Department of Neurobiology, University of Osnabrück, Osnabrück, Germany.
J Cell Biol. 2011 Feb 21;192(4):647-61. doi: 10.1083/jcb.201007161.
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 Ca(2+) 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.
在阿尔茨海默病（AD）和与 17 号染色体相关的额颞叶痴呆伴帕金森病（FTDP-17）中，微管相关蛋白 tau 的变化是核心。然而，导致类似 AD 的神经病变的 FTDP-17 tau 突变 R406W 的功能后果尚不清楚。我们发现 R406W 突变不会影响微管相互作用，但会破坏 tau 的膜结合。结合的丧失与在神经突尖端的捕获减少和在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（AnxA2）为 tau 的潜在相互作用伙伴。一致地，野生型 tau 但不是 R406W tau 在异源酵母表达系统中与 AnxA2 相互作用。Ca（2+）的隔离或 AnxA2 的敲低会消除野生型和 R406W tau 的差异捕获。我们认为，R406W 突变的病理作用是由膜结合受损引起的，这涉及与 AnxA2 的功能相互作用，作为膜 - 细胞骨架连接物。
