Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy.
Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy.
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DOI：
10.1186/1747-1028-2-5
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发表时间：
2007-02-06
期刊：
影响因子：
2.3
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Higa LA;Zhang H
Cullin 4（CUL 4）的最新研究已经将这类多蛋白泛素E3连接酶推向了中心舞台，作为不同过程的关键调节剂，包括细胞周期调节，发育模式，DNA复制，DNA损伤和修复以及基因表达的表观遗传控制。CUL 4与DNA损伤结合蛋白1（DDB 1）结合，组装一种遍在蛋白E3连接酶，该连接酶靶向蛋白质底物进行遍在蛋白依赖性蛋白水解。CUL 4连接酶活性也受泛素样蛋白NEDD 8与CUL 4的共价连接或neddylation以及去除这种重要修饰的COP 9信号体复合物（CSN）的调节。最近，发现多个WD 40重复蛋白（WDR）与DDB 1相互作用，并作为底物识别亚基的CUL 4-DDB 1泛素连接酶。由于人类基因组中存在超过150-300种WDR蛋白，这些发现通过CUL 4连接酶介导的蛋白水解影响了广泛的生物过程。本文综述了近年来对CUL 4泛素E3连接酶作用机制的研究进展，并通过与基于CUL 1的E3 s（SCF）的比较，讨论了CUL 4组装的E3泛素连接酶复合物的结构。然后，我们将回顾几个例子来强调CUL 4泛素连接酶在基因组稳定性，细胞周期调控和组蛋白赖氨酸甲基化中的关键作用。总之，这些研究提供了深入了解这种新的泛素连接酶在重要的生物过程的调节机制。
Recent investigation of Cullin 4 (CUL4) has ushered this class of multiprotein ubiquitin E3 ligases to center stage as critical regulators of diverse processes including cell cycle regulation, developmental patterning, DNA replication, DNA damage and repair, and epigenetic control of gene expression. CUL4 associates with DNA Damage Binding protein 1 (DDB1) to assemble an ubiquitin E3 ligase that targets protein substrates for ubiquitin-dependent proteolysis. CUL4 ligase activity is also regulated by the covalent attachment of the ubiquitin-like protein NEDD8 to CUL4, or neddylation, and the COP9 signalosome complex (CSN) that removes this important modification. Recently, multiple WD40-repeat proteins (WDR) were found to interact with DDB1 and serve as the substrate-recognition subunits of the CUL4-DDB1 ubiquitin ligase. As more than 150–300 WDR proteins exist in the human genome, these findings impact a wide array of biological processes through CUL4 ligase-mediated proteolysis. Here, we review the recent progress in understanding the mechanism of CUL4 ubiquitin E3 ligase and discuss the architecture of CUL4-assembled E3 ubiquitin ligase complexes by comparison to CUL1-based E3s (SCF). Then, we will review several examples to highlight the critical roles of CUL4 ubiquitin ligase in genome stability, cell cycle regulation, and histone lysine methylation. Together, these studies provide insights into the mechanism of this novel ubiquitin ligase in the regulation of important biological processes.
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