The New Family of NEET Proteins: 2Fe-2S Protein Mediated Health and Disease

描述(申请人提供)：全球肥胖率的上升与肥胖相关疾病的急剧增加同步，最明显的是II型糖尿病。据预测，这种疾病在未来几十年内将达到流行的程度。因此，了解II型糖尿病潜在的生化过程并确定新的治疗干预目标对国家和世界健康至关重要。一些最广泛用于治疗II型糖尿病的胰岛素增敏药物属于噻唑烷二酮(TZD)类分子。这些药物被发现还可以减少与代谢综合征相关的许多病理疾病，包括高血压、腹型肥胖、冠状动脉炎症、多发性硬化症、阿尔茨海默病和肌萎缩侧索硬化症。虽然TZD最初被认为仅通过激活核转录因子PPAR�发挥其作用，但已知许多有益的影响是通过PPAR�不依赖的方式介导的。TZD最近被证明与一种名为mitoNEET的新型线粒体蛋白靶标相互作用。我们报道了mitoNEET蛋白是一个氧化还原活性的、pH不稳定的2Fe-2S簇，含有位于线粒体膜外的蛋白。这是线粒体膜外膜中唯一已知的铁-S蛋白。此外，我们还发现，在氧化应激条件下，mitoNEET在铁的管理中起着重要作用。Miner1是mitoNEET的内质网同系物，在维持健康和长寿方面非常重要，并与癌症和神经退行性疾病相关的蛋白质相互作用。这些蛋白质已经成为从糖尿病到阿尔茨海默氏症等疾病的重要治疗靶点。这项提议的重点是这种新的结构、生化和功能表征 蛋白质家族。具体地说，我们正在研究药物结合的分子决定因素作为氧化状态变化的函数，并询问药物结合如何影响新发现的参与调节细胞生存和死亡过程的蛋白质-蛋白质相互作用。这个 所提出的研究对于理解这种蛋白质-药物识别以及识别新的治疗方法都具有基础性意义。

DESCRIPTION (provided by applicant): The rise in obesity worldwide parallels a dramatic increase in obesity-associated diseases, most notably type-II diabetes. This disease is predicted to reach epidemic proportions in the next several decades. Thus, understanding the biochemical processes underlying type-II diabetes and identifying new targets for therapeutic intervention are critical for national and world health. Some of the most widely prescribed insulin-sensitizing drugs to treat type-II diabetes belong to the thiazolidinedione (TZD) class of molecules. These drugs were found to also reduce many of the pathologies related to metabolic syndrome including hypertension, abdominal obesity, coronary artery inflammation, multiple sclerosis, Alzheimer's disease and Amyotrophic lateral sclerosis. While the TZDs were originally thought to exert their effects solely through activation of the nuclear transcription factor PPAR�, it is nw known that many of the beneficial effects are mediated in a PPAR�-independent manner. The TZDs were recently shown to interact with a novel mitochondrial protein target called mitoNEET. We reported that the protein mitoNEET is a redox-active, pH-labile 2Fe-2S cluster containing protein in the outer mitochondrial membrane. This is the only known Fe-S protein in the outer mitochondrial membrane. In addition, we discovered that MitoNEET plays an important role in iron management under oxidative stress conditions. Miner1, an endoplasmic reticulum homolog of mitoNEET, is important in maintaining health and longevity and interacts with proteins associated with cancer as well as neurodegenerative diseases. These proteins have emerged as important new therapeutic targets in diseases ranging from diabetes to Alzheimer's. The focus of this proposal is the structural, biochemical and functional characterization of this novel protein family. Specifically, we are investigating the molecular determinants of drug binding as a function of changes in oxidation state and asking how drug binding impacts newly discovered protein-protein interactions that are involved in regulating cell survival and death processes. The proposed studies are of both fundamental significance in understanding this protein-drug recognition as well as the identification of novel therapeutics.