Mutagenesis of the central hydrophobic cluster in Aβ42 Alzheimer's pepticle -: Side-chain properties correlate with aggregation propensities
Mutagenesis of the central hydrophobic cluster in Aβ42 Alzheimer's pepticle -: Side-chain properties correlate with aggregation propensities
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DOI：
10.1111/j.1742-4658.2005.05102.x
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发表时间：
2006-02-01
期刊：
影响因子：
5.4
通讯作者：
Ventura, S
中科院分区：
文献类型：
--
作者：
de Groot, NS;Aviles, FX;Ventura, S
蛋白质错误折叠和沉积是越来越多的使人衰弱的疾病的基础。阿尔茨海默病的病理特征在于脑中存在大量不溶性淀粉样蛋白斑块，主要由42个氨基酸的人β-淀粉样蛋白肽（A β 42）组成。A β 42中的疾病相关突变发生在包含残基17-21的中心疏水簇中或附近。我们利用绿色荧光蛋白作为上游融合A β 42变体聚集的报告者的能力来表征在该疏水序列的中心位置处的大量单点突变以及与位于该区域中或接近该区域的疾病的早期发作相关的取代的影响。不同蛋白质变体的聚集性质与突变点侧链的内在理化性质的变化明显相关。疏水性和β-shcet倾向的降低导致体内荧光的增加，表明聚集的破坏，如合成A β 42变体的体外分析所证实的。结果证实了中心疏水性伸展对A β 42沉积的关键作用，并支持序列调节多肽聚集倾向的假设。
Protein misfolding and deposition underlie an increasing number of debilitating human disorders. Alzheimer's disease is pathologically characterized by the presence of numerous insoluble amyloid plaques in the brain, composed primarily of the 42 amino acid human beta-amyloid peptide (A beta 42). Disease-linked mutations in A beta 42 occur in or near a central hydrophobic cluster comprising residues 17-21. We exploited the ability of green fluorescent protein to act as a reporter of the aggregation of upstream fused A beta 42 variants to characterize the effects of a large set of single-point mutations at the central position of this hydrophobic sequence as well as substitutions linked to early onset of the disease located in or close to this region. The aggregational properties of the different protein variants clearly correlated with changes in the intrinsic physicochemical properties of the side chains at the point of mutation. Reduction in hydrophobicity and beta-shcet propensity resulted in an increase of in vivo fluorescence indicating disruption of aggregation, as confirmed by the in vitro analysis of synthetic A beta 42 variants. The results confirm the key role played by the central hydrophobic stretch on A beta 42 deposition and support the hypothesis that sequence tunes the aggregation propensities of polypeptides.