Abstract
Amyloid fibrils are self-assembled filamentous structures associated with protein deposition conditions including Alzheimer's disease and the transmissible spongiform encephalopathies. Despite the immense medical importance of amyloid fibrils, no atomic-resolution structures are available for these materials, because the intact fibrils are insoluble and do not form diffraction-quality 3D crystals. Here we report the high-resolution structure of a peptide fragment of the amyloidogenic protein transthyretin, TTR(105-115), in its fibrillar form, determined by magic angle spinning NMR spectroscopy. The structure resolves not only the backbone fold but also the precise conformation of the side chains. Nearly complete C-13 and N-15 resonance assignments for TTR(105115) formed the basis for the extraction of a set of distance and dihedral angle restraints. A total of 76 self-consistent experimental measurements, including 41 restraints on 19 backbone dihedral angles and 35 C-13-N-15 distances between 3 and 6 Angstrom were obtained from 2D and 3D NMR spectra recorded on three fibril samples uniformly C-13,N-15-labeled in consecutive stretches of four amino acids and used to calculate an ensemble of peptide structures. Our results indicate that TTR(105-115) adopts an extended beta-strand conformation in the amyloid fibrils such that both the main- and side-chain torsion angles are close to their optimal values. Moreover, the structure of this peptide in the fibrillar form has a degree of long-range order that is generally associated only with crystalline materials. These findings provide an explanation of the unusual stability and characteristic properties of this form of polypeptide assembly.
Original language | English |
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Pages (from-to) | 711-716 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences (PNAS) |
Volume | 101 |
Issue number | 3 |
DOIs | |
Publication status | Published - 20 Jan 2004 |
Keywords / Materials (for Non-textual outputs)
- SOLID-STATE NMR
- X-RAY-DIFFRACTION
- PRION PROTEIN
- ROTATING SOLIDS
- CHEMICAL-SHIFT
- TRANSTHYRETIN
- FRAGMENT
- MODEL
- CONSTRAINTS
- CRYSTALLOGRAPHY