Developing ubiquitin chain- and target-specific deubiquitinase probes

开发泛素链和靶标特异性去泛素酶探针

• 批准号: 8772352
• 负责人: Zhihao Zhuang
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772352
• 关键词: Address; Cell physiology; Cells; Chemicals; Cleaved cell; Collaborations; Complex; Cysteine; Deubiquitination; Development; Disease; Esters; Eukaryotic Cell; Generations; Human; Immunoprecipitation; Intervention; Investigation; Label; Length; Letters; Ligation; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Nerve Degeneration; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Physiological; Polyubiquitin; Proliferating Cell Nuclear Antigen; Proteins; Proteomics; Sampling; Small Interfering RNA; Specificity; Speed; Structure; Testing; Therapeutic; Therapeutic Intervention; UBD protein; Ubiquitin; Ubiquitination; Viral Cancer; Virus Diseases; abstracting; alpha synuclein; base; human disease; in vitro Assay; novel therapeutics; public health relevance; research study

DESCRIPTION (provided by applicant): Developing ubiquitin chain- and target protein-specific deubiquitinase probes Abstract Abnormal function of human deubiquitinases (DUBs) has been linked to the pathogenesis of a number of human diseases including neurodegenerative disorders, cancer and viral infection. Human DUBs are emerging as promising targets for pharmacological intervention. However, the lack of understanding of ubiquitin chain- and target protein-specificity of DUBs has hindered the progress in developing novel therapeutics. Although a myriad of cellular proteins have been found to be ubiquitinated, the DUBs or DUB complexes responsible for the deubiquitination of many of these proteins remain unknown. DUB probes that allow the identification of DUBs and the investigation of the chain and target protein specificity are highly desirable. This application focuses on the development a new class of DUB probes that contain an electrophilic group that can trap DUBs that contains a catalytic cysteine. The probes will be used to elucidate the polyubiquitin chain specificity of human DUBs and to identify DUBs specific for ubiquitinated protein α-synuclein that is implicated in Parkinson's disease. The DUB(s) responsible for α-synuclein deubiquitination will serve as a potential target for therapeutic intervention of Parkinson's disease (PD).

描述（申请人提供）：开发泛素链和靶蛋白特异性去泛素化酶探针摘要人去泛素化酶（DUBs）的异常功能与许多人类疾病的发病机制有关，包括神经退行性疾病、癌症和病毒感染。人DUB正在成为药理学干预的有前途的靶点。然而，对DUBs的泛素链特异性和靶蛋白特异性缺乏了解阻碍了开发新疗法的进展。虽然已经发现无数的细胞蛋白质是泛素化的，但负责这些蛋白质中的许多去泛素化的DUB或DUB复合物仍然未知。DUB探针允许DUB的鉴定和链和靶蛋白特异性的研究是非常需要的。本申请专注于开发一类新的DUB探针，其含有亲电基团，可以捕获含有催化半胱氨酸的DUB。这些探针将用于阐明人DUB的多聚泛素链特异性，并鉴定与帕金森病有关的泛素化蛋白α-突触核蛋白特异性DUB。负责α-突触核蛋白去泛素化的DUB将作为帕金森病（PD）治疗干预的潜在靶点。