Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau.
Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau.
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DOI：
10.1038/s41467-017-00480-0
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发表时间：
2017-08-17
影响因子：
16.6
通讯作者：
Zweckstetter M
中科院分区：
文献类型：
--
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
Tau蛋白在阿尔茨海默病患者的大脑中聚集成缠结。然而，在溶液中，Tau本质上是无序的，高度可溶，并结合到微管。目前还不清楚是什么引发了从高溶解度和功能性的无害相到固体状神经毒性沉积物的转化。在这里，我们表明，微管结合重复的Tau，这是赖氨酸丰富，在溶液中进行液-液相分离。液-液分层导致Tau的淀粉样蛋白促进元件的分子拥挤并驱动静电凝聚。此外，我们证明了三个重复和四个重复的Tau亚型在其分层能力上不同。因此，Tau的选择性剪接可以调节含Tau的无膜区室的形成。此外，Tau重复序列的磷酸化在细胞蛋白质条件下促进液-液相分离。组合的数据提出了一种机制，其中由Tau的带正电荷的微管结合结构域形成的液滴与带负电荷的分子进行凝聚以促进淀粉样蛋白形成。Tau在阿尔茨海默病患者的大脑中形成聚集体。在这里，作者确定了Tau的微管结合重复序列经历磷酸化依赖性液-液相分离的条件，导致形成的Tau液滴中的分子拥挤，并通过NMR和其他生物物理方法对其进行表征。
The protein Tau aggregates into tangles in the brain of patients with Alzheimer’s disease. In solution, however, Tau is intrinsically disordered, highly soluble, and binds to microtubules. It is still unclear what initiates the conversion from an innocuous phase of high solubility and functionality to solid-like neurotoxic deposits. Here, we show that the microtubule-binding repeats of Tau, which are lysine-rich, undergo liquid–liquid phase separation in solution. Liquid–liquid demixing causes molecular crowding of amyloid-promoting elements of Tau and drives electrostatic coacervation. Furthermore, we demonstrate that three-repeat and four-repeat isoforms of Tau differ in their ability for demixing. Alternative splicing of Tau can thus regulate the formation of Tau-containing membrane-less compartments. In addition, phosphorylation of Tau repeats promotes liquid–liquid phase separation at cellular protein conditions. The combined data propose a mechanism in which liquid droplets formed by the positively charged microtubule-binding domain of Tau undergo coacervation with negatively charged molecules to promote amyloid formation. Tau forms aggregates in the brains of Alzheimer patients. Here, the authors identify conditions, where the microtubule-binding repeats of Tau undergo a phosphorylation-dependent liquid–liquid phase separation, leading to molecular crowding in the formed Tau liquid droplets and characterize them by NMR and other biophysical methods.
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DOI：
10.1083/jcb.115.3.717
发表时间：
1991-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Butner KA;Kirschner MW
通讯作者：
Kirschner MW
影响因子：
4.8
作者：
DREWES, G;TRINCZEK, B;MANDELKOW, E
通讯作者：
MANDELKOW, E
影响因子：
21.8
作者：
Aumiller, William M., Jr.;Keating, Christine D.
通讯作者：
Keating, Christine D.
影响因子：
64.5
作者：
Banani SF;Rice AM;Peeples WB;Lin Y;Jain S;Parker R;Rosen MK
通讯作者：
Rosen MK
DOI：
10.1073/pnas.1630428100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Gamblin, TC;Chen, F;Cryns, VL
通讯作者：
Cryns, VL