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首页> 外文期刊>Journal of Molecular Biology >Mutations that reduce aggregation of the Alzheimer's Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis.
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Mutations that reduce aggregation of the Alzheimer's Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis.

机译：减少阿尔茨海默氏症Abeta42肽聚集的突变：无偏搜索Abeta淀粉样蛋白生成的序列决定因素。

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摘要

The primary component of amyloid plaque in the brains of Alzheimer's patients is the 42 residue amyloid-beta-peptide (Abeta42). Although the amino acid residue sequence of Abeta42 is known, the molecular determinants of Abeta amyloidogenesis have not been elucidated. To facilitate an unbiased search for the sequence determinants of Abeta aggregation, we developed a genetic screen that couples a readily observable phenotype in E. coli to the ability of a mutation in Abeta42 to reduce aggregation. The screen is based on our finding that fusions of the wild-type Abeta42 sequence to green fluorescent protein (GFP) form insoluble aggregates in which GFP is inactive. Cells expressing such fusions do not fluoresce. To isolate variants of Abeta42 with reduced tendencies to aggregate, we constructed and screened libraries of Abeta42-GFP fusions in which the sequence of Abeta42 was mutated randomly. Cells expressing GFP fusions to soluble (non-aggregating) variants of Abeta42 exhibit green fluorescence. Implementation of this screen enabled the isolation of 36 variants of Abeta42 with reduced tendencies to aggregate. The sequences of most of these variants are consistent with previous models implicating hydrophobic regions as determinants of Abeta42 aggregation. Some of the variants, however, contain amino acid substitutions not implicated in pre-existing models of Abeta amyloidogenesis.
机译：阿尔茨海默氏病患者大脑中淀粉样斑块的主要成分是42个残基的淀粉样β肽（Abeta42）。尽管Abeta42的氨基酸残基序列是已知的，但尚未阐明Abeta淀粉样蛋白生成的分子决定因素。为了促进对Abeta聚集的序列决定子的无偏搜索，我们开发了一种遗传筛选，该遗传筛选将大肠杆菌中易于观察到的表型与Abeta42突变减少聚集的能力相结合。该筛选基于我们的发现，即野生型Abeta42序列与绿色荧光蛋白（GFP）的融合形成了GFP失活的不溶性聚集体。表达这种融合的细胞不发荧光。为了分离具有降低的聚集趋势的Abeta42变体，我们构建并筛选了Abeta42-GFP融合蛋白的文库，其中Abeta42的序列是随机突变的。表达GFP与Abeta42可溶性（非聚集）变体融合的细胞显示绿色荧光。此屏幕的实现使Abeta42的36个变体得以分离，并且具有降低的聚集趋势。这些变体中的大多数序列与先前的模型一致，后者涉及疏水区域作为Abeta42聚集的决定因素。但是，某些变体包含在Abeta淀粉样蛋白生成的现有模型中未涉及的氨基酸取代。

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