Chemistry and Biology of ADP-Ribosylation-Dependent Signaling

摘要 蛋白质ADP-核糖基化是一个复杂的高度动态过程，受不同的作者、读者和 擦除蛋白。作为一种关键的翻译后修饰，蛋白质ADP-核糖基化是由ADP- 通过使用烟酰胺腺嘌呤二核苷酸（NAD+）作为共底物， 在调节大量生理和病理生理过程中起重要作用。ADP- 核糖基化的蛋白质可以被阅读器蛋白识别，触发下游信号级联或效应子 以直接或间接的方式发挥作用。ADP-核糖基化介导的信号可以被橡皮擦调节 快速去除共价连接的ADP-核糖单位的蛋白质。除了广泛参与 在生理事件中，蛋白质ADP-核糖基化的编写者、阅读者和擦除者广泛地牵涉到 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是一个谜 和许多疾病的发病机制。尽管技术进步，但关于 用于单个ADP-核糖基化蛋白的读取器和擦除器的身份，优选的ADP-核糖基化蛋白 一个或多个特定的阅读器或擦除器蛋白质，和ADP-核糖基化为中心的相互作用网络。和 工具和技术尚未开发用于明确映射ADP-核糖基化依赖的 相互作用体MIRA项目的目标是开发新的化学工具来应对这些重大挑战。 在接下来的五年里，我们的目标是产生新的双功能NAD+分子， ADP-核糖基化依赖性相互作用组的解剖和定义它们在细胞信号传导中的作用。成功 这项工作的完成将产生一套新的和重要的化学工具，用于应对 研究ADP-核糖基化依赖的事件和过程跨多个领域。这些创新工具 可能导致对细胞功能和蛋白质ADP的调节作用的理解的重大突破， 核糖基化在生理学和病理生理学以及新型诊断和治疗学的发展中的应用 靶向ADP-核糖基化相关的活动和许多人类疾病的途径。

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.