STRUCTURAL AND FUNCTIONAL STUDIES OF DJ-1

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 DJ-1是一种普遍表达的人类蛋白质，其缺失或失活导致早发性帕金森症，并且其过量与某些类型的癌症有关。 DJ-1的生物化学功能尚不清楚，但已知其保护细胞免受氧化应激，具有针对α-突触核蛋白的氧化还原调节的伴侣蛋白活性，参与Akt/PTEN途径，参与许多应激反应蛋白的转录调节，并在谷胱甘肽代谢中具有间接作用。 DJ-1的这些保护功能中的一些通过关键保守的半胱氨酸残基（C106）氧化为半胱氨酸-亚磺酸来调节，然而氧化增强DJ-1的保护功能的机制尚不清楚。 我们已经研究了DJ-1功能的氧化还原调节，采用结构和生物物理方法来测试的假设，DJ-1是稳定的C106氧化为C106-亚磺酸，但不稳定的C106的进一步氧化。由于DJ-1受到半胱氨酸氧化的调节，并与多种人类疾病有关，因此它与理解细胞氧化还原状态对细胞存活和人类健康的作用直接相关。

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.