Redox regulation of protein functions in the plastid of Toxoplasma gondii

弓形虫质体蛋白质功能的氧化还原调节

• 批准号: MR/S024573/1
• 负责人: Lilach Sheiner
• 金额: $ 42.72万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS024573%2F1
• 关键词: Redox; regulation; protein; functions; plastid

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

所有的人类和动物都是由数十亿个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。细胞本身被分成不同的区室。这种分裂允许蛋白质，细胞的“工人”，在细胞的某些部分执行它们的功能，这些部分的条件最适合它们的任务。因此，细胞分隔成具有特定条件的隔室是细胞正常功能所必需的。影响每个亚细胞隔室内条件的一个重要因素是“氧化”蛋白质（即从蛋白质中带走电子）的化学物质与“还原”蛋白质（即给蛋白质电子）的化学物质之间的平衡。这种平衡统称为“氧化还原”。蛋白质功能的调节以适应它们工作的隔室中的氧化还原条件是一种至关重要的细胞控制机制，如果它出错，细胞或整个动物可能会死亡。在隔室中的氧化还原条件和该隔室中的蛋白质活性之间进行调节的关键因素是称为硫氧还蛋白（Trxs）的专门分子。Trx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。这项研究的重点是单细胞寄生虫，它们被命名为顶复门寄生虫。顶复虫是一种有害的寄生虫，引起疟疾和弓形虫病等疾病，每年在英国和世界各地造成数百万人死亡或残疾。这些寄生虫致病的能力取决于一种只有在这些寄生虫中才能发现的独特结构--顶质体--没有它寄生虫就无法生存。顶质体在寄生虫细胞中包括四个隔室。我们假设，在这些隔室中的每一个特殊的顶质体Trxs（ATrxs）控制其他蛋白质的活性，这些ATrxs将是至关重要的顶质体功能，对寄生虫的survival.We开始测试这一假设在一个apicomplexan寄生虫命名为弓形虫。我们发现了两个apicoplast活动，ATrxs的调节。我们的工作进一步发现，其中一种ATrxs具有在人类Trxs中没有的独特特征，因此现在正在研究将其作为疟疾的新药物靶标。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靶点候选人，在同一途径中运作，尽可能。有充分的理由相信，其他球员的氧化还原调节网络的apicoplast功能也将是必不可少的，独特的这些寄生虫和有前途的候选药物targets.We已经确定了七个ATRX，我们预计将调节许多蛋白质的apicoplast。我们建议确定这些新的ATrxs调控的顶质体中的蛋白质，并表征每个ATrxs在这个关键的调控机制中的作用。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。这些知识将可能继续为顶复门的药物发现提供种子。您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，并已发表在“对话”中：http://theconversation.com/finding-the-achilles-heel-of-the-cat-parasite-could-mean-more-effective-treatment-for-toxoplasmosis-and-malaria-92232

项目成果

A Toxoplasma gondii Oxopurine Transporter Binds Nucleobases and Nucleosides Using Different Binding Modes.

• DOI: 10.3390/ijms23020710
• 发表时间: 2022-01-10
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Campagnaro GD;Elati HAA;Balaska S;Martin Abril ME;Natto MJ;Hulpia F;Lee K;Sheiner L;Van Calenbergh S;de Koning HP
• 通讯作者: de Koning HP

Protein control of membrane and organelle dynamics: Insights from the divergent eukaryote Toxoplasma gondii.

• DOI: 10.1016/j.ceb.2022.102085
• 发表时间: 2022-06
• 期刊: CURRENT OPINION IN CELL BIOLOGY
• 影响因子: 7.5
• 作者: Ovciarikova, Jana;Souza, Rodolpho Ornitz Oliveira;Arrizabalaga, Gustavo;Sheiner, Lilach
• 通讯作者: Sheiner, Lilach

Plasmodium falciparum LipB mutants display altered redox and carbon metabolism in asexual stages and cannot complete sporogony in Anopheles mosquitoes.

• DOI: 10.1016/j.ijpara.2020.10.011
• 发表时间: 2021-05
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Biddau M;Santha Kumar TR;Henrich P;Laine LM;Blackburn GJ;Chokkathukalam A;Li T;Lee Sim K;King L;Hoffman SL;Barrett MP;Coombs GH;McFadden GI;Fidock DA;Müller S;Sheiner L
• 通讯作者: Sheiner L

Replication and partitioning of the apicoplast genome of Toxoplasma gondii is linked to the cell cycle and requires DNA polymerase and gyrase.

• DOI: 10.1016/j.ijpara.2020.11.004
• 发表时间: 2021-05
• 期刊: International journal for parasitology
• 影响因子: 4
• 作者: Martins-Duarte ÉS;Sheiner L;Reiff SB;de Souza W;Striepen B
• 通讯作者: Striepen B

Using Diatom and Apicomplexan Models to Study the Heme Pathway of Chromera velia.

• DOI: 10.3390/ijms22126495
• 发表时间: 2021-06-17
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Richtová J;Sheiner L;Gruber A;Yang SM;Kořený L;Striepen B;Oborník M
• 通讯作者: Oborník M