O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation
O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation
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O-糖基化诱导淀粉样蛋白-β 形成易降解的新原纤维多晶型物。
DOI：
10.1021/jacs.1c08607
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发表时间：
2021-12-08
影响因子：
15
通讯作者：
Dong, Suwei
中科院分区：
文献类型：
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作者：
Liu, Dangliang;Wei, Qijia;Dong, Suwei
在阿尔茨海默病（AD）的进展过程中，大脑中淀粉样蛋白- β (A β)肽的积累（由于生物合成和清除之间的平衡被破坏）发生。A - β肽具有多种翻译后修饰（PTMs），这些修饰以不同的方式调节A - β聚集成原纤维，但了解PTMs在这些过程中的机制作用仍然是一个挑战。在这里，我们化学合成了三种具有Tyr10 o糖基化的A β(1-42)肽的均匀修饰亚型，Tyr10 o糖基化是一种最初从AD患者脑脊液样本中发现的不寻常的PTM。我们发现，多糖显著影响A β的聚集和降解（42）。通过结合冷冻电镜和各种生化分析，我们证明了Gal β 1-3GalNAc修饰重定向a β(42)形成新的纤维多态性结构，该结构不太稳定，更容易受到a β降解酶（例如胰岛素降解酶）的影响。因此，除了显示特定的o糖基化修饰如何在分子水平上影响A β(42)聚集外，我们的研究还提供了强大的实验工具，以支持进一步研究PTMs如何影响A β(42)原纤维聚集和ad相关的神经毒性。
Brain accumulation of amyloid-beta (A beta) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression of Alzheimer's disease (AD). A beta peptides have diverse posttranslational modifications (PTMs) that variously modulate A beta aggregation into fibrils, but understanding the mechanistic roles of PTMs in these processes remains a challenge. Here, we chemically synthesized three homogeneously modified isoforms of A beta (1-42) peptides bearing Tyr10 O-glycosylation, an unusual PTM initially identified from the cerebrospinal fluid samples of AD patients. We discovered that Oglycans significantly affect both the aggregation and degradation of A beta(42). By combining cryo-EM and various biochemical assays, we demonstrate that a Gal beta 1-3GalNAc modification redirects A beta(42) to form a new fibril polymorphic structure that is less stable and more vulnerable to A beta-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation modifications affect A beta(42) aggregation at the molecular level, our study provides powerful experimental tools to support further investigations about how PTMs affect A beta(42) fibril aggregation and AD-related neurotoxicity.