α-Synuclein (α-syn) is most well-known for its involvement in the etiology of Parkinson’s disease, where α-syn amyloid fibrils are found in Lewy bodies, a histopathological hallmark. Membrane association of α-syn is associated with its biological function and implicated in pathogenesis. Upon membrane association, α-syn adopts an α-helical structure, whereas in solution, the protein is disordered. In a disease state, β-sheet rich, amyloid fibrils of aggregated α-syn accumulate in the cytosol. In this work, we are using Raman spectroscopy to study α-syn conformational dynamics upon lipid association. The coupled vibrational modes of the polypeptide backbone, amide-I (C=O stretch), report on protein secondary structural changes, allowing us to identify whether the protein has adopted an α-helical form. For example, the disordered protein in solution exhibits a broad amide-I peak with a maximum around 1673 cm−1, whereas in the presence of lysophosphatidylcholine micelles, the amide peak narrows and shifts to lower energy to 1650 cm−1. To examine the effect of protein sequence on lipid interactions, we have studied a disease-related C-terminally truncated variant (1–115) where the last 25 residues have been removed, which revealed that the C-terminal region modulated α-helical formation propensity of α-syn. Both Raman and circular dichroism results point to an increase in α-helical content for the 1–115 variant. Building upon the fundamental understanding of α-syn–lipid interactions, we are using Raman micospectroscopy to enable the studies of protein conformational dynamics to cellular membranes.

Lipid interactions of α-synuclein probed by Raman spectroscopy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.