The oxidation state of DJ-1 regulates its chaperone activity toward α-synuclein
The oxidation state of DJ-1 regulates its chaperone activity toward α-synuclein
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DOI：
10.1016/j.jmb.2005.12.030
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发表时间：
2006-03-03
影响因子：
5.6
通讯作者：
Fink, AL
中科院分区：
文献类型：
--
作者：
Zhou, WB;Zhu, M;Fink, AL
据报道，Dj-1通过阻止某些蛋白质的聚集而具有伴侣活性，其结构类似于Hsp31。L166P突变与家族性早发性帕金森病（PD）有关。由于α -synuclein的聚集被认为是PD病因学的关键步骤，我们研究了野生型j-1及其氧化形式与a-synuclein的相互作用。原生（未氧化的）Dj-1不抑制a-synuclein的纤颤，也没有证据表明α -synuclein和原生Dj-1之间存在稳定的相互作用。然而，Dj-1很容易被氧化，通过添加两个氧原子形成Cys106 （20 Dj-1）的亚磺酸（没有10氧化状态可检测到）。通过添加浓度高达20倍摩尔过量的H2O2，可以很容易地制备20 j-1。Cys106氧化为亚磺酸对Dj-1的结构性能影响很小。然而，20 j-1在防止a-synuclein的纤颤方面非常有效，只有这种形式的j-1似乎对α -synuclein具有显著的抗聚集特性。Dj-1的进一步氧化导致一些二级结构的丧失，并失去抑制a-突触核蛋白纤维性颤动的能力。我们的观察结果证实了Dj-1可能作为氧化应激诱导的伴侣来防止a-突触核蛋白纤颤的建议。由于氧化应激与PD相关，这一观察结果可能解释了为什么Dj-1突变可能是PD的一个促成因素，也表明过量的氧化应激也可能导致a-synuclein聚集增强，从而导致PD。(c) 2005 Elsevier Ltd版权所有。
Dj-1 has been reported to have chaperone activity by preventing the aggregation of some proteins, and by structural analogy to Hsp31. The L166P mutation has been linked to a familial early onset form of Parkinson's disease (PD). Since the aggregation of alpha-synuclein is believed to be a critical step in the etiology of PD, we have investigated the interaction of wild-type Dj-1 and its oxidized forms with a-synuclein. Native (unoxidized) Dj-1 did not inhibit a-synuclein fibrillation, and no evidence for stable interactions between alpha-synuclein and native Dj-1 was observed. However, Dj-1 is very susceptible to oxidation by the addition of two oxygen atoms to form the sulfinic acid of Cys106 (20 Dj-1) (no 10 oxidized state is detectable). 20 Dj-1 was readily prepared by the addition of H2O2 at concentrations up to a 20-fold molar excess. The oxidation of Cys106 to the sulfinic acid had minimal effect on the structural properties of Dj-1. However, 20 Dj-1 was very effective in preventing the fibrillation of a-synuclein, and only this form of Dj-1 appears to have significant antiaggregation properties against alpha-synuclein. Further oxidation of Dj-1 leads to loss of some secondary structure, and to loss of the ability to inhibit a-synuclein fibrillation. Our observations confirm the suggestion that Dj-1 may act as an oxidative-stress-induced chaperone to prevent a-synuclein fibrillation. Since oxidative stress has been associated with PD, this observation may explain why mutations of Dj-1 could be a contributing factor in PD, and also indicates that excess oxidative stress could also lead to enhanced a-synuclein aggregation and hence PD. (c) 2005 Elsevier Ltd. All rights reserved.