Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril
Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril
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DOI：
10.1073/pnas.1600749113
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发表时间：
2016-08-23
影响因子：
11.1
通讯作者：
Riek, Roland
中科院分区：
文献类型：
--
作者：
Walti, Marielle Aulikki;Ravotti, Francesco;Riek, Roland
淀粉样蛋白-β（A β）作为淀粉样蛋白前体蛋白的39至42个氨基酸残基的代谢产物存在于人类中。尽管两种主要形式A β（1-40）和A β（1-42）仅在两个残基上不同，但它们显示出不同的生物物理学、生物学和临床行为。A β（1-42）是一种神经毒性更强、聚集速度更快的物质，在阿尔茨海默病（AD）患者的老年斑中占主导地位。尽管小A β寡聚体被认为是神经毒性物质，但A β淀粉样蛋白原纤维由于其存在于斑块中，是AD的病理标志，并且似乎通过细胞间传递性在疾病进展中发挥重要作用。在这里，我们解决了疾病相关的A β（1-42）原纤维多晶型物的3D结构，结合固态NMR光谱学和EM的质量/长度测量数据。3D结构由每个原纤维层的两个分子组成，其中残基15-42形成具有最大程度地掩埋的疏水侧链的双马蹄形交叉β-折叠实体。残基1-14是部分有序的并且处于β-链构象，但与核心结构的其余部分不显示明确的距离限制。
Amyloid-beta (A beta) is present in humans as a 39-to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, A beta(1-40) and A beta(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. A beta(1-42) is the more neurotoxic species, aggre-gatesmuch faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small A beta oligomers are believed to be the neurotoxic species, A beta amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a diseaserelevant A beta(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-beta-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a beta-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.