Japan_IPAP: Expanding epiproteome signalling with a new synthetic ubiquitin code

除了基因组之外，蛋白质组的精确调控现在被认为是生物体健康和疾病的主要贡献者。蛋白质组中的蛋白质受各种化学修饰的调节，这些化学修饰共同组成表观蛋白质组。表观蛋白质组最重要的调节修饰之一是由小的保守蛋白泛素进行的。泛素与底物的连接起许多信号传导作用，包括调节底物稳定性、细胞定位、活性和构象。因此，泛素系统的功能障碍导致严重的细胞应激，并且是不同真核生物发育缺陷的主要原因，包括人类病理学，如神经退行性疾病、自身免疫、心肌病和遗传性疾病如囊性纤维化。那么，泛素是如何控制这么多不同的过程的呢？泛素可以作为单体或作为泛素分子的互连链连接到底物。在自然界中，泛素有八种不同的方式可以连接到自己。这八种不同的拓扑结构通过与特定的泛素结合域蛋白（UBDPs）相关联，各自充当细胞信号传导的平台。因此，不同的泛素链拓扑结构可以调节不同的细胞过程。泛素对健康和疾病的重要性使其成为生物医学、药理学和农业生物技术干预战略的主要目标。因此，已经工程化了具有新特性的合成泛素变体和合成泛素化蛋白。然而，尚未考虑设计自然界中不存在的新型泛素链拓扑结构，但提供了在体内产生全新合成信号平台的潜力。在这里，我们建议建立合成的泛素链拓扑结构是完全新颖的，因此可以作为一个独特的细胞信号平台。为此，我们还将使用智能设计来构建专门识别这些合成链拓扑结构的新UBDPs。总的来说，我们的方法有可能创造新的细胞信号平台，以设计解决方案来对抗生物医学和药理学中的疾病，并减轻气候变化对农业生物技术的影响。

In addition to the genome, precise regulation of the proteome is now recognised to be a major contributor to organismal health and disease. Proteins of the proteome are regulated by various chemical modifications that together make up the epiproteome. One of the most important regulatory modifications of the epiproteome is made by the small conserved protein ubiquitin. Attachment of ubiquitin to substates serves many signalling roles, including regulation of substrate stability, cellular localisation, activity and conformation. Consequently, dysfunction of the ubiquitin system causes severe cellular stress and is a leading cause of developmental defects across different eukaryotes, including human pathologies such as neurodegenerative diseases, autoimmunity, cardiomyopathy, and genetic disorders like cystic fibrosis. So how does ubiquitin control so many different processes? Ubiquitin can be attached to substrates as a monomer or as an interlinked chain of ubiquitin molecules. In nature there are eight different ways in which ubiquitin can be attached to itself. These eight different topologies each serve as a platform for cellular signalling by associating with specific ubiquitin-binding domain proteins (UBDPs). Thus, distinct ubiquitin chain topologies can regulate different cellular processes. The importance of ubiquitin to health and disease has made it a major target for intervention strategies in biomedicine, pharmacology and in agricultural biotechnology. Consequently, synthetic ubiquitin variants and synthetic ubiquitinated proteins with novel properties have been engineered. However, engineering novel ubiquitin chain topologies that do not exist in nature has not yet been considered, yet offers the potential to generate completely new synthetic signalling platforms in vivo. Here we propose to build synthetic ubiquitin chain topologies that are completely novel and thus can be utilised as a unique cell signalling platform. To that end we will also use intelligent design to build new UBDPs that specifically recognise these synthetic chain topologies. Taken together, our approach has the potential to create new cellular signalling platforms to engineer solutions to combat disease in biomedicine and pharmacology, and mitigate the effects of climate change in agricultural biotechnology.