Eletr Ziad M, Wilkinson Keith D
Department of Biochemistry, Emory University, Atlanta GA 30322, USA.
Biochim Biophys Acta. 2014 Jan;1843(1):114-28. doi: 10.1016/j.bbamcr.2013.06.027. Epub 2013 Jul 9.
The post-translational attachment of one or several ubiquitin molecules to a protein generates a variety of targeting signals that are used in many different ways in the cell. Ubiquitination can alter the activity, localization, protein-protein interactions or stability of the targeted protein. Further, a very large number of proteins are subject to regulation by ubiquitin-dependent processes, meaning that virtually all cellular functions are impacted by these pathways. Nearly a hundred enzymes from five different gene families (the deubiquitinating enzymes or DUBs), reverse this modification by hydrolyzing the (iso)peptide bond tethering ubiquitin to itself or the target protein. Four of these families are thiol proteases and one is a metalloprotease. DUBs of the Ubiquitin C-terminal Hydrolase (UCH) family act on small molecule adducts of ubiquitin, process the ubiquitin proprotein, and trim ubiquitin from the distal end of a polyubiquitin chain. Ubiquitin Specific Proteases (USPs) tend to recognize and encounter their substrates by interaction of the variable regions of their sequence with the substrate protein directly, or with scaffolds or substrate adapters in multiprotein complexes. Ovarian Tumor (OTU) domain DUBs show remarkable specificity for different Ub chain linkages and may have evolved to recognize substrates on the basis of those linkages. The Josephin family of DUBs may specialize in distinguishing between polyubiquitin chains of different lengths. Finally, the JAB1/MPN+/MOV34 (JAMM) domain metalloproteases cleave the isopeptide bond near the attachment point of polyubiquitin and substrate, as well as being highly specific for the K63 poly-Ub linkage. These DUBs regulate proteolysis by: directly interacting with and co-regulating E3 ligases; altering the level of substrate ubiquitination; hydrolyzing or remodeling ubiquitinated and poly-ubiquitinated substrates; acting in specific locations in the cell and altering the localization of the target protein; and acting on proteasome bound substrates to facilitate or inhibit proteolysis. Thus, the scope and regulation of the ubiquitin pathway is very similar to that of phosphorylation, with the DUBs serving the same functions as the phosphatase. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
一个或多个泛素分子在翻译后与蛋白质连接，会产生多种靶向信号，这些信号在细胞中有多种不同的用途。泛素化可以改变靶向蛋白质的活性、定位、蛋白质 - 蛋白质相互作用或稳定性。此外，大量蛋白质受到泛素依赖性过程的调控，这意味着几乎所有细胞功能都受到这些途径的影响。来自五个不同基因家族的近百种酶（去泛素化酶或DUBs）通过水解将泛素连接到自身或靶蛋白的（异）肽键来逆转这种修饰。其中四个家族是硫醇蛋白酶，一个是金属蛋白酶。泛素C末端水解酶（UCH）家族的DUBs作用于泛素的小分子加合物，加工泛素前体蛋白，并从多聚泛素链的远端去除泛素。泛素特异性蛋白酶（USPs）倾向于通过其序列可变区与底物蛋白直接相互作用，或与多蛋白复合物中的支架或底物适配器相互作用来识别和接触其底物。卵巢肿瘤（OTU）结构域DUBs对不同的泛素链连接显示出显著的特异性，并且可能已经进化到基于这些连接来识别底物。DUBs的约瑟芬家族可能专门用于区分不同长度的多聚泛素链。最后，JAB1/MPN + /MOV34（JAMM）结构域金属蛋白酶切割多聚泛素与底物连接点附近的异肽键，并且对K63多聚泛素连接具有高度特异性。这些DUBs通过以下方式调节蛋白水解：直接与E3连接酶相互作用并共同调节；改变底物泛素化水平；水解或重塑泛素化和多聚泛素化底物；在细胞中的特定位置起作用并改变靶蛋白的定位；以及作用于与蛋白酶体结合的底物以促进或抑制蛋白水解。因此，泛素途径的范围和调控与磷酸化非常相似，DUBs的功能与磷酸酶相同。本文是名为：泛素 - 蛋白酶体系统的特刊的一部分。客座编辑：托马斯·索默和迪特尔·H·沃尔夫。
