Molecular Mechanisms and inhibition of Protein Acetyltransferases

描述(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，人类蛋白质组的绝大多数是乙酰化的。蛋白质乙酰化是由蛋白质赖氨酸乙酰转移酶(KATS)介导的，KATS分为组蛋白ATS(HATS)和非组蛋白ATS(HATS)，以及蛋白质N末端ATS(NAT)。在哺乳动物细胞中，KATS可乙酰化数千种蛋白质，包括转录因子、激酶、泛素连接酶、核糖体蛋白和代谢酶，并调节广泛的细胞活动，包括细胞周期控制、DNA损伤检查点、细胞骨架组织、内吞作用和新陈代谢。NAT的翻译后和共翻译过程发生在人类85%的蛋白质上，还参与了许多生物学过程，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。AT活性的异常也与一些疾病有关，包括实体癌和血液癌、罕见的遗传疾病以及代谢和神经退行性疾病，从而使ATS成为有吸引力的治疗药物靶点。尽管ATS很重要，但机制信息在很大程度上仅限于分离的催化AT结构域，AT辅助因子和辅助蛋白在介导AT调节的细胞通路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，有效的、选择性的和细胞透过性的AT抑制剂通常是不可用的。这项建议的总体目标是了解HATS、非组蛋白KATS和NAT对蛋白质乙酰化的分子机制，特别关注解决该领域尚未解决的重要问题和目标：(A)HATS如何由辅因子蛋白调节底物特异性乙酰化？(B)非组蛋白猫科动物独特的AT特性是什么？(C)辅助蛋白和核糖体结合如何促进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?