The human neuronal protein alpha-synuclein (aS) has long been associated with Parkinson’s disease; while many studies have focused on aS's aggregation to form disease-associated amyloid aggregates, more recent hypotheses associated with disease have focused on alpha-synuclein’s role as a peripheral membrane protein whose membrane-bound structures are intrinsic to its still undetermined function(s). Introduction of thiocyanate infrared probe groups at key sites on aS provides new and unique information about the membrane-bound conformational distribution of aS, which can change in observable ways due to post-translational modifications of the protein, specific mutations associated with familial Parkinson’s disease, and the curvature and composition of lipid bilayers. IR probes are particularly useful reporters in the complicated and heterogeneous membrane-bound context because they can provide signals in essentially any environment (regardless of membrane particle size, composition, and phase), and because their lineshapes provide a direct readout of local conformational distributions rather than a line-narrowed ensemble average.  New insights into aS membrane binding made possible by this probe-based technique will be discussed.

Membrane-bound structures of alpha-synuclein as reported by vibrational probe groups

ACS Spring 2022

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