Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias
Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias
复制标题
DOI：
10.1021/bi000850r
复制
发表时间：
2000-09-26
期刊：
影响因子：
2.9
通讯作者：
Mandelkow, E
中科院分区：
文献类型：
--
作者：
Barghorn, S;Zheng-Fischhöfer, Q;Mandelkow, E
我们研究了与17号染色体（FTDP-17）连锁的额颞叶痴呆和帕金森综合征中发现的几种错义和缺失的tau蛋白突变体（G272 V、N279 K、Delta K280、P301 L、V337 M、R406 W）的生化和结构参数。基于全长tau（htau 40）和衍生自重复结构域的构建体表达突变蛋白。分析了它们增强微管组装、tau与微管结合、二级结构含量和聚集成阿尔茨海默氏症样成对螺旋或直丝的能力。我们发现，突变导致微管相互作用和稳定性的适度降低，与野生型蛋白质的天然未折叠构象相比，它们没有显示出总体结构变化，但聚集成PHFs强烈增强，特别是对于突变体Delta K280和P301 L。这种病理性聚集的获得与疾病的常染色体显性遗传性质一致。
We have studied biochemical and structural parameters of several missense and deletion mutants of tau protein (G272V, N279K, Delta K280, P301L, V337M, R406W) found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The mutant proteins were expressed on the basis of both full-length tau (htau40) and constructs derived from the repeat domain. They were analyzed with respect to the capacity to enhance microtubule assembly, binding of tau to microtubules, secondary structure content, and aggregation into Alzheimer-like paired helical or straight filaments. We find that the mutations cause a moderate decrease in microtubule interactions and stabilization, and they show no gross structural changes compared with the natively unfolded conformation of the wild-type protein, but the aggregation into PHFs is strongly enhanced, particularly for the mutants Delta K280 and P301L. This gain of pathological aggregation would be consistent with the autosomal dominant nature of the disease.