Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation.
Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation.
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DOI：
10.1073/pnas.2119952119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
电子冷冻显微镜（cryo - EM）的应用极大地拓展了我们对成熟病理性淀粉样纤维原子结构的理解，但在纤维形成起始的分子层面知之甚少。RNA已被证明是tau蛋白纤维形成的一种辅助因子，并且已知它还能与其他蛋白质结合，包括形成病理性包涵体的TDP - 43、FUS和HNRNPA2。我们关于重组tau蛋白与RNA的冷冻电镜结构显示，一个36个残基的C末端纤维核心与RNA结合，且RNA与纤维轴平行。我们推测这种结构可能代表了tau纤维形成的早期阶段。
在包括阿尔茨海默病和肌萎缩侧索硬化症在内的神经退行性疾病中，结合RNA的蛋白质在尸检大脑中以聚集形式被发现。有证据表明RNA有助于这些病理性聚集体的成核；然而，其机制尚未在原子结构层面进行研究。在此，我们展示了通过电子冷冻显微镜（cryo - EM）确定的在有RNA存在的情况下全长重组tau蛋白纤维的3.4 Å分辨率结构。该结构显示出常见的同排交叉-β淀粉样蛋白支架，但纤维核心较小，跨越Glu391到Ala426残基，这是在所有先前研究的tau多态体的模糊外层中无序的区域。RNA在纤维表面与带正电荷的残基Arg406和His407结合，并与纤维轴平行。当加入核糖核酸酶时纤维溶解，表明RNA对纤维完整性是必需的。虽然这种结构不可能与从患者大脑中提取的tau纤维结构同时存在，但可以想象它能解释RNA辅助因子的成核效应，随后随着纤维成熟而发生重塑。
Application of electron cryomicroscopy (cryo-EM) has greatly expanded our understanding of the atomic structures of mature pathological amyloid fibrils, but little is known at the molecular level of the initiation of fibril formation. RNA has been shown to be one cofactor in the formation of fibrils of tau protein and is also known to bind to other proteins, including TDP-43, FUS, and HNRNPA2, which form pathological inclusions. Our cryo-EM structure of recombinant tau protein with RNA reveals a 36-residue, C-terminal fibril core bound to RNA which runs parallel to the fibril axis. We speculate that this structure could represent an early step in the formation of tau fibrils. In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms in autopsied brains. Evidence suggests that RNA aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at the level of atomic structure. Here, we present the 3.4-Å resolution structure of fibrils of full-length recombinant tau protein in the presence of RNA, determined by electron cryomicroscopy (cryo-EM). The structure reveals the familiar in-register cross-β amyloid scaffold but with a small fibril core spanning residues Glu391 to Ala426, a region disordered in the fuzzy coat in all previously studied tau polymorphs. RNA is bound on the fibril surface to the positively charged residues Arg406 and His407 and runs parallel to the fibril axis. The fibrils dissolve when RNase is added, showing that RNA is necessary for fibril integrity. While this structure cannot exist simultaneously with the tau fibril structures extracted from patients’ brains, it could conceivably account for the nucleating effects of RNA cofactors followed by remodeling as fibrils mature.
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影响因子：
16.2
作者：
Kaufman SK;Sanders DW;Thomas TL;Ruchinskas AJ;Vaquer-Alicea J;Sharma AM;Miller TM;Diamond MI
通讯作者：
Diamond MI
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：
16.6
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
通讯作者：
Zweckstetter M
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3
作者：
He, Shaoda;Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.