Structural organization of α-synuclein fibrils studied by site-directed spin labeling

Abstract

Despite its importance in Parkinson's disease, a detailed understanding of the structure and mechanism of α-synuclein fibril formation remains elusive. In this study, we used site-directed spin labeling and electron paramagnetic resonance spectroscopy to study the structural features of monomeric and fibrillar α-synuclein. Our results indicate that monomeric α-synuclein, in solution, has a highly dynamic structure, in agreement with the notion that α-synuclein is a natively unfolded protein. In contrast, fibrillar aggregates of α-synuclein exhibit a distinct domain organization. Our data identify a highly ordered and specifically folded central core region of ∼70 amino acids, whereas the N terminus is structurally more heterogeneous and the C terminus (∼40 amino acids) is completely unfolded. Interestingly, the central core region of