title: Structural organization of alpha-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 alpha-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 alpha-synuclein. Our results indicate that monomeric alpha-synuclein, in solution, has a highly dynamic structure, in agreement with the notion that alpha-synuclein is a natively unfolded protein. In contrast, fibrillar aggregates of alpha-synuclein exhibit a distinct domain organization. Our data identify a highly ordered and specifically folded central core region of approximately 70 amino acids, whereas the N terminus is structurally more heterogeneous and the C terminus ( approximately 40 amino acids) is completely unfolded. Interestingly, the central core region of alpha-synuclein exhibits several features reminiscent of those observed in the core region of fibrillar Alzheimer's amyloid beta 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.
authors.affiliation: Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90089, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Der-Sarkissian
authors.forename: Christine C
authors.initials: CC
authors.lastname: Jao
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D017510:Protein Folding; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein