Molecular Mechanisms and inhibition of Protein Acetyltransferases

蛋白质乙酰转移酶的分子机制和抑制

• 批准号: 9437627
• 负责人: Ronen Marmorstein
• 金额: $ 5.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9437627
• 关键词: Acetylation; Acetyltransferase; Address; Apoptosis; Biological Process; Cell Cycle Regulation; Cells; Cytoskeleton; DNA Damage; Disease; Endocytosis; Enzymes; Goals; Hematologic Neoplasms; Hereditary Disease; Histone Acetylation; Histones; Human; Lead; Lysine; Mammalian Cell; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Probes; N-terminal; Neurodegenerative Disorders; Pathway interactions; Permeability; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Property; Protein Acetylation; Protein Inhibition; Proteins; Proteome; Recombinant DNA; Regulation; Ribosomal Proteins; Ribosomes; Role; Solid; Transcriptional Regulation; cofactor; histone acetyltransferase; human disease; inhibitor/antagonist; novel; protein degradation; public health relevance; small molecule; targeted treatment; transcription factor

DESCRIPTION (provided by applicant): Protein acetylation is the most ancient and common form of posttranslational modification, and the vast majority of the human proteome is acetylated. Protein acetylation is mediated by protein lysine acetyltransferases (KATs), which are grouped into Histone ATs (HATs) and non-histone ATs, and protein N-terminal ATs (NATs). In mammalian cells, KATs acetylate thousands of proteins, spanning a wide class spectrum, including transcription factors, kinases, ubiquitinligases, ribosomal proteins and metabolic enzymes, and mediating a broad range of cellular activities, including cell cycle control, DNA damage check-points, cytoskeleton organization, endocytosis and metabolism. The posttranslational and cotranslational process of N-terminal acetylation by NATs occurs on ~85% of human proteins and is also involved in numerous biological processes including cellular apoptosis, enzyme regulation, protein localization, rDNA transcriptional regulation and protein degradation. Aberrant AT activities have also been associated with several diseases including solid and haematological cancers, rare genetic disorders, and metabolic and neurodegenerative disorders, thus implicating ATs as attractive drug targets for therapy. Despite the importance of ATs, mechanistic information is largely limited to the isolated catalytic AT domains, and the critical role played by AT cofactor and auxiliary proteins in mediating AT-regulated cellular pathways are largely unknown. In addition, potent, selective and cell permeable AT inhibitors as molecular probes for AT-mediated pathways and as lead molecules for therapy are generally not available. The overall goal of this proposal is to understand the molecular mechanisms of protein acetylation by HATs, non-histone KATs and NATs, with a particular focus on addressing the following unresolved and important questions and goals in the field: (A) How are HATs regulated by cofactor proteins for substrate-specific acetylation? (B) What are the unique AT properties of non-histone KATs? (C) How do auxiliary proteins and ribosome association contribute to NAT function? (D) Can we leverage mechanistic and structural information to develop potent and selective protein AT inhibitors?

描述（由申请人提供）：蛋白质乙酰化是最古老和最常见的翻译后修饰形式，绝大多数人类蛋白质组都是乙酰化的。蛋白质乙酰化是由蛋白质赖氨酸乙酰转移酶 (KAT) 介导的，其分为组蛋白 AT (HAT) 和非组蛋白 AT，以及蛋白质 N 末端 AT (NAT)。在哺乳动物细胞中，KAT 乙酰化数千种蛋白质，涵盖广泛的类别，包括转录因子、激酶、泛素连接酶、核糖体蛋白质和代谢酶，并介导广泛的细胞活动，包括细胞周期控制、DNA 损伤检查点、细胞骨架组织、内吞作用和代谢。 NAT 的 N 末端乙酰化的翻译后和共翻译过程发生在约 85% 的人类蛋白质上，并且还参与许多生物过程，包括细胞凋亡、酶调节、蛋白质定位、rDNA 转录调节和蛋白质降解。异常的 AT 活性还与多种疾病有关，包括实体癌和血液癌、罕见的遗传性疾病以及代谢和神经退行性疾病，因此表明 AT 是有吸引力的治疗药物靶点。尽管 AT 很重要，但机制信息在很大程度上仅限于孤立的催化 AT 结构域，并且 AT 辅因子和辅助蛋白在介导 AT 调节的细胞途径中所起的关键作用在很大程度上尚不清楚。此外，作为 AT 介导途径的分子探针和治疗的先导分子，通常无法获得有效的、选择性的和细胞渗透性的 AT 抑制剂。本提案的总体目标是了解 HAT、非组蛋白 KAT 和 NAT 进行蛋白质乙酰化的分子机制，特别关注解决该领域以下未解决的重要问题和目标： (A) HAT 是如何监管的通过辅因子蛋白进行底物特异性乙酰化？ (B) 非组蛋白 KAT 的独特 AT 特性是什么？ (C) 辅助蛋白和核糖体关联如何促进 NAT 功能？ (D) 我们能否利用机制和结构信息来开发有效的选择性蛋白质 AT 抑制剂？