REGULATION AND FUNCTION OF SUMO-1 PROTEIN MODIFICATION

SUMO-1 蛋白修饰的调控和功能

• 批准号: 6520185
• 负责人: MICHAEL J. MATUNIS
• 金额: $ 25.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520185
• 关键词: cell nucleus; chemical conjugate; intracellular transport; laboratory rat; nuclear membrane; posttranslational modifications; protein localization; protein protein interaction; protein structure function; ubiquitin

SUMO-1 is a 101 amino acid polypeptide that shares 18 percent sequence identity with ubiquitin. Like ubiquitin, SUMO-1 is posttransationally conjugated to a significant number of intracellular proteins. However, SUMO-1 conjugation appears to regulate the function and/or localization of targeted substrates, rather than their proteolysis. SUMO-1 conjugation has been implicated, either directly or indirectly, as a regulator of a wide range of important cell functions. Proteins identified as substrates for SUMO-1 conjugation include RanGAP1 (a regulator of nucleocytoplasmic transport), PML and Sp100 (components of intranuclear structures linked to cancer and neurodegenerative disease), and IkappaBalpha (a regulator of signaling pathways that control immune and inflammatory responses). SUMO-1 conjugation has also been implicated as a regulator of the cell cycle and DNA repair. In spite of the preliminary indications that SUMO-1 conjugation regulates a host of cell functions, the precise effects that SUMO-1 conjugation has on individual proteins, and consequently on cellular processes, remains unclear. The Specific Aims outlined in this proposal are designed to provide a more detailed understanding of SUMO- 1 conjugation, its specific effects on protein function, and its more global effects on cellular processes. These goals will be achieved through analysis of the factors and signals regulating SUMO-1 conjugation and deconjugation, characterization of novel SUMO-1 substrates, and characterization of the SUMO-1 related protein, SUMO-2. The hypothesis that SUMO-1 conjugation is regulated by E3-like protein ligases, as well as by deconjugating enzymes, will be investigated. Also, the functional relationships between SUMO-1 conjugation and PML nuclear bodies will be investigated through analysis of BLM, a novel SUMO-1/SUMO-2 substrate, and through analysis of substrates associated with the XY body of pachytene spermatocytes. The hypothesis that the XY body and PML nuclear bodies are functionally related and share common SUMO-1 conjugates will also be investigated.

SUMO-1是101个氨基酸多肽，与泛素共享18％的序列同一性。 像泛素一样，SUMO-1在术后结合到大量细胞内蛋白。 但是，SUMO-1共轭似乎调节了靶向底物的功能和/或定位，而不是其蛋白水解。 SUMO-1结合已直接或间接地作为广泛的重要细胞功能的调节剂。 被鉴定为SUMO-1结合的底物的蛋白质包括Rangap1（核质传输的调节剂），PML和SP100（与癌症和神经退行性疾病相关的核内结构的成分）和IKAPPABALPHA（控制免疫和炎症反应的信号通道调节剂）。 SUMO-1结合也被认为是细胞周期和DNA修复的调节剂。 尽管有初步迹象表明SUMO-1共轭调节了许多细胞功能，但SUMO-1结合对单个蛋白质以及因此对细胞过程的确切作用仍不清楚。 本提案中概述的具体目的旨在提供对Sumo-1共轭，其对蛋白质功能的特定影响以及对细胞过程的全球影响的更详细的理解。 这些目标将通过分析调节SUMO-1共轭和解共轭，新型SUMO-1底物的表征以及SUMO-1相关蛋白SUMO-2的表征来实现这些目标。 将研究SUMO-1结合受E3样蛋白连接酶以及将酶调节的假设。 同样，将通过分析BLM，一种新型的SUMO-1/SUMO-2底物研究SUMO-1共轭与PML核体之间的功能关系，并通过分析与Pachytene精子细胞的XY体相关的底物。 XY体和PML核体在功能上相关并共享共同的SUMO-1偶联物的假设也将进行研究。