Redox regulation of protein functions in the plastid of Toxoplasma gondii

所有人类和动物都是由数十亿个被称为细胞的微观单位组成的。有些生物，比如我们在这个项目中研究的寄生虫，只包含一个细胞。细胞本身被分成小室。这种分裂允许蛋白质，细胞的“工人”，在条件最适合其任务的细胞部分执行其功能。因此，细胞分裂成具有特殊条件的室是细胞正常功能所必需的。影响每个亚细胞区室内部状况的一个重要因素是“氧化”蛋白质的化学物质（即从蛋白质中带走电子）和“还原”蛋白质的化学物质（即给蛋白质电子）之间的平衡。这种平衡统称为“氧化还原”。调节蛋白质的功能以适应它们工作的隔间中的氧化还原条件是一种至关重要的细胞控制机制，如果出现问题，细胞或整个动物可能会死亡。调节细胞间氧化还原条件和细胞间蛋白质活性的关键因素是一种叫做硫氧还毒素（Trxs）的特殊分子。Trxs通过改变在该隔室中工作的蛋白质的活性来对隔室的氧化还原条件作出反应。本研究重点研究的单细胞寄生虫被命名为顶复合体寄生虫。顶复体虫是一种有害的寄生虫，可引起疟疾和弓形虫病等疾病，每年在英国和全世界造成数百万人死亡或残疾。这些寄生虫引起疾病的能力取决于仅在这些寄生虫中发现的一种称为顶质体的独特结构，没有顶质体，寄生虫就无法生存。在寄生虫细胞中，顶质体由四个室室组成。我们假设，每个隔室中的特殊顶质体Trxs （ATrxs）控制着其中其他蛋白质的活性；这些atrx对于顶质体的功能至关重要，而顶质体的功能对寄生虫的生存至关重要。我们开始在一种名为刚地弓形虫的顶复合体寄生虫中测试这一假设。我们发现了两种顶质体活动是由ATrxs调节的。我们的工作进一步发现，其中一种ATrxs具有人类Trxs所没有的独特特征，因此现在正在研究它作为疟疾的新药物靶点。然而，由于药物发现是一个特别不可预测的过程，我们认为，为了最大限度地提高成功的机会，我们应该确定尽可能多的潜在药物候选靶点，在相同的途径下运作。我们有充分的理由相信，顶质体氧化还原调控网络的其他参与者也将是必不可少的，对这些寄生虫来说是独一无二的，也是有希望成为药物靶点的候选物。我们一共鉴定了7个atrx，我们预计这些atrx可以调节顶质体中的许多蛋白质。我们建议鉴定顶质体中受这些新ATrxs调控的蛋白，并描述每种ATrxs在这一关键调控机制中的作用。这项工作将加强对这种独特而重要的寄生虫结构如何工作的理解。由此产生的知识可能会继续为顶复杂体的药物发现埋下种子。你可以阅读更多关于这个项目的重要性，以及我们为这个项目所做的工作，并已经发表在“对话”：http://theconversation.com/finding-the-achilles-heel-of-the-cat-parasite-could-mean-more-effective-treatment-for-toxoplasmosis-and-malaria-92232

All humans and animals are made of billions of microscopic units named cells. Some organisms, like the parasites we study in this project, comprise only a single cell. Cells are themselves divided into compartments. This division allows proteins, the cell's "workers", to perform their functions in parts of the cell where the conditions are the most suitable for their task. Thus, cell partitioning into compartments with specialized conditions is necessary for proper cell function.An important factor affecting the conditions within each sub-cellular compartment is the balance between chemicals that "oxidize" proteins, namely that take away electrons from them, and chemicals that "reduce" proteins, namely that give proteins electrons. This balance is collectively named "redox". The adjustment of protein function to the redox conditions in the compartment where they work is a crucial cellular control mechanism and if it goes wrong, the cell or the whole animal may die.The key factors that mediate between the redox conditions in a compartment and the activity of the proteins in that compartment are specialized molecules called thioredoxins (Trxs). Trxs react to the compartment's redox conditions by altering the activity of proteins that work in that compartment. The single-celled parasites that are the focus on this study are named apicomplexan parasites. Apicomplexans are harmful parasites causing diseases such as malaria and toxoplasmosis, which kill or cause disabilities to millions of people in the UK and worldwide annually. The ability of these parasites to cause disease depends on a unique structure found only in these parasites - called the apicoplast - without which the parasites cannot survive.The apicoplast comprises four compartments in the parasite cell. We hypothesize that special Apicoplast Trxs (ATrxs) in each of these compartments control the activity of other proteins in them; and that these ATrxs will be essential for the apicoplast functions that are critical to the parasites' survival.We started testing this hypothesis in an apicomplexan parasite named Toxoplasma gondii. We discovered two apicoplast activities that are regulated by ATrxs. Our work further found that one of the ATrxs has unique features that are not found in human Trxs, so it is now being studied as a new drug target for malaria. However, with drug-discovery being a particularly unpredictable process, we believe that to maximise the chances of success we should identify as many potential drug target candidates, operating in the same pathway, as possible. There is every reason to believe that other players of the redox regulatory network of apicoplast functions will also be essential, unique to these parasites and promising candidate for drug targets.We have identified total of seven ATrxs which we expect to regulate many proteins in the apicoplast. We propose to identify the proteins in the apicoplast that are regulated by these new ATrxs and to characterize the roles of each of the ATrxs in this critical regulatory mechanism. This work will enhance the understanding of how this unique and essential parasite structure works. The knowledge that will be generated will likely continue to seed drug discovery for apicomplexans.You can read more about the importance of this project and about the work that we did leading to this project and already published in "the conversation": http://theconversation.com/finding-the-achilles-heel-of-the-cat-parasite-could-mean-more-effective-treatment-for-toxoplasmosis-and-malaria-92232