期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2008
卷号:105
期号:25
页码:8637-8642
DOI:10.1073/pnas.0712179105
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要:The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of {alpha}-synuclein ({alpha}-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of {alpha}-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 {approx}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.