Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins
Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins
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DOI：
10.1074/jbc.m114.590141
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发表时间：
2014-12-26
影响因子：
4.8
通讯作者：
Obermann, Wolfgang M. J.
中科院分区：
文献类型：
--
作者：
Tripathi, Vishwadeepak;Darnauer, Stefanie;Obermann, Wolfgang M. J.
Aha 1（Hsp 90 ATP酶的激活剂）刺激分子伴侣Hsp 90的ATP酶活性以加速客户蛋白质达到其最终形状的构象循环。因此，Aha 1促进Hsp 90依赖性客户端如类固醇受体和许多参与细胞信号传导的激酶的有效折叠。在我们目前的研究中，我们发现Aha 1除了调节Hsp 90 ATP水解速率外，还发挥着一种新的额外作用。我们提出了一个新的概念，这表明Aha 1作为一个自主的伴侣，并与应激变性蛋白质，以防止它们聚集类似的伴侣GroEL。我们的研究表明，22个氨基酸的N-末端序列，存在于人类中，但不存在于酵母Aha 1，是这种能力的关键。然而，代替促进它们的重折叠，Aha 1允许通过E3泛素连接酶CHIP对结合的客户进行泛素化。因此，Aha 1可以通过细胞蛋白质质量控制促进折叠缺陷蛋白质的处理。
Aha1 (activator of Hsp90 ATPase) stimulates the ATPase activity of the molecular chaperone Hsp90 to accelerate the conformational cycle during which client proteins attain their final shape. Thereby, Aha1 promotes effective folding of Hsp90-dependent clients such as steroid receptors and many kinases involved in cellular signaling. In our current study, we find that Aha1 plays a novel, additional role beyond regulating the Hsp90 ATP hydrolysis rate. We propose a new concept suggesting that Aha1 acts as an autonomous chaperone and associates with stress-denatured proteins to prevent them from aggregation similar to the chaperonin GroEL. Our study reveals that an N-terminal sequence of 22 amino acids, present in human but absent from yeast Aha1, is critical for this capability. However, in lieu of fostering their refolding, Aha1 allows ubiquitination of bound clients by the E3 ubiquitin ligase CHIP. Accordingly, Aha1 may promote disposal of folding defective proteins by the cellular protein quality control.