Chemistry and Biology of ADP-Ribosylation-Dependent Signaling

ADP 核糖基化依赖性信号传导的化学和生物学

• 批准号: 10426310
• 负责人: Yong Zhang
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426310
• 关键词: ADP Ribose Transferases; ADP ribosylation; Address; Adenosine Diphosphate Ribose; Area; Biological Process; Biology; Cell physiology; Chemicals; Chemistry; Complex; Development; Disease; Dissection; Event; Functional disorder; Goals; Health; Human; Individual; Lead; Mediating; Nicotinamide adenine dinucleotide; Pathogenesis; Pathway interactions; Physiological; Physiology; Play; Post-Translational Protein Processing; Process; Proteins; Reader; Research; Role; Signal Transduction; Technology; Work; human disease; innovation; new therapeutic target; novel; novel diagnostics; tool

Abstract Protein ADP-ribosylation is a complex and highly dynamic process regulated by distinct writer, reader and eraser proteins. As a key post-translational modification, protein ADP-ribosylation is catalyzed by ADP- ribosyltransferases (ARTs) by using nicotinamide adenine dinucleotide (NAD+) as a co-substrate and plays important roles in regulating a significant number of physiological and pathophysiological processes. ADP- ribosylated proteins can be recognized by reader proteins, triggering downstream signaling cascades or effector functions in direct or indirect manners. The ADP-ribosylation-mediated signaling can be modulated by eraser proteins that rapidly remove covalently attached ADP-ribose unit(s). In addition to their extensive involvements in physiological events, the writers, readers, and erasers of protein ADP-ribosylation are broadly implicated in numerous diseases. However, it remains elusive for the functions and roles of ADP-ribosylation in human health and pathogenesis of many diseases. Despite technological advancement, little information is known regarding the identity of the reader(s) and eraser(s) for individual ADP-ribosylated proteins, the preferred ADP-ribosylated protein(s) for a specific reader or eraser protein, and the ADP-ribosylation-centered interaction networks. And tools and technologies have yet to be developed for unambiguously mapping ADP-ribosylation-dependent interactome. The goal of this MIRA project is to develop novel chemical tools to address these major challenges. In next five years, we are aimed to generate novel bifunctional NAD+ molecules for unbiased and faithful dissection of ADP-ribosylation-dependent interactome and define their roles in cell signaling. Successful completion of this work will result in a set of novel and important chemical tools for addressing challenges in research on ADP-ribosylation-dependent events and processes across multiple areas. These innovative tools may lead to major breakthroughs in understanding of the cellular functions and regulatory roles of protein ADP- ribosylation in physiology and pathophysiology and in the development of novel diagnostics and therapeutics targeting ADP-ribosylation-associated activities and pathways for many human diseases.

抽象的 蛋白质 ADP-核糖基化是一个复杂且高度动态的过程，受不同的作者、读者和 橡皮擦蛋白。作为关键的翻译后修饰，蛋白质 ADP-核糖基化由 ADP- 催化 使用烟酰胺腺嘌呤二核苷酸 (NAD+) 作为共底物的核糖基转移酶 (ART) 并发挥作用 在调节大量生理和病理生理过程中发挥重要作用。 ADP- 核糖基化蛋白可以被阅读器蛋白识别，触发下游信号级联或效应器 以直接或间接的方式发挥作用。 ADP-核糖基化介导的信号传导可以通过擦除器调节 快速去除共价连接的 ADP-核糖单元的蛋白质。除了他们的广泛参与 在生理事件中，蛋白质 ADP 核糖基化的写入者、读取者和擦除者广泛涉及 许多疾病。然而，ADP-核糖基化在人类健康中的功能和作用仍然难以捉摸 以及许多疾病的发病机制。尽管技术不断进步，但人们对这方面的信息知之甚少。 单个 ADP 核糖基化蛋白的读取器和擦除器的身份，首选 ADP 核糖基化蛋白 特定读取器或擦除器蛋白的蛋白质，以及以 ADP 核糖基化为中心的相互作用网络。和 尚未开发出用于明确绘制 ADP 核糖基化依赖性图谱的工具和技术 相互作用组。 MIRA 项目的目标是开发新型化学工具来应对这些重大挑战。 未来五年，我们的目标是生产新型双功能 NAD+ 分子，以实现公正和忠实的目标 剖析 ADP-核糖基化依赖性相互作用组并定义它们在细胞信号传导中的作用。成功的 这项工作的完成将产生一套新颖且重要的化学工具，用于应对挑战 跨多个领域的 ADP 核糖基化依赖性事件和过程的研究。这些创新工具 可能会在理解蛋白质 ADP- 的细胞功能和调节作用方面带来重大突破 生理学和病理生理学以及新型诊断和治疗方法开发中的核糖基化 针对许多人类疾病的 ADP-核糖基化相关活性和途径。