Nakagawa Makiko, Nakagawa Tadashi
Institute of Gene Research, Yamaguchi University Science Research Center, Yamaguchi 755-8505, Japan.
Advanced Technology Institute, Life Science Division, Yamaguchi University, Yamaguchi 755-8611, Japan.
Cells. 2025 Jan 7;14(2):63. doi: 10.3390/cells14020063.
Ubiquitylation is a post-translational modification that modulates protein function and stability. It is orchestrated by the concerted action of three types of enzymes, with substrate specificity governed by ubiquitin ligases (E3s), which may exist as single proteins or as part of multi-protein complexes. Although Cullin (CUL) proteins lack intrinsic enzymatic activity, they participate in the formation of active ubiquitin ligase complexes, known as Cullin-Ring ubiquitin Ligases (CRLs), through their association with ROC1 or ROC2, along with substrate adaptor and receptor proteins. Mammalian genomes encode several CUL proteins (CUL1-9), each contributing to distinct CRLs. Among these CUL proteins, CUL1, CUL3, and CUL4 are believed to be the most ancient and evolutionarily conserved from yeast to mammals, with CUL4 uniquely duplicated in vertebrates. Genetic evidence strongly implicates CUL4-based ubiquitin ligases (CRL4s) in chromatin regulation across various species and suggests that, in vertebrates, CRL4s have also acquired a cytosolic role, which is facilitated by a cytosol-localizing paralog of CUL4. Substrates identified through biochemical studies have elucidated the molecular mechanisms by which CRL4s regulate chromatin and cytosolic processes. The substantial body of knowledge on CUL4 biology amassed over the past two decades provides a unique opportunity to explore the functional evolution of CRL4. In this review, we synthesize the available structural, genetic, and biochemical data on CRL4 from various model organisms and discuss the conserved and novel functions of CRL4s.
泛素化是一种翻译后修饰，可调节蛋白质的功能和稳定性。它由三种类型的酶协同作用来调控，其底物特异性由泛素连接酶（E3）决定，E3可以单体形式存在，也可以是多蛋白复合物的一部分。尽管Cullin（CUL）蛋白缺乏内在的酶活性，但它们通过与ROC1或ROC2以及底物衔接蛋白和受体蛋白结合，参与形成活性泛素连接酶复合物，即Cullin-Ring泛素连接酶（CRL）。哺乳动物基因组编码多种CUL蛋白（CUL1-9），每种都对不同的CRL有贡献。在这些CUL蛋白中，CUL1、CUL3和CUL4被认为是从酵母到哺乳动物中最古老且进化上保守的，其中CUL4在脊椎动物中独特地发生了复制。遗传学证据有力地表明，基于CUL4的泛素连接酶（CRL4）在跨物种的染色质调控中起作用，并表明在脊椎动物中，CRL4也获得了一种胞质作用，这是由CUL4的胞质定位旁系同源物促成的。通过生化研究鉴定出的底物阐明了CRL4调控染色质和胞质过程的分子机制。在过去二十年中积累的关于CUL4生物学的大量知识为探索CRL4的功能进化提供了独特的机会。在这篇综述中，我们综合了来自各种模式生物的关于CRL4的现有结构、遗传和生化数据，并讨论了CRL4的保守和新功能。
