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Hierarchical chemical determination of amyloid polymorphs in neurodegenerative disease.
神经退行性疾病中淀粉样多晶型物的分级化学测定。
- 影响因子:0
- DOI:10.1038/s41589-020-00708-z
- 作者列表:"Li D","Liu C
- 发表时间:2021-03-01
Abstract
:Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.
摘要
: 淀粉样蛋白聚集,其破坏蛋白质稳态,是人类神经退行性疾病 (NDs) 中发生的常见病理事件。大量证据表明,结构多样性,即所谓的多态性,对淀粉样蛋白病理学具有决定性作用,并且与ND的发病、进展和表型密切相关。但是一个蛋白质怎么会形成这么多稳定的结构呢?最近,原子结构证据迅速增加,以描述化学修饰参与淀粉样蛋白原纤维形成。从这个角度来看,我们的目标是提出一种化学修饰的分级调节,包括共价翻译后修饰 (PTMs) 和非共价辅因子结合,主要基于最新的 α-突触核蛋白和Tau原纤维结构来控制多态性淀粉样蛋白的形成。我们希望强调化学修饰在淀粉样蛋白组装和病理学中的决定性作用,并唤起化学生物学方法来领导蛋白质淀粉样蛋白状态和相关NDs的基础和治疗研究。
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