoded in the protein's primary sequence and completed only upon its interaction with binding partners. Our findings imply a broad role of ligand-interaction in the context of folding and functions of disordered proteins.