title: Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril.
abstract: Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1-40) and Aβ(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1-42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-β-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.
authors.affiliation: Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland;
authors.forename: Marielle Aulikki
authors.initials: MA
authors.lastname: Wälti
authors.affiliation: Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland;
authors.forename: Francesco
authors.initials: F
authors.lastname: Ravotti
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697;
authors.forename: Hiromi
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.affiliation: Brookhaven National Laboratory, Upton, NY 11973-5000;
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Wall
authors.affiliation: Institut de Biologie et Chimie des Protéines, Bases Moléculaires et Structurales des Systèmes Infectieux, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, 69007 Lyon, France; a.bockmann@ibcp.fr beme@ethz.ch roland.riek@phys.chem.ethz.ch.
authors.forename: Anja
authors.initials: A
authors.lastname: Böckmann
authors.affiliation: Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland; Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, Goethe University Frankfurt am Main, 60438 Frankfurt am Main, Germany; Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Peter
authors.initials: P
authors.lastname: Güntert
authors.affiliation: Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland; a.bockmann@ibcp.fr beme@ethz.ch roland.riek@phys.chem.ethz.ch.
authors.forename: Beat H
authors.initials: BH
authors.lastname: Meier
authors.affiliation: Laboratorium für Physikalische Chemie, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland; a.bockmann@ibcp.fr beme@ethz.ch roland.riek@phys.chem.ethz.ch.
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000648:ultrastructure*; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000235:genetics / Q000648:ultrastructure*; D000072757:Protein Conformation, beta-Strand; D011994:Recombinant Proteins / Q000235:genetics / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; amyloid; protein structure; solid-state NMR