Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
基本信息
- 批准号:RGPIN-2017-05985
- 负责人:
- 金额:$ 1.89万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2018
- 资助国家:加拿大
- 起止时间:2018-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Ubiquitin signalling is critical in many cellular processes. The covalent attachment of ubiquitin to substrate proteins affects their biological functions. The best characterized function is 26S mediated proteasomal degradation of the substrate protein. Ubiquitin is attached to substrate proteins through an enzymatic cascade consisting of E1, E2 and E3 enzymes. Ubiquitin can also be cleaved from substrate proteins by deubiquitinases (DUBs). Deubiquitination activity must be highly regulated otherwise proteins would be targeted by these enzymes non-specifically resulting in deregulated cellular processes. Pathogenic organisms have the ability to manipulate ubiquitin signalling in host organisms to their advantage. This is a critical step in invasion by the pathogen. A variety of pathogenic organisms including bacteria and viruses possess proteins involved in ubiquitin signalling including bacterial/viral E3 ligases and DUBs that are used to dampen the immune response to enable infection.***The long-term goals of my lab are to investigate the function of bacterial, viral and human deubiquitinases to provide in-depth understanding of their roles in cellular processes. The objective of this research program is to characterize a bacterial and several viral DUBs by elucidating their function, substrates and mechanism of action in host organisms. We are now expanding our research theme to include DUBs from various pathogenic organisms. The project is divided into several short term objectives:****[1] Structural and Functional Characterization of the E. coli deubiquitinase ElaD. Very little is known about E. coli ElaD. We will identify host substrates and characterize the structural basis of interaction between ElaD and its host substrates.***[2] Characterization of viral deubiquitinases BPLF1, ORF64, UL36 and UL48. BPLF1, ORF64, UL36 and UL48 are deubiquitinases from different herpesviruses. There is very little known about the function of these proteins. For instance, few host substrate proteins have been identified for three of the four viral DUBs. BPLF1 interacts with and deubiquitinates PCNA, TRAF6 and NEMO, UL36 deubiquitinates TRAF3 and ORF64 deubiquitinates RIG-1. ***[3] Identification of BPLF1, ORF64, UL36 and UL48 host substrate(s) and interacting proteins. There are very few host substrates known for viral DUBS. In this part of the proposal we will identify novel host substrates using affinity purification-mass spectrometry. We will follow up by validating the identified viral DUB substrates in human cells with a variety of experiments.***Significance: Pathogenic organisms utilize a variety of methods to overcome the immune response during infection. The proposed studies will enhance our knowledge of the role of pathogenic deubiquitinases during infection by identifying substrates and pathways that are manipulated by the bacteria or viruses.
