The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner.
The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner.
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DOI：
10.1083/jcb.201007161
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发表时间：
2011-02-21
期刊：
影响因子：
--
通讯作者：
Brandt R
中科院分区：
文献类型：
--
作者：
Gauthier-Kemper A;Weissmann C;Golovyashkina N;Sebö-Lemke Z;Drewes G;Gerke V;Heinisch JJ;Brandt R
R406 W突变阻止tau蛋白作为膜和微管细胞骨架之间的连接体发挥作用。微管相关蛋白tau的变化是阿尔茨海默病（AD）和与17号染色体相关的帕金森氏症（FTDP-17）的额颞叶痴呆的核心。然而，FTDP-17 tau突变R406 W的功能后果，导致临床上类似AD的tau蛋白病，还没有很好地理解。我们发现，R406 W突变不影响微管相互作用，但取消tau蛋白的膜结合。结合的损失与在突起尖端的捕获减少和过程生长期间的长度波动增加有关。串联亲和纯化标签纯化和质谱鉴定钙调节的质膜结合蛋白膜联蛋白A2（AnxA 2）作为tau的潜在相互作用伴侣。一致地，野生型tau蛋白而不是R406 W tau蛋白在异源酵母表达系统中与AnxA 2相互作用。螯合Ca 2+或敲低AnxA 2消除了野生型和R406 W tau的差异捕获。我们认为R406 W突变的病理效应是由受损的膜结合引起的，这涉及与AnxA 2作为膜-细胞骨架连接器的功能相互作用。
The R406W mutation prevents tau from functioning as a linker between the membrane and the microtubule cytoskeleton. Changes of the microtubule-associated protein tau are central in Alzheimer’s disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). However, the functional consequence of the FTDP-17 tau mutation R406W, which causes a tauopathy clinically resembling AD, is not well understood. We find that the R406W mutation does not affect microtubule interaction but abolishes tau’s membrane binding. Loss of binding is associated with decreased trapping at the tip of neurites and increased length fluctuations during process growth. Tandem affinity purification tag purification and mass spectrometry identify the calcium-regulated plasma membrane–binding protein annexin A2 (AnxA2) as a potential interaction partner of tau. Consistently, wild-type tau but not R406W tau interacts with AnxA2 in a heterologous yeast expression system. Sequestration of Ca2+ or knockdown of AnxA2 abolishes the differential trapping of wild-type and R406W tau. We suggest that the pathological effect of the R406W mutation is caused by impaired membrane binding, which involves a functional interaction with AnxA2 as a membrane–cytoskeleton linker.
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影响因子：
6
作者：
DeTure, M;Ko, LW;Yen, SH
通讯作者：
Yen, SH
阿尔茨海默氏病的GSK3假设。
影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1016/0006-291x(91)90666-u
发表时间：
1991-06-28
影响因子：
3.1
作者：
FOX, MT;PRENTICE, DA;HUGHES, JP
通讯作者：
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影响因子：
4.7
作者：
Chang, Edward;Kim, Sohee;Yin, Haishan;Nagaraja, Haikady N.;Kuret, Jeff
通讯作者：
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