Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.
Biochem Biophys Res Commun. 2021 Mar 19;545:119-124. doi: 10.1016/j.bbrc.2021.01.081. Epub 2021 Feb 3.
Aβ42 aggregation plays a central role in the pathogenesis of Alzheimer's disease. In addition to the insoluble fibrils that comprise the amyloid plaques, Aβ42 also forms soluble aggregates collectively called oligomers, which are more toxic and pathogenic than fibrils. Understanding the structure and dynamics of Aβ42 oligomers is critical for developing effective therapeutic interventions against these oligomers. Here we studied the structural dynamics of Aβ42 globulomers, a type of Aβ42 oligomers prepared in the presence of sodium dodecyl sulfate, using site-directed spin labeling. Spin labels were introduced, one at a time, at all 42 residue positions of Aβ42 sequence. Electron paramagnetic resonance spectra of spin-labeled samples reveal four structural segments based on site-dependent spin label mobility pattern. Segment-1 consists of residues 1-6, which have the highest mobility that is consistent with complete disorder. Segment-3 is the most immobilized region, including residues 31-34. Segment-2 and -4 have intermediate mobility and are composed of residues 7-30 and 35-42, respectively. Considering the inverse relationship between protein dynamics and stability, our results suggest that residues 31-34 are the most stable segment in Aβ42 oligomers. At the same time, the EPR spectral lineshape suggests that Aβ42 globulomers lack a well-packed structural core akin to that of globular proteins.
Aβ42 聚集在阿尔茨海默病的发病机制中起着核心作用。除了构成淀粉样斑块的不溶性纤维外，Aβ42 还形成可溶性聚集物，统称为寡聚物，寡聚物比纤维更具毒性和致病性。了解 Aβ42 寡聚物的结构和动态对于开发针对这些寡聚物的有效治疗干预措施至关重要。在这里，我们使用定点自旋标记研究了 Aβ42 球团，一种在十二烷基硫酸钠存在下制备的 Aβ42 寡聚物的结构动力学。将自旋标记一个一个地引入 Aβ42 序列的所有 42 个残基位置。自旋标记样品的电子顺磁共振光谱根据位置依赖的自旋标记迁移模式显示出四个结构片段。片段 1 由残基 1-6 组成，迁移率最高，与完全无序一致。片段 3 是最固定的区域，包括残基 31-34。片段 2 和 -4 具有中等迁移率，分别由残基 7-30 和 35-42 组成。考虑到蛋白质动力学与稳定性之间的反比关系，我们的结果表明，残基 31-34 是 Aβ42 寡聚物中最稳定的片段。同时，EPR 光谱线形状表明，Aβ42 球团缺乏类似球状蛋白的紧密堆积结构核心。