泛素信号在许多细胞过程中起着至关重要的作用。泛素与底物蛋白的共价结合影响底物蛋白的生物学功能。最具特征的功能是26S介导的蛋白酶体对底物蛋白的降解。泛素通过由E1、E2和E3酶组成的酶级联作用于底物蛋白。泛素也可以通过去泛素酶(deubiquitinases, DUBs)从底物蛋白中分离出来。去泛素化活性必须高度调控,否则蛋白质将被这些酶非特异性地靶向,导致细胞过程失控。病原生物有能力操纵宿主生物中的泛素信号以使其受益。这是病原体入侵的关键一步。包括细菌和病毒在内的多种致病生物都具有参与泛素信号传导的蛋白质,包括细菌/病毒E3连接酶和dub,用于抑制免疫反应,使感染成为可能。***我实验室的长期目标是研究细菌、病毒和人类去泛素酶的功能,以深入了解它们在细胞过程中的作用。本研究计划的目的是通过阐明其在宿主生物中的功能、底物和作用机制来表征一种细菌和几种病毒DUBs。我们现在正在扩大我们的研究主题,包括来自各种致病生物的dub。该项目分为几个短期目标:****[1]大肠杆菌去泛素酶ElaD的结构和功能表征。我们对大肠杆菌ElaD知之甚少。我们将鉴定宿主底物,并表征ElaD与其宿主底物之间相互作用的结构基础。***[2]病毒去泛素酶BPLF1、ORF64、UL36和UL48的鉴定。BPLF1、ORF64、UL36和UL48是来自不同疱疹病毒的去泛素酶。对这些蛋白质的功能所知甚少。例如,对于四种病毒dub中的三种,很少有宿主底物蛋白被鉴定出来。BPLF1与PCNA、TRAF6和NEMO相互作用并去泛素化,UL36去泛素化TRAF3, ORF64去泛素化RIG-1。***[3] BPLF1、ORF64、UL36和UL48宿主底物及其相互作用蛋白的鉴定。很少有已知的病毒DUBS宿主底物。在这部分的建议中,我们将使用亲和纯化-质谱法鉴定新的宿主底物。我们将通过各种实验在人类细胞中验证已鉴定的病毒DUB底物。***意义:病原生物在感染过程中利用多种方法克服免疫反应。提出的研究将通过确定细菌或病毒操纵的底物和途径,增强我们对致病性去泛素酶在感染过程中的作用的认识。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Saridakis, Vivian其他文献
Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7
- DOI:
10.1074/jbc.m115.710632 - 发表时间:
2016-03-18 - 期刊:
- 影响因子:4.8
- 作者:
Chavoshi, Sara;Egorova, Olga;Saridakis, Vivian - 通讯作者:
Saridakis, Vivian
The hydrophobic motif of ROCK2 requires association with the N-terminal extension for kinase activity
- DOI:
10.1042/bj20081376 - 发表时间:
2009-04-01 - 期刊:
- 影响因子:4.1
- 作者:
Couzens, Amber L.;Saridakis, Vivian;Scheid, Michael P. - 通讯作者:
Scheid, Michael P.
Structural insight on the mechanism of regulation of the MarR family of proteins:: High-resolution crystal structure of a transcriptional repressor from Methanobacterium thermoautotrophicum
- DOI:
10.1016/j.jmb.2008.01.001 - 发表时间:
2008-03-28 - 期刊:
- 影响因子:5.6
- 作者:
Saridakis, Vivian;Shahinas, Dea;Christendat, Dinesh - 通讯作者:
Christendat, Dinesh
Structural Basis of the Interaction Between Ubiquitin Specific Protease 7 and Enhancer of Zeste Homolog 2
- DOI:
10.1016/j.jmb.2019.12.026 - 发表时间:
2020-02-14 - 期刊:
- 影响因子:5.6
- 作者:
Gagarina, Varvara;Bojagora, Anna;Saridakis, Vivian - 通讯作者:
Saridakis, Vivian
Saridakis, Vivian的其他文献
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{{ truncateString('Saridakis, Vivian', 18)}}的其他基金
Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
- 批准号:
RGPIN-2017-05985 - 财政年份:2022
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
- 批准号:
RGPIN-2017-05985 - 财政年份:2021
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
- 批准号:
RGPIN-2017-05985 - 财政年份:2020
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
- 批准号:
RGPIN-2017-05985 - 财政年份:2019
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and Functional Analysis of Bacterial and Viral Deubiquitinases
细菌和病毒去泛素酶的结构和功能分析
- 批准号:
RGPIN-2017-05985 - 财政年份:2017
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and biochemical analysis of yeast ubiquitin-specific protease 15
酵母泛素特异性蛋白酶 15 的结构和生化分析
- 批准号:
342060-2007 - 财政年份:2011
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and biochemical analysis of yeast ubiquitin-specific protease 15
酵母泛素特异性蛋白酶 15 的结构和生化分析
- 批准号:
342060-2007 - 财政年份:2010
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and biochemical analysis of yeast ubiquitin-specific protease 15
酵母泛素特异性蛋白酶 15 的结构和生化分析
- 批准号:
342060-2007 - 财政年份:2009
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and biochemical analysis of yeast ubiquitin-specific protease 15
酵母泛素特异性蛋白酶 15 的结构和生化分析
- 批准号:
342060-2007 - 财政年份:2008
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
Structural and biochemical analysis of yeast ubiquitin-specific protease 15
酵母泛素特异性蛋白酶 15 的结构和生化分析
- 批准号:
342060-2007 - 财政年份:2007
- 资助金额:
$ 1.89万 - 项目类别:
Discovery Grants Program - Individual
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