title: Antiparallel triple-strand architecture for prefibrillar Aβ42 oligomers.
abstract: Aβ42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that Aβ42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar Aβ42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each Aβ42 protein forms a single β-sheet with three β-strands in an antiparallel arrangement. Each β-sheet consists of four Aβ42 molecules in a head-to-tail arrangement. Four β-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different β-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein β-strands undergo an ∼90° rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils.
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California 90095.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California 90095,; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China, and.
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico 87131.
authors.forename: James C
authors.initials: JC
authors.lastname: Stroud
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California 90095.
authors.forename: Sam
authors.initials: S
authors.lastname: Ngo
authors.affiliation: Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California 90095.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Brain Research Institute, Molecular Biology Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, California 90095. Electronic address: zhefeng@ucla.edu.
authors.forename: Zhefeng
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Electron Paramagnetic Resonance (EPR); Protein Aggregation; Protein Structure; Spin Labeling