Evolution of ubiquitin-specific proteases

泛素特异性蛋白酶的进化

• 批准号: RGPIN-2015-05879
• 负责人: Gray, Douglas
• 金额: $ 2.19万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613801
• 关键词: Evolution; ubiquitin; specific; proteases

Ubiquitin is a small protein that is attached to other cellular proteins. In many cases further ubiquitin molecules are added to the first to form chains of various topologies - these chains can affect the stability or function of the proteins to which they are attached. A mammalian cell contains hundreds of different enzymes that direct the attachment of ubiquitin and assembly of chains, and in the order of one hundred cell that can edit or remove the chains ("deubiquitinating enzymes", or DUBs). In simpler organisms such as yeast there are far fewer DUBs, and it may be that during evolution DUB genes have been duplicated and have taken on new functions. Despite their involvement in critical regulatory pathways the evolution of DUBs has not been well studied. My laboratory was responsible for the discovery of one of the first mammalian DUBs to be identified. This enzyme (designated USP4) has one very close relative (USP15), and one that is slightly more distant (USP11). We hypothesize that these genes arose from gene duplication events, and propose to use computational analysis of large protein and DNA databases to determine how the three genes evolved (when the duplications occurred and in what order). We have mice that have mutations in their USP4 or USP15 genes, and by crossing these strains together we will determine whether mice require at least one functional gene and reveal the consequences of deficiency in these proteins. We will also explore the function of these genes in the zebrafish, a species that has an altered version of USP15.  USP4 and USP15 represent the ideal model system to explore the evolution of deubiquitinating enzymes. These studies will contribute to our long term objective, which is to understand of how cellular networks can be "rewired" following gene duplications.

泛素是一种附着在其他细胞蛋白上的小蛋白。在许多情况下，更多的泛素分子被添加到第一个泛素分子中，形成各种拓扑结构的链--这些链可以影响它们所附着的蛋白质的稳定性或功能。哺乳动物细胞包含数百种不同的酶，这些酶指导泛素的附着和链的组装，并且大约有一百个细胞可以编辑或移除链(脱泛素酶，简称DUBS)。在酵母等较简单的生物中，Dub基因的数量要少得多，可能是因为在进化过程中，Dub基因被复制并承担了新的功能。尽管它们参与了关键的调控途径，但Dub的进化还没有得到很好的研究。 我的实验室负责发现了第一批被鉴定的哺乳动物配音之一。这种酶(命名为USP4)有一个非常接近的亲缘关系(USP15)，另一个略远一些的亲缘关系(USP11)。我们假设这些基因起源于基因复制事件，并建议使用大型蛋白质和DNA数据库的计算分析来确定这三个基因是如何进化的(复制发生的时间和顺序)。我们有USP4或USP15基因突变的小鼠，通过将这些菌株杂交，我们将确定小鼠是否需要至少一个功能基因，并揭示这些蛋白质缺乏的后果。我们还将探索这些基因在斑马鱼中的功能，斑马鱼是一种具有USP15改变版本的物种。USP4和USP15代表了探索去泛素化酶进化的理想模型系统。这些研究将有助于我们的长期目标，即了解细胞网络如何在基因复制后重新连接。