STRUCTURAL AND FUNCTIONAL STUDIES OF DJ-1

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 DJ-1是一种普遍表达的人类蛋白，其缺失或失活会导致早发性帕金森症，其过多与某些类型的癌症有关。DJ-1的生化功能尚不清楚，但已知其具有保护细胞免受氧化应激的作用，具有氧化还原调节的伴侣活性，对抗α-突触核蛋白，参与Akt/PTEN途径，参与许多应激反应蛋白的转录调控，并在谷胱甘肽代谢中起间接作用。DJ-1的这些保护功能中的一些是通过将关键保守的半胱氨酸残基(C106)氧化成半胱氨酸-亚磺酸来调节的，但氧化增强DJ-1保护功能的机制尚不清楚。我们通过结构和生物物理方法研究了DJ-1功能的氧化还原调节，以验证DJ-1通过C106氧化为C106亚磺酸而稳定，但通过C106进一步氧化而不稳定的假说。由于DJ-1受半胱氨酸氧化的调节，并与多种人类疾病有关，因此了解细胞氧化还原状态对细胞生存和人类健康的作用具有直接意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DJ-1 is a ubiquitously expressed human protein whose absence or inactivation causes early-onset Parkinsonism and whose overabundance has been implicated in certain types of cancer. The biochemical function of DJ-1 is obscure, however it is known to protect cells from oxidative stress, possess a redox-regulated chaperone activity against a-synuclein, is involved in the Akt/PTEN pathway, is involved in transcriptional regulation of many stress-response proteins, and has an indirect role in glutathione metabolism. Some of these protective functions of DJ-1 are regulated by the oxidation of a key conserved cysteine residue (C106) to a cysteine-sulfinic acid, however the mechanism by which oxidation enhances the protective functions of DJ-1 is unknown. We have investigated the redox regulation of DJ-1 function by employing structural and biophysical methods to test the hypothesis that DJ-1 is stabilized by oxidation of C106 to C106-sulfinc acid, but destabilized by further oxidation of C106. Because DJ-1 is subject to regulatory cysteine oxidation and is implicated in multiple human diseases, it is of direct relevance for understanding the role of cellular redox status on cell survival and human health.