Studying native protein structures at near-atomic resolution in a crowded environment presents challenges. Consequently, understanding the structural intricacies of proteins within pathologically affected tissues often relies on mass spectrometry and proteomic analysis. Here, we utilized cryoelectron microscopy (cryo-EM) and the Build and Retrieve (BaR) method to investigate protein complexes’ structural characteristics such as post-translational modification, active site occupancy, and arrested conformational state in Alzheimer’s disease (AD) using brain lysate from a rat model (TgF344-AD). Our findings reveal novel insights into the architecture of these complexes, corroborated through mass spectrometry analysis. Interestingly, it has been shown that the dysfunction of these protein complexes extends beyond AD, implicating them in cancer, as well as other neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, and schizophrenia. By elucidating these structural details, our work not only enhances our understanding of disease pathology but also suggests new avenues for future approaches in therapeutic intervention.

中文翻译：

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揭示阿尔茨海默病大鼠大脑模型的结构蛋白质组


在拥挤的环境中以近原子分辨率研究天然蛋白质结构是一项挑战。因此，了解病理受影响组织中蛋白质的结构复杂性通常依赖于质谱和蛋白质组学分析。在这里，我们利用冷冻电子显微镜 （cryo-EM） 和构建和检索 （BaR） 方法研究蛋白质复合物的结构特征，例如翻译后修饰、活性位点占据和阿尔茨海默病 （AD） 中的定象停滞状态使用来自大鼠模型的脑裂解物 （TgF344-AD）。我们的研究结果揭示了对这些复合物结构的新见解，并通过质谱分析得到了证实。有趣的是，已经表明这些蛋白质复合物的功能障碍超出了 AD，与癌症以及其他神经退行性疾病（如帕金森病、亨廷顿病和精神分裂症）有关。通过阐明这些结构细节，我们的工作不仅增强了我们对疾病病理学的理解，还为未来的治疗干预方法提出了新的途径。