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J Biol Chem. 2014 Sep 26;289(39):27300-13. doi: 10.1074/jbc.M114.569004. Epub 2014 Aug 12.

Antiparallel triple-strand architecture for prefibrillar Aβ42 oligomers.

Author information

  • 1From Department of Neurology, Brain Research Institute, Molecular Biology Institute.
  • 2Departments 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.
  • 3Department of Chemistry and Chemical Biology, Center for Biomedical Engineering, University of New Mexico, Albuquerque, New Mexico 87131.
  • 4Departments 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.
  • 5From Department of Neurology, Brain Research Institute, Molecular Biology Institute, zhefeng@ucla.edu.

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.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

Alzheimer Disease; Amyloid; Electron Paramagnetic Resonance (EPR); Protein Aggregation; Protein Structure; Spin Labeling

PMID:
25118290
[PubMed - indexed for MEDLINE]
PMCID:
PMC4175361
[Available on 2015/9/26]
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