Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption.
Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption.
复制标题
DOI：
10.1021/bi201857v
复制
发表时间：
2012-03-27
期刊：
影响因子：
2.9
通讯作者：
Chi, Eva Y.
中科院分区：
文献类型：
--
作者：
Jones, Emmalee M.;Dubey, Manish;Camp, Phillip J.;Vernon, Briana C.;Biernat, Jacek;Mandelkow, Eckhard;Majewski, Jaroslaw;Chi, Eva Y.
本质上无序的微管相关 tau 蛋白错误折叠并聚集成神经原纤维缠结，与阿尔茨海默病的发病机制有关。然而，tau 蛋白聚集和毒性的机制仍不清楚。最近的研究表明，脂质膜可以诱导 tau 聚集，而膜透化可能是蛋白质聚集体发挥毒性的途径，这表明质膜可能在 tau 病理学中发挥双重作用。这促使我们的研究评估 tau 与膜相互作用的倾向，并阐明这种相互作用在 tau 和膜中引起的相互破坏的结构扰动。我们发现，尽管带高电荷且可溶，全长 tau (hTau40) 也具有高表面活性，选择性插入阴离子 DMPG 脂质单层并诱导膜形态变化。为了解析与脂质膜相关的 hTau40 的分子尺度结构细节，利用了 X 射线和中子散射技术。 X 射线反射率表明 hTau40 存在于 DMPG 单层下方并渗透到脂质头基和尾基中，而掠入射 X 射线衍射表明 hTau40 插入破坏了脂质堆积。此外，空气/水和 DMPG 脂质膜界面都会诱导无序的 hTau40 部分采用更紧凑的构象，其密度与折叠蛋白的密度相似。中子反射率表明 tau 完全破坏了受支持的 DMPG 双层，同时保持中性 DPPC 双层完好无损。我们的结果表明，hTau40 与阴离子脂质的强烈相互作用会诱导 tau 结构压缩和膜破坏，这表明神经退行性疾病中 tau 聚集和毒性可能存在基于膜的机制。
The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's disease. However, the mechanisms of tau aggregation and toxicity remain unknown. Recent work has shown that lipid membrane can induce tau aggregation and that membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity, suggesting that the plasma membrane may play dual roles in tau pathology. This prompted our investigation to assess tau's propensity to interact with membranes and to elucidate the mutually disruptive structural perturbations the interactions induce in both tau and the membrane. We show that although highly charged and soluble, the full-length tau (hTau40) is also highly surface active, selectively inserts into anionic DMPG lipid monolayers and induces membrane morphological changes. To resolve molecular-scale structural details of hTau40 associated with lipid membranes, X-ray and neutron scattering techniques are utilized. X-ray reflectivity indicates hTau40's presence underneath a DMPG monolayer and penetration into the lipid headgroups and tailgroups, whereas grazing incidence X-ray diffraction shows that hTau40 insertion disrupts lipid packing. Moreover, both air/water and DMPG lipid membrane interfaces induce the disordered hTau40 to partially adopt a more compact conformation with density similar to that of a folded protein. Neutron reflectivity shows that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact. Our results show that hTau40's strong interaction with anionic lipids induces tau structural compaction and membrane disruption, suggesting possible membrane-based mechanisms of tau aggregation and toxicity in neurodegenerative diseases.
登录
查看更多内容
影响因子：
2.9
作者：
Chi, Eva Y.;Ege, Canay;Lee, Ka Yee C.
通讯作者：
Lee, Ka Yee C.
影响因子：
4.8
作者：
Deshpande, Atul;Win, Khin May;Busciglio, Jorge
通讯作者：
Busciglio, Jorge
影响因子：
4
作者：
Campos-Pena, Victoria;Tapia-Ramirez, Jose;Antonio Meraz-Rios, Marco
通讯作者：
Antonio Meraz-Rios, Marco
影响因子：
5.6
作者：
Bokvist, M;Lindström, F;Gröbner, G
通讯作者：
Gröbner, G
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT