HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation
HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation
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DOI：
10.1074/jbc.m117.803411
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发表时间：
2018-02-23
影响因子：
4.8
通讯作者：
Nath, Abhinav
中科院分区：
文献类型：
--
作者：
Baughman, Hannah E. R.;Clouser, Amanda F.;Nath, Abhinav
微管相关蛋白 tau 在各种痴呆症中形成不溶性淀粉样蛋白型聚集体，尤其是阿尔茨海默病。细胞伴侣蛋白在维持蛋白质溶解度和防止拥挤的细胞环境中聚集方面发挥着重要作用。尽管已知 tau 蛋白与众多伴侣蛋白相互作用，但仍不清楚这些伴侣蛋白如何在机制上发挥作用以防止 tau 聚集，以及不同类别的伴侣蛋白在机制方面如何比较。在这里，我们重点关注小热休克蛋白 HspB1（也称为 Hsp27）和组成型伴侣 Hsc70（也称为 HspA8），并报告每个伴侣如何与 tau 相互作用以防止其原纤维形成。使用荧光和核磁共振光谱，我们表明这两种分子伴侣通过不同的机制抑制 tau 原纤维的形成。 HspB1 通过与聚集过程中的早期物种微弱相互作用来延迟 tau 原纤维的形成，而 Hsc70 可以高效地阻止 tau 原纤维伸长，可能是通过封盖 tau 原纤维的末端。两个伴侣都识别出 tau 微管结合重复区域内易于聚集的基序。然而，HspB1 结合在聚集促进和非聚集条件下均保持短暂，而 Hsc70 结合在聚集促进条件下明显更紧密。这些差异凸显了这样一个事实，即来自不同家族的伴侣在预防病理性蛋白质聚集方面发挥着不同但互补的作用。
The microtubule-associated protein tau forms insoluble, amyloid-type aggregates in various dementias, most notably Alzheimer's disease. Cellular chaperone proteins play important roles in maintaining protein solubility and preventing aggregation in the crowded cellular environment. Although tau is known to interact with numerous chaperones, it remains unclear how these chaperones function mechanistically to prevent tau aggregation and how chaperones from different classes compare in terms of mechanism. Here, we focused on the small heat shock protein HspB1 (also known as Hsp27) and the constitutive chaperone Hsc70 (also known as HspA8) and report how each chaperone interacts with tau to prevent its fibril formation. Using fluorescence and NMR spectroscopy, we show that the two chaperones inhibit tau fibril formation by distinct mechanisms. HspB1 delayed tau fibril formation by weakly interacting with early species in the aggregation process, whereas Hsc70 was highly efficient at preventing tau fibril elongation, possibly by capping the ends of tau fibrils. Both chaperones recognized aggregation-prone motifs within the microtubule-binding repeat region of tau. However, HspB1 binding remained transient in both aggregation-promoting and non-aggregating conditions, whereas Hsc70 binding was significantly tighter under aggregation-promoting conditions. These differences highlight the fact that chaperones from different families play distinct but complementary roles in the prevention of pathological protein aggregation.