期刊
STRUCTURE
卷 23, 期 1, 页码 216-227出版社
CELL PRESS
DOI: 10.1016/j.str.2014.10.022
关键词
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资金
- National Institute of Diabetes, Digestive, and Kidney Disease
- National Institute of Allergy and Infectious Diseases
- Intramural AIDS-Targeted Antiviral Program of the Office of the Director
- NIH
- Research Foundation at the State University of New York
- National Science Foundation [NSF 0922815]
Determining the structures of amyloid fibrils is an important first step toward understanding the molecular basis of neurodegenerative diseases. For beta-amyloid (A beta) fibrils, conventional solid-state NMR structure determination using uniform labeling is limited by extensive peak overlap. We describe the characterization of a distinct structural polymorph of Ab using solid-state NMR, transmission electron microscopy (TEM), and Rosetta model building. First, the overall fibril arrangement is established using mass-per-length measurements from TEM. Then, the fibril backbone arrangement, stacking registry, and steric zipper'' core interactions are determined using a number of solid-state NMR techniques on sparsely C-13-labeled samples. Finally, we perform Rosetta structure calculations with an explicitly symmetric representation of the system. We demonstrate the power of the hybrid Rosetta/NMR approach by modeling the in-register, parallel Iowa'' mutant (D23N) at high resolution (1.2 angstrom backbone rmsd). The final models are validated using an independent set of NMR experiments that confirm key features.
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