Dinoto Luca, Deture Michael A, Purich Daniel L
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610-0245, USA.
Microsc Res Tech. 2005 Jul;67(3-4):156-63. doi: 10.1002/jemt.20195.
Although Tau and MAP2 readily assemble into straight filaments (SFs), Tau's unique ability to form paired-helical filaments (PHFs) may offer clues as to why Tau's microtubule-binding region (MTBR) is the exclusive building block of the neurofibrillary tangles that accumulate during Alzheimer's disease. To learn more about the factors permitting Tau to form both SFs and PHFs, we investigated the microtubule binding, thiol oxidation, and polymerization reactions of the monomer and dimer forms of Tau and MAP2 MTBRs. This review focuses on electron microscopic evidence (1) that facilitated the identification of amino acid residues within 3-repeat Tau that promote PHF formation; and (2) provided experimental evidence for the polymerization of S-glutathionylated three-repeat Tau, a reaction that unambiguously demonstrates that disulfide-linked Tau-S-S-Tau dimer formation is not a compulsory step in filament assembly. We also consider these findings within the context of current views on the genetic and biochemical basis of Tau fibrillogenesis.
尽管Tau蛋白和微管相关蛋白2(MAP2)能轻易组装成直丝(SFs),但Tau蛋白形成双螺旋丝(PHFs)的独特能力或许能为以下问题提供线索,即为何Tau蛋白的微管结合区域(MTBR)是阿尔茨海默病期间积累的神经原纤维缠结的唯一组成部分。为了更深入了解促使Tau蛋白形成SFs和PHFs的因素,我们研究了Tau蛋白和MAP2蛋白MTBRs的单体和二聚体形式的微管结合、硫醇氧化及聚合反应。本综述聚焦于电子显微镜证据:(1)有助于识别3重复Tau蛋白中促进PHF形成的氨基酸残基;(2)为S-谷胱甘肽化三重复Tau蛋白的聚合提供实验证据,该反应明确表明二硫键连接的Tau-S-S-Tau二聚体形成并非丝状体组装的必要步骤。我们还结合当前关于Tau蛋白纤维形成的遗传和生化基础的观点来考量这些发现。