The fold of alpha-synuclein fibrils
The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of a-synuclein (alpha-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of a-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five beta-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 beta-sheet secondary structure. The data suggest that beta 1-strand interacts with beta 2, beta 2 with beta 3, beta 3 with beta 4, and beta 4 with beta 5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of approximate to 2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed.
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Vilar, M., Chou, H.-T., Luehrs, T., Maji, S. K., Riek-Loher, D., Verel, R., Manning, G., Stahlberg, H., & Riek, R. (2008). The fold of alpha-synuclein fibrils. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 105(25), 8637–8642. https://doi.org/10.1073/pnas.0712179105
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2008-06-12
105
25
8637
8642
REVIEWED
OTHER