High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy

被引:428
作者
Jaroniec, CP
MacPhee, CE [1 ]
Bajaj, VS
McMahon, MT
Dobson, CM
Griffin, RG
机构
[1] MIT, Francis Bitter Natl Magnet Lab, Dept Chem, Cambridge, MA 02139 USA
[2] MIT, Francis Bitter Natl Magnet Lab, Ctr Magnet Resonance, Cambridge, MA 02139 USA
[3] Univ Cambridge, Cavendish Lab, Cambridge CB3 0HE, England
[4] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
关键词
D O I
10.1073/pnas.0304849101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:711 / 716
页数:6
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