title: 3D structure of Alzheimer's amyloid-beta(1-42) fibrils.
abstract: Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(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 (beta1) and 31-42 (beta2). At least two molecules of Abeta(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 beta1 of the nth molecule and the even-numbered residues of strand beta2 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 Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lührs
authors.forename: Christiane
authors.initials: C
authors.lastname: Ritter
authors.forename: Marc
authors.initials: M
authors.lastname: Adrian
authors.forename: Dominique
authors.initials: D
authors.lastname: Riek-Loher
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.forename: Heinz
authors.initials: H
authors.lastname: Döbeli
authors.forename: David
authors.initials: D
authors.lastname: Schubert
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D003903:Deuterium; D006801:Humans; D006859:Hydrogen; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009587:Nitrogen Isotopes; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D009587:Nitrogen Isotopes; D006859:Hydrogen; D003903:Deuterium