Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 41, Pages 16938-16943Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112600108
Keywords
amyloid aggregation; 3D profile; protofilaments; heterotypic zipper
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Funding
- Chinese Academy of Science
- National Institutes of Health
- Department of Energy
- Howard Hughes Medical Institute
- Direct For Biological Sciences [0958111] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [0958111] Funding Source: National Science Foundation
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Amyloid-beta (A beta) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A beta molecules form beta-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A beta has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A beta polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A beta. These structures, all of short, self-complementing pairs of beta-sheets termed steric zippers, reveal a variety of modes of self-association of A beta. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A beta. These structures and molecular models contribute fundamental information for understanding A beta polymorphic nature and pathogenesis.
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