Japan_IPAP: Expanding epiproteome signalling with a new synthetic ubiquitin code
Japan_IPAP:用新的合成泛素代码扩展表蛋白质组信号传导
基本信息
- 批准号:BB/X012514/1
- 负责人:
- 金额:$ 19.35万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2023
- 资助国家:英国
- 起止时间:2023 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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.
除了基因组,蛋白质组的精确调控现在被认为是机体健康和疾病的主要因素。蛋白质组中的蛋白质受到各种化学修饰的调节,这些修饰共同构成了表观蛋白质组。表观蛋白质组最重要的调控修饰之一是由小的保守蛋白泛素进行的。泛素附着在底物上具有多种信号作用,包括底物稳定性、细胞定位、活性和构象的调节。因此,泛素系统的功能障碍导致严重的细胞应激,是不同真核生物发育缺陷的主要原因,包括神经退行性疾病、自身免疫、心肌病和囊性纤维化等遗传性疾病等人类疾病。那么泛素是如何控制这么多不同的过程的呢?泛素可以作为单体附着在底物上,也可以作为泛素分子的相互连接链附着在底物上。在自然界中,泛素可以通过八种不同的方式附着在自身上。这八种不同的拓扑结构通过与特定的泛素结合结构域蛋白(ubdp)相关而作为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领域干预策略的主要目标。因此,合成泛素变体和合成泛素化蛋白具有新的性质已经被设计。然而,自然界中不存在的工程新颖泛素链拓扑尚未被考虑,但它提供了在体内产生全新合成信号平台的潜力。在这里,我们建议构建合成的泛素链拓扑结构,这是完全新颖的,因此可以用作独特的细胞信号传导平台。为此,我们还将使用智能设计来构建新的ubdp,专门识别这些合成链拓扑。综上所述,我们的方法有可能创造新的细胞信号平台来设计解决方案,以对抗生物医学和药理学中的疾病,并减轻农业生物技术中气候变化的影响。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SUMOylation regulates Lem2 function in centromere clustering and silencing.
- DOI:10.1242/jcs.260868
- 发表时间:2023-12-01
- 期刊:
- 影响因子:4
- 作者:
- 通讯作者:
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Steven Spoel其他文献
SAシグナルの鍵転写補助因子NPR1はMYC-MED25複合体を標的としてJAシグナルを抑制する
SA 信号传导的关键转录辅因子 NPR1 靶向 MYC-MED25 复合物以抑制 JA 信号传导
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
野元美佳;Michael Skelly;板谷知健;鈴木孝征;松下智直;時澤睦朋;桑田啓子;森仁志;山本義治;東山哲也;塚越啓央;Steven Spoel;多田安臣 - 通讯作者:
多田安臣
Steven Spoel的其他文献
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{{ truncateString('Steven Spoel', 18)}}的其他基金
Cellular Functions of Proteasome-Associated Ubiquitin Ligase Activity
蛋白酶体相关泛素连接酶活性的细胞功能
- 批准号:
BB/S016767/1 - 财政年份:2019
- 资助金额:
$ 19.35万 - 项目类别:
Research Grant
Licensing Transcription Activator Activity with Ubiquitin Time Clocks
使用泛素时钟许可转录激活剂活动
- 批准号:
BB/L006219/1 - 财政年份:2014
- 资助金额:
$ 19.35万 - 项目类别:
Research Grant
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