Glycogen synthase kinase-3,β is complexed with tau protein in brain microtubules
Glycogen synthase kinase-3,β is complexed with tau protein in brain microtubules
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DOI：
10.1074/jbc.m107182200
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发表时间：
2002-04-05
影响因子：
4.8
通讯作者：
Paudel, HK
中科院分区：
文献类型：
--
作者：
Sun, W;Qureshi, HY;Paudel, HK
在阿尔茨海默病中，微管相关蛋白tau通过未知机制过度磷酸化，并聚集成成对的螺旋丝。过度磷酸化导致tau蛋白功能丧失、微管不稳定和神经变性。糖原合成酶激酶-3 β（GSK 3 β）与正常和阿尔茨海默病脑中tau蛋白的磷酸化有关。GSK 3 β-tau相互作用的分子机制尚未阐明。在这项研究中，我们发现，当微管被拆卸，微管相关的GSK 3 β从微管解离。从凝胶过滤柱中，解离的GSK 3 β以类似于400-kDa复合物的形式洗脱。当含有类似于400-kDa复合物的组分通过抗-GSK 3 β免疫亲和柱层析时，tau与GSK 3 β共洗脱。从含有类似于400-kDa复合物的组分中，tau蛋白和GSK 3 β相互免疫共沉淀。GSK 3 β结合非磷酸化tau，并且GSK 3 β结合区位于tau的N-末端投射结构域内。在体外，GSK 3 β仅在tau存在的情况下与微管结合。从脑提取物中，与tau蛋白共免疫沉淀的GSK 3 β比GSK 3 α多6倍。这些数据表明，在大脑中，GSK 3 β与tau蛋白结合在一个类似于400-kDa微管相关复合物中，GSK 3 β通过tau蛋白与微管相关。
In Alzheimer's disease, microtubule-associated protein tau is hyperphosphorylated by an unknown mechanism and is aggregated into paired helical filaments. Hyperphosphorylation causes loss of tau function, microtubule instability, and neurodegeneration. Glycogen synthase kinase-3beta (GSK3beta) has been implicated in the phosphorylation of tau in normal and Alzheimer's disease brain. The molecular mechanism of GSK3beta-tau interaction has not been clarified. In this study, we find that when microtubules are disassembled, microtubule-associated GSK3beta dissociates from microtubules. From a gel filtration column, the dissociated GSK3beta elutes as an similar to400-kDa complex. When fractions containing the similar to400-kDa complex are chromatographed through an anti-GSK3beta immunoaffinity column, tau co-elutes with GSK3beta. From fractions containing the similar to400-kDa complex, both tau and GSK3beta co-immunoprecipitate with each other. GSK3beta binds to nonphosphorylated tau, and the GSK3beta-binding region is located within the N-terminal projection domain of tau. In vitro, GSK3beta associates with microtubules only in the presence of tau. From brain extract, similar to6-fold more GSK3beta co-immunoprecipitates with tau than GSK3alpha. These data indicate that, in brain, GSK3beta is bound to tau within a similar to400-kDa microtubule-associated complex, and GSK3beta associates with microtubules via tau.