Raman optical activity of human α-synuclein in intrinsically disordered, micelle-bound α-helical, molten globule and oligomeric β-sheet state

Alpha-synuclein (-syn) is a 140 residue protein that plays a central role in Parkinson's disease and other neurological disorders. The precise function and pathological properties of -syn remain however poorly understood. While -syn is considered to be a flexible and disordered protein under native conditions, its ability to adopt a variety of conformational ensembles depending on the environment is considered to be related to its pathology. Raman optical activity (ROA) is a chiroptical spectroscopic technique that is uniquely sensitive to the secondary structure of proteins in solution and was used here for the first time to study the different conformational ensembles of -syn. In this paper, the Raman and ROA spectral characteristics of these different conformations of -syn are investigated. We show that Raman and ROA spectroscopy are sensitive enough not only to detect transitions from a disordered to an -helical or a -sheet rich ensemble but also to differentiate between the -helical forms of wild-type and C-terminal truncated -syn 107. Using increasing concentrations of fluorinated alcohols, we induce the aggregation pathway of -syn and identify a molten globule intermediate structure and -sheet rich oligomers. Taken together, these results demonstrate the power of Raman and ROA spectroscopies for the structural elucidation of proteins that are challenging to characterise. Copyright (c) 2017 John Wiley & Sons, Ltd.