Expanding Roles of E2 and E3 Enzymes in Ubiquitin Transfer

E2 和 E3 酶在泛素转移中的扩大作用

• 批准号: 8710250
• 负责人: Rachel E Klevit
• 金额: $ 52.82万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-21 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710250
• 关键词: Active Sites; BARD1 gene; BRCA1 Protein; BRCA1 gene; Binding; Biochemical; Biological; Biological Process; C-terminal; Caenorhabditis elegans; Cells; Disease; Engineering; Enzymes; Exhibits; Future; Generations; Goals; Health; Human; Hybrids; Individual; Investigation; Lead; Ligase; Lysine; Malignant Neoplasms; Muscle; Mutation; Nematoda; Neurodegenerative Disorders; Organism; Orthologous Gene; Pathway interactions; Predisposition; Process; Property; Proteins; Residual state; Role; Scanning; Site; Structure; Testing; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; Variant; Work; base; design; in vivo; insight; malignant breast neoplasm; mutant; new technology; novel; parkin gene/protein; public health relevance; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): The regulatory process known as protein ubiquitination modifies cellular proteins with far-reaching impacts on human health and disease. It is involved in every known biological process and is implicated in a growing range of diseases that includes cancers, neurodegenerative diseases, muscle wasting, etc. We are studying the expanding roles of protein ubiquitination to understand underlying principles of the process that can guide future efforts to manipulate or target the process. Over its thirteen-year course, the scope of the project has expanded beyond the single ubiquitin E3 ligase, the breast cancer susceptibility protein, BRCA1/BARD1, and its E2 conjugating enzymes. To reflect our expanding field of investigation and the expanding functionalities of E2s and E3s we have uncovered, the project is renamed "Expanding Roles of E2 and E3 enzymes in Ubiquitin Transfer." In Aim 1, we will use new mechanistic insights and new technology to generate RING E3s with enhanced activities for use in functional studies. In Aim 2, we will investigate the RING-Between-RING E3s, newly identified as a novel RING-HECT hybrid class of E3s. In Aim 3, we seek to define novel mechanisms used by E2s.

描述（由申请人提供）：被称为蛋白质泛素化的调节过程会修饰细胞蛋白质，对人类健康和疾病产生深远影响。它涉及所有已知的生物过程，并与越来越多的疾病有关，包括癌症、神经退行性疾病、肌肉萎缩等。我们正在研究蛋白质泛素化的不断扩大的作用，以了解该过程的基本原理，从而指导未来的工作操纵或瞄准该过程。在其十三年的历程中，该项目的范围已经超出了单一泛素 E3 连接酶、乳腺癌易感蛋白、BRCA1/BARD1 及其 E2 结合酶的范围。为了反映我们不断扩大的研究领域以及我们发现的 E2 和 E3 功能的扩展，该项目更名为“E2 和 E3 酶在泛素转移中的扩展作用”。在目标 1 中，我们将利用新的机制见解和新技术来生成具有增强活性的 RING E3，用于功能研究。在目标 2 中，我们将研究 RING-Between-RING E3，它是新确定的新型 RING-HECT 混合类 E3。在目标 3 中，我们寻求定义 E2 使用的新颖机制。