The E22SS-type mutant of amyloid SS peptide (ASS) adopts distinct selfassembly mechanisms from wild- type ASS.
The E22SS-type mutant of amyloid SS peptide (ASS) adopts distinct selfassembly mechanisms from wild- type ASS.
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淀粉样蛋白 SS 肽 (ASS) 的 E22SS 型突变体采用与野生型 ASS 不同的自组装机制。
DOI：
10.1016/j.bmc.2011.04.056
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Yoshiaki Kiso
中科院分区：
文献类型：
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作者：
Youhei Sohma;Hui Wang;Atsuhiko Taniguchi;Yuta Hirayama;Taeko Kakizawa;Hidehito Mukai;Yoshiaki Kiso
据报道，最近鉴定的 E22Δ 型淀粉样蛋白 β 肽 (Aβ) 突变体有利于寡聚化而不是纤维化，并且比野生型 (WT) Aβ 表现出更有效的突触毒性。因此，Aβ(E22Δ) 突变体有望成为阐明 Aβ 寡聚体对阿尔茨海默病（或阿尔茨海默病型痴呆）影响的工具。然而，Aβ(E22Δ)的生化和生物物理特性尚未最终确定。在这里，我们评估了由水溶性、非聚集的 O-酰基异肽前体产生的 Aβ(E22Δ) 突变体的自组装途径。圆二色光谱、Western blot 分析、硫黄素-T 荧光强度和细胞毒性测定表明 Aβ(E22Δ) 的自组装途径与 Aβ(WT) 不同。 Aβ1–40（E22Δ）在其单体或低分子量寡聚状态下经历了快速的无规卷曲→β-折叠构象变化，而Aβ1–40（WT）逐渐自组装而没有失去其形成无规卷曲结构的倾向。 Aβ1–42(E22Δ) 单体比 Aβ1–42(WT) 更快地形成富含 β 折叠的寡聚物。此外，Aβ1–42(E22Δ) 寡聚物似乎在大小、形状或两者上都不同于 Aβ1–42(WT) 寡聚物。这些结果应该为 Aβ(E22Δ) 突变体的功能提供新的见解。
The recently identified E22Δ-type amyloid β peptide (Aβ) mutants are reported to favor oligomerization over fibrillization and to exhibit more-potent synaptotoxicity than does wild-type (WT) Aβ. Aβ(E22Δ) mutants can thus be expected to serve as tools for clarifying the impact of Aβ oligomers in Alzheimer’s disease (or Alzheimer’s-type dementia). However, the biochemical and biophysical properties of Aβ(E22Δ) have not been conclusively determined. Here, we evaluated the self-assembly pathways of Aβ(E22Δ) mutants generated from water-soluble, non-aggregativeO-acyl isopeptide precursors. Circular dichroism spectroscopy, Western blot analysis, and thioflavin-T fluorescence intensity and cellular toxicity assays suggest that the self-assembly pathways of Aβ(E22Δ) differed from those of Aβ(WT). Aβ1–40(E22Δ) underwent a rapid random coil→β-sheet conformational change in its monomeric or low-molecular-weight oligomeric states, whereas Aβ1–40(WT) self-assembled gradually without losing its propensity to form random coil structures. The Aβ1–42(E22Δ) monomer formed β-sheet-rich oligomers more rapidly than did Aβ1–42(WT). Additionally, the Aβ1–42(E22Δ) oligomers appear to differ from Aβ1–42(WT) oligomers in size, shape, or both. These results should provide new insights into the functions of Aβ(E22Δ) mutants.