Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 45, Pages 18990-18995Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910080106
Keywords
amyloid; fibril structure
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Funding
- National Science Foundation
- Department of Energy/Office of Biological and Environmental Research
- National Institutes of Health
- Howard Hughes Medical Institute
- University of California Los Angeles National Science Foundation Integrative Graduate Education and Research Traineeship
- Department of Energy/Office of Health and Environment Research
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In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-beta spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 angstrom resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated beta-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.
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