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 是一种由 101 个氨基酸组成的多肽，与泛素有 18% 的序列同一性。 与泛素一样，SUMO-1 在翻译后与大量细胞内蛋白质缀合。 然而，SUMO-1 缀合似乎调节目标底物的功能和/或定位，而不是其蛋白水解。 SUMO-1 缀合直接或间接地涉及多种重要细胞功能的调节剂。 被确定为 SUMO-1 缀合底物的蛋白质包括 RanGAP1（核细胞质运输的调节因子）、PML 和 Sp100（与癌症和神经退行性疾病相关的核内结构的组成部分）和 IkappaBalpha（控制免疫和炎症反应的信号通路的调节因子）。 SUMO-1 缀合也被认为是细胞周期和 DNA 修复的调节剂。 尽管初步迹象表明 SUMO-1 缀合可调节许多细胞功能，但 SUMO-1 缀合对单个蛋白质以及因此对细胞过程的确切影响仍不清楚。 该提案中概述的具体目标旨在提供对 SUMO-1 缀合、其对蛋白质功能的具体影响以及其对细胞过程的更全面影响的更详细的了解。 这些目标将通过分析调节 SUMO-1 缀合和解缀合的因素和信号、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。 将研究 SUMO-1 缀合受 E3 样蛋白连接酶以及解缀合酶调节的假设。 此外，还将通过分析 BLM（一种新型 SUMO-1/SUMO-2 底物）以及分析与粗线期精母细胞 XY 体相关的底物来研究 SUMO-1 缀合与 PML 核体之间的功能关系。 XY 体和 PML 核体在功能上相关并具有共同的 SUMO-1 缀合物的假设也将得到研究。