SOLUTION CONFORMATIONS AND AGGREGATIONAL PROPERTIES OF SYNTHETIC AMYLOID BETA-PEPTIDES OF ALZHEIMERS-DISEASE - ANALYSIS OF CIRCULAR-DICHROISM SPECTRA
SOLUTION CONFORMATIONS AND AGGREGATIONAL PROPERTIES OF SYNTHETIC AMYLOID BETA-PEPTIDES OF ALZHEIMERS-DISEASE - ANALYSIS OF CIRCULAR-DICHROISM SPECTRA
复制标题
DOI：
10.1016/0022-2836(92)90106-t
复制
发表时间：
1992-06-20
影响因子：
5.6
通讯作者：
ZAGORSKI, MG
中科院分区：
文献类型：
--
作者：
BARROW, CJ;YASUDA, A;ZAGORSKI, MG
A4或β肽(39到43个氨基酸残基)是阿尔茨海默病淀粉样蛋白沉积的主要蛋白质成分。用圆二色谱(C.D.)研究了4种合成淀粉样蛋白β-肽：β-(1-28)、β-(1-39)、β-(1-42)和β-(29-42)的二级结构和在溶液中的聚集性质。脑血管沉淀物和细胞外淀粉样蛋白斑块的天然成分为β-(1-39)和β-(1-42)，而β-(1-28)和β-(29-42)为非天然碎片，β-(1-28)、β-(1-39)和β-(1-42)肽采用β-折叠、α-螺旋和随机卷曲结构的混合结构，每个二级结构的相对比例强烈依赖于溶液条件。在水溶液中，β-(1-39)和β-(1-42)多肽更有利于β-(1-39)和α-(1-42)的形成，而在含三氟乙醇或六氟异丙醇的水溶液中，这3种多肽都更倾向于HSPs-螺旋结构。α-螺旋结构随温度升高而展开，在pH 1~4和pH 7~10范围内有利于β-SHAP构象的形成；β-SHAP构象对温度不敏感，在pH 4~7范围内有利于α-SHAP构象的形成。寡聚β-Sheet结构(α-螺旋→随机卷曲→β-Sheet)的聚集速度也取决于溶液条件，如pH和肽浓度；在pH为5.4时β-Sheet的形成最大。这些结果表明，β-肽不是一种本质上不可溶的多肽。因此，在阿尔茨海默病中可能发生的溶液异常以及局部高肽浓度可能有助于淀粉样斑块的形成。疏水性β-(29-42)肽在水溶液中仅采用分子间β-Sheet构象，无论温度或pH如何变化。因此，该片段可能是β-肽的第一个聚集区域，并可能指导完整的β-肽的折叠，以产生在淀粉样蛋白沉积中发现的β折叠片状结构。β-(1-39)和β-(1-42)多肽溶液构象的差异表明，最后3个C-末端氨基酸对淀粉样蛋白沉积是至关重要的。
The A4 or β-peptide (39 to 43 amino acid residues) is the principal proteinaceous component of amyloid deposits in Alzheimer's disease. Using circular dichroism (c.d.), we have studied the secondary structures and aggregational properties in solution of 4 synthetic amyloid β-peptides: β-(1–28), β-(1–39), β-(1–42) and β-(29–42). The natural components of cerebrovascular deposits and extracellular amyloid plaques are β-(1–39) and β-(1–42), while β-(1–28) and β-(29–42) are unnatural fragments.The β-(1–28), β-(1–39) and β-(1–42) peptides adopt mixtures of β-sheet, α-helix and random coil structures, with the relative proportions of each secondary structure being strongly dependent upon the solution conditions. In aqueous solution, β-sheet structure is favored for the β-(1–39) and β-(1–42) peptides, while in aqueous solution containing trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP), α-helical structure is favored for all 3 peptides. The α-helical structure unfolds with increasing temperature and is favored at pH 1 to 4 and pH 7 to 10; the β-sheet conformation is temperature insensitive and is favored at pH 4 to 7. Peptide concentration studies showed that the β-sheet conformation is oligomeric (intermolecular), whereas the α-helical conformation is monomeric (intramolecular). The rate of aggregation to the oligomeric β-sheet structure (α-helix → random coil → β-sheet) is also dependent upon the solution conditions such as the pH and peptide concentration; maximum β-sheet formation occurs at pH 5.4. These results suggest that β-peptide is not an intrinsically insoluble peptide. Thus, solution abnormalities, together with localized high peptide concentrations, which may occur in Alzheimer's disease, may contribute to the formation of amyloid plaques.The hydrophobic β-(29–42) peptide adopts exclusively an intermolecular β-sheet conformation in aqueous solution despite changes in temperature or pH. Therefore, this segment may be the first region of the β-peptide to aggregate and may direct the folding of the complete β-peptide to produce the β-pleated sheet structure found in amyloid deposits. Differences between the solution conformations of the β-(1–39) and β-(1–42) peptides suggests that the last 3 C-terminal amino acids are crucial to amyloid deposition.