MAP2 caps tau fibrils and inhibits aggregation.
MAP2 caps tau fibrils and inhibits aggregation.
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DOI：
10.1016/j.jbc.2023.104891
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Margittai, Martin
中科院分区：
文献类型：
--
作者：
Holden, Michael R.;Krzesinski, Brad J.;Weismiller, Hilary A.;Shady, Justin R.;Margittai, Martin
微管相关蛋白 tau 的原纤维与阿尔茨海默病 (AD) 和相关神经退行性疾病的病理密切相关。当前人脑中病理学传播的范例是，短 tau 蛋白原纤维在神经元之间转移，然后将初始 tau 蛋白单体募集到其尖端，以高保真度和速度维持原纤维构象。尽管已知可以以细胞特异性方式调节繁殖，从而有助于表型多样性，但对选择分子如何参与这一过程的了解仍然有限。 MAP2 是一种神经元蛋白，与 tau 的重复淀粉样蛋白核心区域具有显着的序列同源性。关于 MAP2 参与病理学及其与 tau 纤维化的关系存在差异。在这里，我们利用 3R 和 4R MAP2 的整个重复区域来研究它们在 tau 纤维化中的调节作用。我们发现这两种蛋白都能阻断 4R tau 的自发聚集和种子聚集，其中 4R MAP2 的效力稍强一些。在体外、HEK293 细胞和 AD 脑提取物中观察到 tau 播种的抑制作用，强调了其更广泛的范围。 MAP2 单体特异性结合 tau 原纤维末端，防止更多 tau 和 MAP2 单体募集到原纤维尖端。这些发现揭示了 MAP2 作为 tau 原纤维帽的新功能，可以在调节疾病中 tau 增殖方面发挥重要作用，并有望成为潜在的内在蛋白抑制剂。
Fibrils of the microtubule-associated protein tau are intimately linked to the pathology of Alzheimer’s disease (AD) and related neurodegenerative disorders. A current paradigm for pathology spreading in the human brain is that short tau fibrils transfer between neurons and then recruit naive tau monomers onto their tips, perpetuating the fibrillar conformation with high fidelity and speed. Although it is known that the propagation could be modulated in a cell-specific manner and thereby contribute to phenotypic diversity, there is still limited understanding of how select molecules are involved in this process. MAP2 is a neuronal protein that shares significant sequence homology with the repeat-bearing amyloid core region of tau. There is discrepancy about MAP2’s involvement in pathology and its relationship with tau fibrillization. Here, we employed the entire repeat regions of 3R and 4R MAP2, to investigate their modulatory role in tau fibrillization. We find that both proteins block the spontaneous and seeded aggregation of 4R tau, with 4R MAP2 being slightly more potent. The inhibition of tau seeding is observed in vitro, in HEK293 cells, and in AD brain extracts, underscoring its broader scope. MAP2 monomers specifically bind to the end of tau fibrils, preventing recruitment of further tau and MAP2 monomers onto the fibril tip. The findings uncover a new function for MAP2 as a tau fibril cap that could play a significant role in modulating tau propagation in disease and may hold promise as a potential intrinsic protein inhibitor.
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DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Biancalana M;Koide S
通讯作者：
Koide S
影响因子：
2.9
作者：
Dinkel PD;Holden MR;Matin N;Margittai M
通讯作者：
Margittai M
DOI：
10.1038/nsb786
发表时间：
2002-05-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
DePace, AH;Weissman, JS
通讯作者：
Weissman, JS
影响因子：
2.9
作者：
Dinkel, Paul D.;Siddiqua, Ayisha;Margittai, Martin
通讯作者：
Margittai, Martin
DOI：
10.1073/pnas.94.1.298
发表时间：
1997-01-07
影响因子：
11.1
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K