Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391).
Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391).
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DOI：
10.3389/fnins.2022.988074
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发表时间：
2022
影响因子：
4.3
通讯作者：
Siemer, Ansgar B. B.
中科院分区：
文献类型：
--
作者：
Al-Hilaly, Youssra K. K.;Hurt, Connor;Rickard, Janet E. E.;Harrington, Charles R. R.;Storey, John M. D.;Wischik, Claude M. M.;Serpell, Louise C. C.;Siemer, Ansgar B. B.
tau蛋白聚集成纤维状交叉β聚集体是阿尔茨海默病（AD）和许多其他神经退行性tau蛋白病的标志。最近，已经解决了患者来源的tau配对螺旋丝（PHF）的几个核心结构，揭示了通常与特定tau蛋白病相关的结构变异性。为了进一步表征这些原纤维核心的动力学，筛选菌株特异性小分子作为潜在的生物标志物和治疗剂，并开发菌株特异性抗体，需要tau细丝的重组体外模型。我们最近表明，一个95个残基的tau片段（从残基297至391），称为dGAE，在体外形成细丝的情况下，聚阴离子辅因子通常用于体外聚集全长tau。Tau（297-391）被鉴定为tau PHF的蛋白水解抗性核心，并且与离体PHF中通过冷冻电子显微镜表征的结构重叠，使其成为体外研究AD tau细丝的有希望的模型。在本研究中，我们使用固态NMR来表征tau（297-391）细丝，并表明在非还原条件下组装的这种细丝比在还原剂DTT存在下制备的细丝更具动态性且更不有序。我们进一步报告了tau（297-391）+DTT细丝的共振分配，并将其与tau的现有核心结构进行比较。
Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer’s diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed. We recently showed that a 95-residue fragment of tau (from residue 297 to 391), termed dGAE, forms filaments in vitro in the absence of polyanionic co-factors often used for in vitro aggregation of full-length tau. Tau(297-391) was identified as the proteolytic resistant core of tau PHFs and overlaps with the structures characterized by cryo-electron microscopy in ex vivo PHFs, making it a promising model for the study of AD tau filaments in vitro. In the present study, we used solid-state NMR to characterize tau(297-391) filaments and show that such filaments assembled under non-reducing conditions are more dynamic and less ordered than those made in the presence of the reducing agent DTT. We further report the resonance assignment of tau(297-391)+DTT filaments and compare it to existing core structures of tau.
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影响因子：
15
作者：
Daebel, Venita;Chinnathambi, Subashchandrabose;Lange, Adam
通讯作者：
Lange, Adam
影响因子：
2.7
作者：
Detken, A;Hardy, EH;Meier, BH
通讯作者：
Meier, BH
影响因子：
1.7
作者：
Baldus, M;Petkova, AT;Griffin, RG
通讯作者：
Griffin, RG
DOI：
10.1073/pnas.1906839116
发表时间：
2019-08-13
影响因子：
11.1
作者：
Dregni, Aurelio J.;Mandala, Venkata S.;Hong, Mei
通讯作者：
Hong, Mei
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA