Chemistry and Biology of ADP-Ribosylation-Dependent Signaling

摘要 蛋白质ADP-核糖化是一个复杂和高度动态的过程，受不同的作者、读者和 橡皮擦蛋白质。作为一种关键的翻译后修饰，蛋白质的ADP-核糖基化是由ADP-核糖基化催化的。 以烟酰胺腺嘌呤二核苷酸为共底物的核糖基转移酶 在调节大量生理和病理生理过程中发挥重要作用。ADP- 核糖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起作用。ADP-核糖化介导的信号转导可被激光调制 快速去除共价连接的腺苷二磷酸-核糖单元的蛋白质(S)。除了他们广泛的参与之外 在生理事件中，蛋白质ADP-核糖化的作者、读者和擦除者被广泛地牵涉到 无数的疾病。然而，ADP-核糖化在人类健康中的功能和作用仍不清楚。 以及多种疾病的发病机制。尽管技术进步，但人们对以下方面知之甚少 阅读器(S)和橡皮擦(S)对于单个腺苷二磷酸核糖化蛋白的同一性，首选腺苷二磷酸核糖化 蛋白质(S)为特定的阅读器或橡皮擦蛋白，与腺苷二磷酸-核糖化为中心的相互作用网络。和 用于明确定位ADP核糖化依赖的工具和技术还有待开发 互动组。米拉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，我们的目标是为公正和忠诚的人创造新型的双功能NAD分子 剖析依赖ADP核糖化的相互作用组并确定它们在细胞信号转导中的作用。成功 这项工作的完成将产生一套新颖和重要的化学工具，用于应对 跨多个领域的ADP核糖化依赖事件和过程的研究。这些创新工具 可能导致在理解蛋白质ADP的细胞功能和调节作用方面的重大突破- 核糖化在生理学和病理生理学以及新的诊断和治疗方法的发展中的作用 针对许多人类疾病的ADP核糖化相关活性和途径。

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.