Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments
Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments
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DOI：
10.1073/pnas.121119298
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发表时间：
2001-06-05
影响因子：
11.1
通讯作者：
Iqbal, K
中科院分区：
文献类型：
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作者：
Alonso, AD;Zaidi, T;Iqbal, K
微管相关蛋白T是一个包含六种异构体的家族，在阿尔茨海默病（AD）患者以及其他几种tau蛋白病患者的大脑中，它会异常过度磷酸化，并以成对螺旋丝（PHF）的形式积聚。在此，我们表明，来自AD脑细胞质的异常过度磷酸化的tau蛋白（AD P - tau）在pH值为6.9、还原条件下、35℃孵育90分钟时，会自聚集成PHF样结构。对AD P - tau进行体外去磷酸化（而非去糖基化）会抑制其自聚合成PHF。此外，过度磷酸化会诱导六种tau异构体各自自组装成PHF缠结和直丝，并且在没有分子其余部分的情况下，微管结合结构域/重复区域也能自组装成PHF。因此，似乎tau是通过微管结合结构域/重复区域的结合而自组装的，并且异常的过度磷酸化通过中和侧翼区域的抑制性碱性电荷，促进了tau自组装成PHF缠结和直丝。
The microtubule-associated protein T is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies, Here. we show that the abnormally hyperphosphorylated tau from AD brain cytosol (AD P-tau) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35 degreesC during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-tau inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six tau isoforms into tangles of PHF and straight filaments, and the microtubule binding domains/repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that tau self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of tau into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.