Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance.
Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance.
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DOI：
10.1021/acs.biochem.0c00342
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发表时间：
2020-06-23
期刊：
影响因子：
2.9
通讯作者：
Hong M
中科院分区：
文献类型：
--
作者：
Dregni AJ;Duan P;Hong M
在患有多种神经退行性疾病（如阿尔茨海默病和皮质基底变性（CBD））的大脑中，微管相关蛋白tau聚集成不同的神经原纤维缠结。tau蛋白错误折叠和聚集的机制尚不清楚。确定tau蛋白细丝的结构、动力学和水分可及性可能有助于深入了解tau蛋白错误折叠的途径。在这里，我们利用固体核磁共振光谱研究了肝素纤化的0N4R tau β-片核的水合作用和动力学。这个β片核心由第二和第三个微管结合重复序列R2和R3组成，它们形成一个发夹。水编辑的2D 13C-13C和15N-13C相关光谱表明，R2和R3结构域的大多数残基具有低水可及性，表明该发夹被其他蛋白质片段包围。但与其他丝氨酸和苏氨酸残基相比，有少量残基，尤其是S285和S316的水化程度较好，说明发夹中部存在一个小的水化通道。为了探究水分可及性是否与蛋白质动力学相关，我们测量了β-片核的主干N-H偶极偶联。有趣的是，第四个微管结合重复序列R4中的残基表现出刚性极限N-H偶极偶联，尽管该结构域在2D 15N-13C相关光谱中表现出较弱的强度。这些结果表明，R4结构域在一些亚基中参与交叉-β氢键，而在其他亚基中表现出动态无序。综上所述，这些水合作用和动力学数据表明，0N4R tau蛋白的R2-R3发夹被外部的其他蛋白质片段屏蔽，但内部含有一个小的水孔。这种结构拓扑结构与CBD tau原纤维结构有各种相似之处，但也表现出特定的差异。在肝素纤维化的4R tau中，R4结构域的紊乱和一个小水渠的存在对患病大脑中tau原纤维的结构有影响。
The microtubule-associated protein tau aggregates into distinct neurofibrillary tangles in brains afflicted with multiple neurodegenerative diseases such as Alzheimer’s disease and corticobasal degeneration (CBD). The mechanism of tau misfolding and aggregation is poorly understood. Determining the structure, dynamics, and water accessibility of tau filaments may give insight into the pathway of tau misfolding. Here, we investigate the hydration and dynamics of the β-sheet core of heparin-fibrillized 0N4R tau using solid-state NMR spectroscopy. This β-sheet core consists of the second and third microtubule-binding repeats, R2 and R3, which form a hairpin. Water-edited 2D 13C-13C and 15N-13C correlation spectra indicate that most residues in R2 and R3 domains have low water accessibility, indicating that this hairpin is surrounded by other proteinaceous segments. However, a small number of residues, especially S285 and S316, are well hydrated compared to other Ser and Thr residues, suggesting that there is a small water channel in the middle of the hairpin. To probe whether water accessibility correlates with protein dynamics, we measured the backbone N-H dipolar couplings of the β-sheet core. Interestingly, residues in the fourth microtubule-binding repeat, R4, show rigid-limit N-H dipolar couplings, even though this domain exhibits weaker intensities in the 2D 15N-13C correlation spectra. These results suggest that the R4 domain participates in cross-β hydrogen bonding in some of the subunits but exhibits dynamic disorder in other subunits. Taken together, these hydration and dynamics data indicate that the R2–R3 hairpin of 0N4R tau is shielded from water by other proteinaceous segments on the exterior, but contains a small water pore in the interior. This structural topology has various similarities with the CBD tau fibril structure, but also shows specific differences. The disorder of the R4 domain and the presence of a small water channel in the heparin-fibrillized 4R tau have implications for the structure of tau fibrils in diseased brains.
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DOI：
10.1074/jbc.m114.589309
发表时间：
2015-01-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
通讯作者：
Bose S
影响因子：
2.7
作者：
Helmus JJ;Jaroniec CP
通讯作者：
Jaroniec CP
影响因子：
2.2
作者：
Hou, Guangjin;Yan, Si;Trebosc, Julien;Amoureux, Jean-Paul;Polenova, Tatyana
通讯作者：
Polenova, Tatyana
影响因子：
4.4
作者：
BENNETT, AE;RIENSTRA, CM;GRIFFIN, RG
通讯作者：
GRIFFIN, RG
影响因子：
1.7
作者：
Baldus, M;Petkova, AT;Griffin, RG
通讯作者：
Griffin, RG