Turn nucleation perturbs amyloid β self-assembly and cytotoxicity.
Turn nucleation perturbs amyloid β self-assembly and cytotoxicity.
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DOI：
10.1016/j.jmb.2012.01.055
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发表时间：
2012-08-10
影响因子：
5.6
通讯作者：
Nilsson BL
中科院分区：
文献类型：
--
作者：
Doran TM;Anderson EA;Latchney SE;Opanashuk LA;Nilsson BL
由淀粉样蛋白-β (a β)原纤维组成的老年斑的积累是阿尔茨海默病（AD）的一个标志，尽管原纤维寡聚物物种被认为是阿尔茨海默病发病机制中主要的神经毒性同源物。关于Aβ寡聚物和纤维形成以及这些聚集体的细胞毒性之间的机制关系的不确定性仍然存在。β-Turn的形成被认为是a β纤维形成过程中一个潜在的速率限制步骤。通过系统地用有效的旋核基序d-ProGly替换Aβ旋核区（残基24-27）的氨基酸对，探讨了旋核对Aβ自组装的影响。对这些突变的动力学、热力学和细胞毒性效应进行了表征。研究发现，与成核位置有关的弯的形成显著地加速了Aβ纤维的自组装。三种含d-ProGlycontaining a β变异体的细胞毒性显著低于野生型a β40，可能是由于低聚物数量减少，从而更快地向成熟原纤维发展；然而，低聚体种群并没有被消除，这表明回合形成也是低聚体结构的一个特征。这些结果表明，转核是a β40纤维形成的关键步骤。
The accumulation of senile plaques composed of amyloid-β (Aβ) fibrils is a hallmark of Alzheimer’s disease (AD), although prefibrillar oligomeric species are believed to be the primary neurotoxic congeners in AD pathogenesis. Uncertainty regarding the mechanistic relationship between Aβ oligomer and fibril formation and the cytotoxicity of these aggregate species persists. β-Turn formation has been proposed to be a potential rate limiting step during Aβ fibrillogenesis. The effect of turn nucleation on Aβ self-assembly was probed by systematically replacing amino acid pairs in the putative turn region of Aβ (residues 24–27) with d-ProGly, an effective turn nucleating motif. The kinetic, thermodynamic, and cytotoxic effects of these mutations were characterized. It was found that turn formation dramatically accelerated Aβ fibril self-assembly dependent on the site of turn nucleation. The cytotoxicity of the three d-ProGlycontaining Aβ variants was significantly lower than that of wild-type Aβ40, presumably due to decreased oligomer populations as a function of more rapid progression to mature fibrils; oligomer populations were not eliminated, however, suggesting that turn formation is also a feature of oligomer structures. These results indicate that turn nucleation is a critical step in Aβ40 fibril formation.