Ubiquitin Signaling: Chemistry Comes to the Rescue,Journal of the American Chemical Society

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Ubiquitin Signaling: Chemistry Comes to the Rescue
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2017-03-28 , DOI: 10.1021/jacs.7b00089
Sachitanand M. Mali ₁ , Sumeet K. Singh ₁ , Emad Eid ₁ , Ashraf Brik ₁

Affiliation

Posttranslational modification of proteins by ubiquitin (Ub), i.e., ubiquitination, mediates a variety of cellular processes, including protein homeostasis, cell cycle, DNA repair, and viral infections. Understanding the molecular mechanism of ubiquitination in these events is the basis for unraveling its precise role in health and disease. However, the inherent complexity of Ub signaling due to the high atomic complexity of Ub conjugates, where Ub is attached to other Ub molecules and to protein substrates in various forms, imposes a major challenge for these studies. In this regard, the enzymatic approaches employed for the preparation of important Ub conjugates have severe limitations to deliver them in high homogeneity and in adequate amounts for the desired study. Recent developments in the area of chemical synthesis and semisynthesis of proteins offer great solutions to the enzymatic limitations and enabling the preparation of various Ub conjugates with precise control over the atomic structure. These conjugates significantly contribute to deciphering Ub signaling at the molecular level, and with the synthetic tools in hand, chemical biologists have become key players in efforts toward understanding the complexity of the Ub code. In this Perspective, we highlight the key contributions of these synthetic approaches and how the development of novel Ub-based reagents is greatly assisting in uncovering unknown aspects of Ub signaling. We also discuss future aspirations to address unresolved questions in this exciting area of research.

中文翻译：

泛素信号：化学来拯救

泛素 (Ub) 对蛋白质的翻译后修饰，即泛素化，介导了多种细胞过程，包括蛋白质稳态、细胞周期、DNA 修复和病毒感染。了解泛素化在这些事件中的分子机制是阐明其在健康和疾病中的确切作用的基础。然而，由于 Ub 缀合物的原子复杂性高，Ub 信号传导的固有复杂性，其中 Ub 连接到其他 Ub 分子和各种形式的蛋白质底物，对这些研究提出了重大挑战。在这方面，用于制备重要 Ub 缀合物的酶促方法具有严重的局限性，无法以高同质性和足够的量提供它们以进行所需的研究。蛋白质的化学合成和半合成领域的最新发展为酶学限制提供了很好的解决方案，并使制备各种 Ub 缀合物能够精确控制原子结构。这些结合物对在分子水平上破译 Ub 信号做出了重大贡献，并且有了手中的合成工具，化学生物学家已成为了解 Ub 代码复杂性的关键参与者。在这个视角中，我们强调了这些合成方法的关键贡献，以及新型 Ub 试剂的开发如何极大地帮助揭示 Ub 信号传导的未知方面。我们还讨论了在这个令人兴奋的研究领域解决未解决问题的未来愿望。

更新日期：2017-03-28

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