A thiol-based intramolecular redox switch in four-repeat tau controls fibril assembly and disassembly.
A thiol-based intramolecular redox switch in four-repeat tau controls fibril assembly and disassembly.
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四重复tau蛋白中基于巯基的分子内氧化还原开关控制原纤维的组装和拆卸。
DOI：
10.1016/j.jbc.2021.101021
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Margittai M
中科院分区：
文献类型：
--
作者：
Weismiller HA;Holub TJ;Krzesinski BJ;Margittai M
氧化应激与包括阿尔茨海默病在内的几种tau蛋白病的发病机制和进展有关。由tau蛋白组成的纤维状内含物的沉积是这些疾病的病理标志之一。尽管越来越明显的是，特定的原纤维结构可能会因tau蛋白病而异，并且人们认识到不同类型的同种型（三重复和四重复tau）可以选择性沉积，但对氧化在聚集中可能发挥的作用知之甚少。四重复tau蛋白含有两个半胱氨酸，可以形成分子内二硫键，导致结构受限的紧凑单体。关于这种单体是否能聚集，存在分歧。使用分离的四个重复tau单体（htau40）与分子内二硫键，我们证明，这些蛋白质形成原纤维。原纤维比在还原条件下形成的原纤维更不稳定，但在接种氧化的tau单体方面非常有效。相反，强的接种屏障阻止还原的tau单体、其中半胱氨酸已被丙氨酸或丝氨酸取代的tau模拟物和三重复tau（htau23）（单半胱氨酸同种型）的掺入。当种子和单体类型颠倒时，屏障也成立，表明氧化和还原的tau彼此不相容。令人惊讶的是，由紧凑的tau组成的原纤维在还原时解聚，突出了分子内二硫键对原纤维稳定性的重要性。这些发现揭示了一种新型的二元氧化还原开关，它控制着这些纤维的聚集和解聚，并扩展了tau聚集体的构象谱。
Oxidative stress has been implicated in the pathogenesis and progression of several tauopathies, including Alzheimer's disease. The deposition of fibrillar inclusions made of tau protein is one of the pathological hallmarks of these disorders. Although it is becoming increasingly evident that the specific fibril structure may vary from one tauopathy to another and it is recognized that different types of isoforms (three-repeat and four-repeat tau) can be selectively deposited, little is known about the role oxidation may play in aggregation. Four-repeat tau contains two cysteines that can form an intramolecular disulfide bond, resulting in a structurally restrained compact monomer. There is discrepancy as to whether this monomer can aggregate or not. Using isolated four-repeat tau monomers (htau40) with intramolecular disulfide bonds, we demonstrate that these proteins form fibrils. The fibrils are less stable than fibrils formed under reducing conditions but are highly effective in seeding oxidized tau monomers. Conversely, a strong seeding barrier prevents incorporation of reduced tau monomers, tau mimics in which the cysteines have been replaced by alanines or serines, and three-repeat tau (htau23), a single-cysteine isoform. The barrier also holds true when seed and monomer types are reversed, indicating that oxidized and reduced tau are incompatible with each other. Surprisingly, fibrils composed of compact tau disaggregate upon reduction, highlighting the importance of the intramolecular disulfide bond for fibril stability. The findings uncover a novel binary redox switch that controls the aggregation and disaggregation of these fibrils and extend the conformational spectrum of tau aggregates.
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影响因子：
2.9
作者：
Dinkel PD;Holden MR;Matin N;Margittai M
通讯作者：
Margittai M
影响因子：
2.9
作者：
Dinkel, Paul D.;Siddiqua, Ayisha;Margittai, Martin
通讯作者：
Margittai, Martin
影响因子：
29
作者：
Gibbons GS;Lee VMY;Trojanowski JQ
通讯作者：
Trojanowski JQ
影响因子：
15
作者：
FLORY, PJ
通讯作者：
FLORY, PJ
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA