Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment
Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment
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DOI：
10.1021/bi027348m
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发表时间：
2003-07-15
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：
Berry, RW;Abraha, A;Binder, LI
微管相关蛋白 tau 的异常聚集发生在许多神经退行性疾病中，因此了解 tau 聚合机制非常重要。先前的研究表明，tau 的 C 端区域在体外抑制聚合，并且越来越多的证据表明 caspase 在 C 端的 Asp 421 处对 tau 进行切割，是阿尔茨海默病中 tau 聚合的重要诱导剂。在本研究中，我们提供了证据表明 caspase 裂解产生的 C 端肽片段抑制 tau 聚合，这表明 caspase 裂解通过去除抑制性控制元件来增强其聚合。此外，我们提供的证据表明，该肽呈现 α 螺旋构型，并通过与微管结合重复区域中的残基 321-375 相互作用来抑制 tau 组装。这些发现表明，阿尔茨海默病病程中纤维状病理的形成可能是由导致半胱天冬酶激活的细胞凋亡事件驱动或维持的。
Abnormal aggregation of the microtubule-associated protein, tau, occurs in many neurodegenerative diseases, making it important to understand the mechanisms of tau polymerization. Previous work has indicated that the C-terminal region of tau inhibits polymerization in vitro, and a growing body of evidence implicates caspase cleavage of tau at Asp 421 in the C-terminus as an important inducer of tau polymerization in Alzheimer's disease. In the present study, we provide evidence that the C-terminal peptide fragment produced by caspase cleavage inhibits tau polymerization, suggesting that caspase cleavage of tau enhances its polymerization by removing the inhibitory control element. Moreover, we provide evidence that the peptide assumes an alpha-helical configuration and inhibits tau assembly by interacting with residues 321-375 in the microtubule binding repeat region. These findings indicate that formation of the fibrillar pathologies during the course of Alzheimer's disease may be driven or sustained by apoptotic events leading to caspase activation.