Structural Organization of α-Synuclein Fibrils Studied by Site-directed Spin Labeling

• Published in: The Journal of biological chemistry 2003-09, Vol.278 (39), p.37530-37535
• Main Authors: Der-Sarkissian, Ani, Jao, Christine C., Chen, Jeannie, Langen, Ralf
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Amyloid beta-Peptides - chemistry; Electron Spin Resonance Spectroscopy; Humans; Models, Molecular; Nerve Tissue Proteins - chemistry; Protein Folding; Synucleins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305266200

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 α-synuclein exhibits several features reminiscent of those observed in the core region of fibrillar Alzheimer's amyloid β peptide, including an in-register parallel structure. Although the lengths of the respective core regions differ, fibrils from different amyloid proteins nevertheless appear to be able to take up highly similar, and possibly conserved, structures.