Molecular Mechanisms and inhibition of Protein Acetyltransferases

描述（由申请人提供）：蛋白质乙酰化是翻译后修饰的最古老和最常见的形式，绝大多数人类蛋白质组是乙酰化的。蛋白质乙酰化由蛋白质赖氨酸乙酰转移酶（KAT）介导，KAT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，跨越广泛的类谱，包括转录因子、激酶、泛素连接酶、核糖体蛋白和代谢酶，并且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。NATs引起的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，并且还涉及许多生物学过程，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活性也与几种疾病相关，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，从而暗示AT是治疗的有吸引力的药物靶标。尽管AT的重要性，机械信息在很大程度上是有限的，孤立的催化AT结构域，和AT辅因子和辅助蛋白在介导AT调节的细胞通路中发挥的关键作用在很大程度上是未知的。此外，有效的，选择性的和细胞渗透性的AT抑制剂作为AT介导的途径的分子探针和作为治疗的先导分子通常是不可用的。本提案的总体目标是了解HAT、非组蛋白KAT和NAT的蛋白质乙酰化的分子机制，特别关注该领域中以下未解决的重要问题和目标：（A）辅助因子蛋白如何调节HAT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)辅助蛋白和核糖体的结合如何影响NAT的功能？(D)我们能否利用机制和结构信息来开发有效的和选择性的蛋白AT抑制剂？

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?