Erschienen:
Proceedings of the National Academy of Sciences, 2005
Erschienen in:
Proceedings of the National Academy of Sciences, 102 (2005) 48, Seite 17342-17347
Sprache:
Englisch
DOI:
10.1073/pnas.0506723102
ISSN:
0027-8424;
1091-6490
Entstehung:
Anmerkungen:
Beschreibung:
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Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-β (Aβ) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Aβ(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 β-sheet arrangement from previous solid-state NMR studies. Although residues 1–17 are disordered, residues 18–42 form a β-strand–turn–β-strand motif that contains two intermolecular, parallel, in-register β-sheets that are formed by residues 18–26 (β1) and 31–42 (β2). At least two molecules of Aβ(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 β1 of the
<jats:italic>n</jats:italic>
th molecule and the even-numbered residues of strand β2 of the (
<jats:italic>n</jats:italic>
– 1)th molecule. This interaction pattern leads to partially unpaired β-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Aβ fibril growth. It also provides a structural basis for fibrillization inhibitors.
</jats:p>