Polyubiquitin binding and disassembly by deubiquitinating enzymes.
Polyubiquitin binding and disassembly by deubiquitinating enzymes.
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DOI：
10.1021/cr800470j
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发表时间：
2009-04
期刊：
影响因子：
62.1
通讯作者：
Wilkinson, Keith D.
中科院分区：
文献类型：
--
作者：
Reyes-Turcu, Francisca E.;Wilkinson, Keith D.
泛素（Ub）是一种高度保守的蛋白，由76个氨基酸组成，与靶蛋白共价连接，改变靶蛋白的定位、功能或稳定性。1-3蛋白可以被大量不同的泛素异构体修饰，而这些不同的泛素被认为代表着不同的结果。如何识别这些不同形式的泛素是理解各种泛素化特异性的核心问题。4-6泛素作为信号，通过三个连续的步骤与蛋白质结合。在第一步中，泛素通过在泛素c端与泛素激活酶或E1的活性位点半胱氨酸之间的atp依赖性硫酯键的形成而被激活。第二步是将泛素分子从E1转移到泛素偶联酶E2的活性位点半胱氨酸上。最后，在泛素连接酶或E3催化的反应中，泛素被转移到目标蛋白的赖氨酸残基上。这最后一步发生在基材特定的方式，它是高度调节。7-9泛素本身可发生多轮泛素化，导致多泛素链的形成。泛素的七种赖氨酸或氨基末端中的任何一种都可以用于聚合泛素，因此可以形成大量不同连接的多泛素信号。链可以由每个泛素（K29、K48、K63等）上相同的赖氨酸连接而成均质链，也可以利用某些泛素上不同的赖氨酸连接而成异质链。在后一种情况下，所使用的赖氨酸可以因泛素而异，或者通过在分支点将两个泛素连接到两个不同的赖氨酸，可以在单个泛素上形成分支链。人们通常认为不同的多泛素链与不同的细胞命运有关。受体被认为可以识别附着在靶蛋白上的不同泛素修饰（单泛素和多泛素），并介导不同的信号转导结果。4,10这些受体具有与泛素或多泛素相互作用的泛素结合域，也可能具有与修饰的靶蛋白或其他大分子相互作用的结构域。像大多数翻译后修饰一样，泛素化是可逆的11，它的去除是由统称为去泛素化酶（DUBs）的酶进行的。dub是一种与多种生物过程有关的蛋白酶。12,13它们负责从靶蛋白中去除泛素或多泛素，处理泛素前体，以及分解无锚定的多泛素（不与另一蛋白质连接的多泛素链），这些多泛素要么是从头合成的，要么是由其他dub的作用释放的。因此，像细胞靶向受体一样，它们识别不同形式的泛素和多泛素。例如，肿瘤抑制因子CYLD仅作用于k63链，酵母OTU1倾向于k48链，15和USP5切割两个连接。人类基因组编码了5个不同蛋白家族的近100个dub。一些DUBs已被证明在体内结合或加工多泛素或多泛素化底物，并且许多DUBs已被证明在体外切割多泛素。本文将讨论dub结合泛素和多泛素的特异性。讨论的dub将仅限于通过结构测定或直接结合和催化研究直接证明结合和特异性的dub。它将集中于目前关于泛素结构的知识体系。
Ubiquitin (Ub) is a highly conserved protein of 76 amino acids that is covalently linked to target proteins altering their localization, function, or stability. 1-3 Proteins can be modified with a large number of different isoforms of ubiquitin, and these different ubiquitins are thought to signal different outcomes. The question of how these different forms of ubiquitin are recognized is central to understanding the specificity of various types of ubiquitination. 4-6 Ubiquitin acts as a signal by being conjugated to proteins through three sequential steps. In the first step, ubiquitin is activated by the ATP-dependent formation of a thiolester bond between the C-terminus of ubiquitin and the active site cysteine of an ubiquitin activating enzyme or E1. The second step involves the transfer of the ubiquitin molecule from the E1 to the active site cysteine of an ubiquitin-conjugating enzyme or E2. Finally, the ubiquitin is transferred to a lysine residue of the target protein in a reaction catalyzed by an ubiquitin ligase or E3. This last step occurs in a substratespecific manner and it is highly regulated. 7-9 Several rounds of ubiquitination can occur on ubiquitin itself, leading to the formation of a polyubiquitin chain. Any of seven lysines, or the amino terminus, of ubiquitin can be used to polymerize ubiquitin, and so there are a huge number of differently linked polyubiquitin signals that can be formed. Chains can be linked by the same lysine on each ubiquitin (K29, K48, K63, etc.) to yield homogeneous chains, or can utilize different lysines on some ubiquitins to yield heterogeneous chains. In the latter case, the lysine used can vary from ubiquitin to ubiquitin, or chains can be formed that are branched at a single ubiquitin by linking two ubiquitins to two different lysines at the branch point. It is commonly assumed that different polyubiquitin chains are associated with different cellular fates. Receptors are thought to recognize the different ubiquitin modifications (mono-and polyubiquitin) attached to the target proteins and to mediate the different signaling outcomes. 4, 10 These receptors have ubiquitin binding domains that interact with ubiquitin or polyubiquitin, and may also have domains that can interact with the modified target proteins or other macromolecules. Like most posttranslational modifications, ubiquitination is reversible, 11 and its removal is carried out by enzymes collectively known as deubiquitinating enzymes (DUBs). 12 DUBs are proteases that have been implicated in a wide variety biological processes. 12, 13 They are responsible for the removal of ubiquitin or polyubiquitin from target proteins, the processing of ubiquitin precursors, and the disassembly of unanchored polyubiquitin (a polyubiquitin chain not attached to another protein) that is either synthesized de novo, or released by the action of other DUBs. Thus, like the cellular targeting receptors they recognize the different forms of ubiquitin and polyubiquitin. For instance, the tumor suppressor CYLD acts exclusively on K63-linked chains, 14 yeast OTU1 prefers long K48-linked chains, 15 and USP5 cleaves both linkages. 16 Nearly 100 DUBs in five different protein families are encoded by the human genome. Several DUBs have been shown to bind or process polyubiquitin or polyubiquitinated substrates in vivo, and many DUBs have been shown to cleave polyubiquitin in vitro. This review will discuss the specificity of ubiquitin and polyubiquitin binding by DUBs. The DUBs discussed will be limited to those where binding and specificity have been directly demonstrated, either through structure determination or direct binding and catalytic studies. It will focus on the current body of knowledge regarding structure of ubiquitin …
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