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：2005
卷号：102
期号：48
页码：17342-17347
DOI：10.1073/pnas.0506723102
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-{beta} (A{beta}) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising A{beta}(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register {beta}-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a {beta}-strand-turn-{beta}-strand motif that contains two intermolecular, parallel, in-register {beta}-sheets that are formed by residues 18-26 ({beta}1) and 31-42 ({beta}2). At least two molecules of A{beta}(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand {beta}1 of the nth molecule and the even-numbered residues of strand {beta}2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired {beta}-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of A{beta} fibril growth. It also provides a structural basis for fibrillization inhibitors.
