A single amino acid substitution differentiates Hsp70-dependent effects on α-synuclein degradation and toxicity
A single amino acid substitution differentiates Hsp70-dependent effects on α-synuclein degradation and toxicity
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DOI：
10.1016/j.bbrc.2004.10.037
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发表时间：
2004-12-03
影响因子：
3.1
通讯作者：
McLean, PJ
中科院分区：
文献类型：
--
作者：
Klucken, J;Shin, Y;McLean, PJ
α-突触核蛋白聚集和毒性在帕金森病和路易体痴呆中起主要作用。热休克蛋白70是一种多用途的应激反应伴侣蛋白，介导错误折叠蛋白的重折叠和降解。我们已经表明，Hsp 70能够阻断α-突触核蛋白的毒性和聚集。在这里，我们引入突变的ATP酶结构域的Hsp 70（K71 S），并证明这废除Hsp 70的重折叠活性。尽管如此，Hsp 70 K71 S继续介导α-突触核蛋白降解并阻断聚集体形成。与野生型Hsp 70相反，ATP酶结构域突变体通过非蛋白酶体抑制剂敏感途径介导α-突触核蛋白降解。虽然Hsp 70 K71 S可以比Hsp 70更大程度地降低α-突触核蛋白的水平，但HSP 70 K71 S不能防止α-突触核蛋白的毒性。Hsp 70 K71 S突变体似乎解离了聚集体的形成，它阻断了聚集体的形成，并且它不阻断毒性。这些数据表明，热休克蛋白70防止毒性的能力是不同的α-突触核蛋白的降解，是依赖于其ATP酶结构域。(C)2004年爱思唯尔公司All rights reserved.
alpha-Synuclein aggregation and toxicity play a major role in Parkinson's disease and dementia with Lewy bodies. Hsp70 is a multipurpose stress response chaperone protein that mediates both refolding and degradation of misfolded proteins. We have shown that Hsp70 is able to block both alpha-synuclein toxicity and aggregation. Here we introduce a mutation into the ATPase domain of Hsp70 (K71S) and demonstrate that this abolishes Hsp70 refolding activity. Nonetheless, Hsp70K71S continues to mediate alpha-synuclein degradation and blocks aggregate formation. In contrast to wild type Hsp70, the ATPase domain mutant mediates alpha-synuclein degradation through a non-proteasome inhibitor sensitive pathway. Although Hsp70K71S can diminish levels of alpha-synuclein to an even greater extent than Hsp70, HSP70K71S does not protect against alpha-synuclein toxicity. The Hsp70K71S mutant appears to dissociate the formation of aggregates, which it blocks, and toxicity, which it does not block. These data suggest that the ability of Hsp70 to prevent toxicity is distinct from degradation of alpha-synuclein and is dependent on its ATPase domain. (C) 2004 Elsevier Inc. All rights reserved.