fold of α-synuclein fibrils

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-06, Vol.105 (25), p.8637-8642
• Main Authors: Vilar, Marçal, Chou, Hui-Ting, Lührs, Thorsten, Maji, Samir K, Riek-Loher, Dominique, Verel, Rene, Manning, Gerard, Stahlberg, Henning, Riek, Roland
• Format: Article
• Language: English
• Subjects: Aggregation; alpha-Synuclein - chemistry; Amides; Amino acids; Amyloid - chemistry; Amyloids; Biological Sciences; Chemical equilibrium; Cryoelectron Microscopy; Deuterium Exchange Measurement; Microscopy, Electron, Transmission; Neurodegenerative diseases; Nuclear Magnetic Resonance, Biomolecular; Parkinson disease; Protein Folding; Protein Structure, Secondary; Solar fibrils; Solvents; Synucleins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712179105

The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of α-synuclein (α-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of α-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five β-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of β-sheet secondary structure. The data suggest that β1-strand interacts with β2, β2 with β3, β3 with β4, and β4 with β5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of [almost equal to]2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of α-syn in the fibrils is proposed and discussed.