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ATP Kinetically Modulates Pathogenic Tau Fibrillations.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-09-11 , DOI: 10.1021/acschemneuro.0c00479
Chae Eun Heo 1, 2 , Jong Yoon Han 1, 2 , Sungsu Lim 3 , Jeeyoung Lee 4 , Dongjoon Im 1, 2 , Min Jae Lee 4 , Yun Kyung Kim 3, 5 , Hugh I Kim 1, 2
Affiliation  

Advanced understanding of Alzheimer’s disease (AD) and several tauopathies over the past decades indicates the pathological importance of tau aggregation in these diseases. Herein, we demonstrated that adenosine triphosphate (ATP), a highly charged anionic molecule found abundantly in the cytosol of cells, catalyzes fibrillation of tau as well as human islet amyloid polypeptide, a representative of basic intrinsically disordered proteins. Our results showed that ATP attracts multiple lysine residues of the four-repeat domain of tau (K18) via supramolecular complexation, thereby forming dimers that are converted to nuclei and accelerate fibril elongation. However, ATP was not directly incorporated into the K18 fibrils, suggesting that ATP plays the role of a catalyst, rather than a reactant, during K18 fibrillation. We also characterized the correlation between ATP dyshomeostasis and tau aggregation in the cellular environment. Our multiple biophysical approaches, including native mass spectrometry (MS), small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulation, provided insights into the molecular-level influence of ATP on the structural changes and fibrillation of tau.

中文翻译:

ATP在动力上调节致病性Tau纤颤。

在过去的几十年中,对阿尔茨海默氏病(AD)和一些tauopathies的深入了解表明tau聚集在这些疾病中的病理重要性。在本文中,我们证明了三磷酸腺苷(ATP)是一种在细胞质中大量发现的高度带电荷的阴离子分子,可催化tau以及人胰岛淀粉样多肽(原发性基本内在无序蛋白)的原纤维化。我们的结果表明,ATP通过超分子络合吸引tau(K18)四重复域的多个赖氨酸残基,从而形成二聚体,该二聚体转化为核并加速原纤维的延长。但是,ATP并未直接掺入K18的原纤维中,这表明ATP在K18的原纤化过程中起着催化剂而不是反应物的作用。我们还表征了细胞环境中ATP动态平衡与tau聚集之间的相关性。我们的多种生物物理方法,包括天然质谱(MS),小角X射线散射(SAXS)和分子动力学(MD)模拟,提供了有关ATP在分子水平上对tau结构变化和原纤维化影响的见解。 。
更新日期:2020-10-07
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