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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >OXIDATION OF CYSTEINE-322 IN THE REPEAT DOMAIN OF MICROTUBULE-ASSOCIATED PROTEIN TAU CONTROLS THE IN VITRO ASSEMBLY OF PAIRED HELICAL FILAMENTS
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OXIDATION OF CYSTEINE-322 IN THE REPEAT DOMAIN OF MICROTUBULE-ASSOCIATED PROTEIN TAU CONTROLS THE IN VITRO ASSEMBLY OF PAIRED HELICAL FILAMENTS

机译：半微管缔合蛋白Tau重复域中半胱氨酸-322的氧化可控制成对螺旋丝的体外组装。

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摘要

One of the hallmarks of Alzheimer disease is the pathological aggregation of tau protein into paired helical filaments (PHFs) and neurofibrillary tangles. Here we describe the in vitro assembly of recombinant tau protein and constructs derived from it into PHFs. Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping tau in a reducing environment all inhibited assembly. With constructs derived from four-repeat tau (having the additional repeat no. 2 and a second Cys-291), PHF assembly was blocked because Cys-291 and Cys-322 interact within the molecule. PHF assembly was enabled again by mutating Cys-291 for Ala. The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. The data imply that the redox potential in the neuron is crucial for PHF assembly, independently or in addition to pathological phosphorylation reactions. [References: 36]
机译：阿尔茨海默氏病的标志之一是tau蛋白在病理学上聚集为成对的螺旋丝（PHF）和神经原纤维缠结。在这里，我们描述了重组tau蛋白的体外组装以及从其衍生的构建体进入PHFs的过程。尽管整个tau组装不良，但包含三个内部重复序列（对应于胎儿tau亚型）的构建体可重复形成PHF。这种能力取决于单个Cys-322形成的分子间二硫键。阻断SH基团，使Ala的Cys突变或将tau保持在还原性环境中均抑制了组装。用衍生自四重复tau的构建体（具有另外的重复序列2和第二个Cys-291），由于Cys-291和Cys-322在分子内相互作用，PHF装配被阻断。通过突变Ala的Cys-291，再次实现了PHF组装，合成的PHF结合了用于阿尔茨海默氏病诊断的染料硫黄素S。数据表明，神经元中的氧化还原电位对于PHF组装至关重要，独立于病理性磷酸化反应或对病理性磷酸化反应而言至关重要。 [参考：36]

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