Parkinsonism proteolysis and proteasomes.
Parkinsonism proteolysis and proteasomes.
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帕金森病蛋白水解和蛋白酶体。
DOI：
10.1038/sj.cdd.4401026
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发表时间：
2002
影响因子：
12.4
通讯作者：
Wang,Z
中科院分区：
文献类型：
--
作者：
Schwartz,LM;Nambu,JR;Wang,Z
科学的普遍真理是，方程的左边总是比右边更受关注。左侧代表综合，而右侧则被认为是失活，是对“可行”方法的倒退。有丝分裂、转录、翻译和磷酸化都比细胞凋亡、核酸酶、蛋白酶或磷酸酶更早、更引起人们的兴趣。然而，随着时间的推移，进一步的调查总是表明，双方在监管的谨慎平衡中都发挥着至关重要的作用。任何给定时间的细胞或分子的稳态数量代表合成和降解之间的平衡。改变其中任何一个，平衡都会发生变化。由于大多数生物过程是由特定蛋白质的活性控制的，因此蛋白水解领域最近引起了细胞调节和分子病理学研究的极大兴趣。泛素蛋白酶体系统 (UPS) 曾经被视为细胞的“垃圾处理器”，现在被认为是负责选择性降解特定蛋白质的复杂、优雅调节的途径（在 1 中进行了综述）。该通路中的细微扰动会导致关键信号分子的不适当稳定或降解，进而导致病理。 2 例如，乳头瘤病毒 E6 蛋白和细胞 E6 相关蛋白 (E6-AP) 对肿瘤抑制蛋白 p53 进行选择性泛素化，导致蛋白酶体依赖性 p53 降解并提高宫颈癌的发病率。 3 虽然 UPS 和疾病在癌症中的直接作用已得到充分证实，但尚不清楚该通路的异常是否会引发神经退行性疾病。在这篇综述中，我们描述了 UPS 并总结了将 UPS 缺陷与帕金森病起始直接联系起来的最新发现。泛素-蛋白质缀合是一个 ATP 依赖性过程，由三类不同的酶介导1（图 1）。级联中的第一个是 E1 泛素激活酶，它最初与泛素形成硫醇酯键。然后泛素被转移到多种 E2 泛素结合酶 (UBC) 中的一种。每个物种都携带多个独立的 E2 基因，这些基因发挥着独特的细胞作用，并且不同的 E2 蛋白在功能上不能相互替代。 4 级联中的最后一个酶是 E3 泛素蛋白连接酶，它
It is a general truism of science that the left hand side of an equation always attracts more attention than the right. The left hand side represents synthesis, while the right-hand side is dismissed as inactivation, a step-back from the can-do approach. Mitosis, transcription, translation and phosphorylation all attracted earlier and keener interest than did apoptosis, nucleases, proteases or phosphatases. With time however, further investigation always reveals that both sides play essential roles in the careful balance of regulation. The steady-state number of cells or molecules at any given time represents a balance between synthesis and degradation. Alter either and the balance shifts. Since most biological processes are controlled by the activity of specific proteins, the field of proteolysis has recently attracted considerable interest in the study of cellular regulation and molecular pathology. The ubiquitinąproteasome system (UPS), once dismissed as the cell'sgarbage disposal', is now appreciated as the complex, elegantly regulated pathway that is responsible for the selective degradation of specific proteins (reviewed in 1). Subtle perturbations in this pathway lead to the inappropriate stabilization or degradation of key signaling molecules, which in turn can result in pathology. 2 For example, selective ubiquitination of the tumor suppressor protein p53 by papilloma virus E6 protein and the cellular E6-Associated Protein (E6-AP), leads to proteasome-dependent p53 degradation and enhanced rates of cervical cancer. 3 While a direct role for the UPS and disease has been well established for cancer it has been less clear if aberrations in this pathway are responsible for initiating neurodegenerative disorders. In this review, we describe the UPS and summarize recent findings directly linking defects in the UPS and the initiation of Parkinsonism.Ubiquitinąprotein conjugation is an ATP-dependent process that is mediated by three distinct classes of enzymes1(Figure 1). First in the cascade is the E1 ubiquitin-activating enzyme, which initially forms a thiolester bond with ubiquitin. Ubiquitin is then transferred to one of a number of E2 ubiquitin-conjugating enzymes (UBCs). Each species carry multiple independent E2 genes that serve unique cellular roles and the different E2 proteins cannot functionally substitute for one another. 4 The last enzyme in the cascade is the E3 ubiquitinąprotein ligase, which