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

描述（由申请人提供）：世界范围内肥胖的增加与肥胖相关疾病的急剧增加是同步的，最明显的是ii型糖尿病。据预测，这种疾病在今后几十年将达到流行病的程度。因此，了解ii型糖尿病的生化过程和确定治疗干预的新靶点对国家和世界健康至关重要。一些用于治疗ii型糖尿病的最广泛的胰岛素增敏药物属于噻唑烷二酮（TZD）类分子。这些药物还被发现可以减少许多与代谢综合征相关的病理，包括高血压、腹部肥胖、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。虽然最初认为TZDs仅通过激活核转录因子PPAR′发挥其作用，但现在知道许多有益作用是通过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点相互作用。我们报道了mitoNEET蛋白是一种氧化还原活性，ph不稳定的2Fe-2S簇蛋白，位于线粒体外膜。这是线粒体外膜上唯一已知的铁硫蛋白。此外，我们发现MitoNEET在氧化应激条件下的铁管理中起着重要作用。Miner1是mitoNEET的内质网同源物，对维持健康和长寿很重要，并与癌症和神经退行性疾病相关的蛋白质相互作用。这些蛋白已成为从糖尿病到阿尔茨海默病等疾病的重要新治疗靶点。本提案的重点是这部小说的结构、生化和功能特征

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.