The mechanism of Hsp90-induced oligomerizaton of Tau
The mechanism of Hsp90-induced oligomerizaton of Tau
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DOI：
10.1126/sciadv.aax6999
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发表时间：
2020-03
期刊：
影响因子：
13.6
通讯作者：
Sabrina Weickert;Magdalena Wawrzyniuk;L. John;S. Rüdiger;M. Drescher
中科院分区：
文献类型：
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作者：
Sabrina Weickert;Magdalena Wawrzyniuk;L. John;S. Rüdiger;M. Drescher
伴侣Hsp90重塑了Tau的结构集合，导致了潜在的神经毒性寡聚体的形成。微管相关蛋白Tau的聚集是阿尔茨海默病的一个标志，Tau寡聚体被怀疑是最有毒的因素。Tau是分子伴侣Hsp90的客户，尽管尚不清楚该伴侣是否以及如何按摩固有的紊乱Tau的结构。利用电子顺磁共振，我们从非常广泛的Tau：Tau的构象系综中提取了结构信息：Tau在溶液中是高度动态和多态的，尽管是由远程接触形成的“回形针”。与Hsp90的相互作用促进了开放的Tau构象，我们认为这是通过将易于聚集的重复结构域暴露于其他Tau分子而形成小Tau低聚物的分子基础。同时，Tau纤维的形成受到抑制。因此，我们提供了伴随淀粉样蛋白客户的纳米级放大，强调了这种生物相关相互作用的结果是寡聚体的形成。
The chaperone Hsp90 remodels the structural ensemble of Tau, resulting in the formation of potentially neurotoxic oligomers. Aggregation of the microtubule-associated protein Tau is a hallmark of Alzheimer’s disease with Tau oligomers suspected as the most toxic agent. Tau is a client of the molecular chaperone Hsp90, although it is unclear whether and how the chaperone massages the structure of intrinsically disordered Tau. Using electron paramagnetic resonance, we extract structural information from the very broad conformational ensemble of Tau: Tau in solution is highly dynamic and polymorphic, although “paper clip”–shaped by long-range contacts. Interaction with Hsp90 promotes an open Tau conformation, which we identify as the molecular basis for the formation of small Tau oligomers by exposure of the aggregation-prone repeat domain to other Tau molecules. At the same time, formation of Tau fibrils is inhibited. We therefore provide the nanometer-scale zoom into chaperoning an amyloid client, highlighting formation of oligomers as the consequence of this biologically relevant interaction.