Evolution of ubiquitin-specific proteases

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分子上，形成各种拓扑结构的链-这些链可以影响它们所连接的蛋白质的稳定性或功能。哺乳动物细胞含有数百种不同的酶，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去除链（“去泛素化酶”，或DUB）。在简单的生物如酵母中，DUB的数量要少得多，这可能是因为在进化过程中DUB基因被复制并具有新的功能。尽管它们参与了关键的调控途径，但DUBs的进化尚未得到很好的研究。 我的实验室负责发现第一批被鉴定的哺乳动物DUB之一。这种酶（命名为USP 4）有一个非常近的亲戚（USP 15），还有一个稍微远一点的亲戚（USP 11）。我们假设这些基因是由基因复制事件引起的，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）。我们有在USP 4或USP 15基因中有突变的小鼠，通过将这些品系杂交在一起，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USP 15改变版本的物种。 USP 4和USP 15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”。

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.