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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy
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High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy

机译：魔角旋转NMR光谱测定淀粉样蛋白原纤维中肽的高分辨率分子结构

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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 ~(13)C and ~(15)N resonance assignments for TTR(105-115) 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 ~(13)C-~(15)N distances between 3 and 6 A were obtained from 2D and 3D NMR spectra recorded on three fibril samples uniformly ~(13)C, ~(15)N-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 β-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 polypep-tide assembly.
机译：淀粉样蛋白原纤维是自组装的丝状结构，与包括阿尔茨海默氏病和可传播的海绵状脑病在内的蛋白质沉积条件有关。尽管淀粉样蛋白原纤维具有巨大的医学重要性，但由于这些原纤维是不溶的并且不形成衍射质量的3D晶体，因此这些材料尚无原子分辨结构。在这里，我们报告的成淀粉样蛋白运甲状腺素蛋白TTR（105-115），其原纤维形式的肽片段的高分辨率结构，通过魔角旋转NMR光谱法测定。该结构不仅解析了骨架折叠，而且解析了侧链的精确构象。 TTR（105-115）的近乎完整的〜（13）C和〜（15）N共振分配为提取一组距离和二面角约束提供了基础。从记录在三个原纤维样品上的2D和3D NMR谱图获得总共76个自洽的实验测量值，包括对19个主干二面角的41个约束以及3和6 A之间的35〜（13）C-〜（15）N距离在四个氨基酸的连续片段中均匀〜（13）C，〜（15）N-标记，并用于计算肽结构的整体。我们的结果表明，TTR（105-115）在淀粉样蛋白原纤维中采用了扩展的β链构象，因此主链和侧链扭转角均接近其最佳值。此外，该原纤维形式的肽的结构具有一定程度的远距离有序，通常仅与结晶物质有关。这些发现为这种形式的多肽组装体的异常稳定性和特性提供了解释。

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