Tau polymerization: Role of the amino terminus
Tau polymerization: Role of the amino terminus
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DOI：
10.1021/bi0272510
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发表时间：
2003-02-25
期刊：
影响因子：
2.9
通讯作者：
Binder, LI
中科院分区：
文献类型：
--
作者：
Gamblin, TC;Berry, RW;Binder, LI
tau分子异常聚合成不溶性细丝是阿尔茨海默病背后的神经退行性过程中的一个重要事件。先前的实验表明，该分子的微管结合重复区域对于其在体外聚合成类似阿尔茨海默病中发现的细丝的能力至关重要。然而，越来越清楚的是，微管结合重复序列外的区域，如外显子2和3以及羧基末端尾部，可以极大地影响其聚合。由于先前假设tau的氨基末端可能参与疾病状态下产生病理构象，因此研究了其在聚合过程中的作用。该报告表明，氨基末端的去除极大地抑制了tau分子的聚合，降低了聚合的速度和程度。这些结果支持了一种假设，即tau形成涉及氨基末端的特定构象的能力是疾病状态下tau聚合物形成的早期事件。此外，精氨酸5突变为亮氨酸((R)5(L))，模拟了在单个FTDP17病例中发现的氨基末端tau突变，增强了tau分子的聚合。因此，tau分子的氨基端，虽然在其聚合研究中很大程度上被忽视，但却是聚合过程的重要贡献者。
The abnormal polymerization of the tau molecule into insoluble filaments is a seminal event in the neurodegenerative process underlying Alzheimer's disease. Previous experimentation has shown that the microtubule-binding repeat region of the molecule is vital for its ability to polymerize in vitro into filaments similar to those found in Alzheimer's disease. However, it is becoming clear that regions outside the microtubule-binding repeat, such as exons 2 and 3 and the carboxy-terminal tail, can greatly influence its polymerization. Since it has been previously postulated that the amino terminus of tau could be involved in generating pathological conformations in the disease state, its role in the polymerization process was investigated. This report demonstrates that the removal of the amino terminus greatly inhibits the polymerization of the tau molecule, reducing both the rate and extent of polymerization. These results support the hypothesis that the ability of tau to form specific conformations involving the amino terminus is an early event in the formation of tau polymers in the disease state. Furthermore, the mutation of arginine 5 to leucine ((R)5(L)), mimicking an amino-terminal tau mutation found in a single case of FTDP17, enhances the polymerization of the tau molecule. Therefore, the amino terminus of the tau molecule, while largely overlooked in studies of its polymerization, is a significant contributor to the polymerization process.