Ubiquitination - More than two to tango
Ubiquitination - More than two to tango
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DOI：
10.1126/science.289.5487.2061
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发表时间：
2000-09-22
期刊：
影响因子：
56.9
通讯作者：
Hunter, T
中科院分区：
文献类型：
--
作者：
Joazeiro, CAP;Hunter, T
将泛素标签添加到蛋白质（泛素化），靶向它们进行降解，是许多细胞过程中的重要步骤，包括信号转导，转录和细胞周期的控制。泛素化需要三种酶-E1（泛素激活剂），E2（泛素结合剂）和E3（泛素蛋白连接酶）。许多E3连接酶是RING指蛋白，含有结合E2的锌稳定RING指基序和结合待降解蛋白质底物的结构域（1）。一个特别令人感兴趣的RING E3是c-Cbl原癌蛋白，其通过诱导活化的生长因子受体酪氨酸激酶的泛素化来关闭活化的生长因子受体酪氨酸激酶的信号传导。c-Cbl究竟如何与E2和受体酪氨酸激酶相互作用以被泛素化尚不清楚。现在，在最近一期的《细胞》杂志上，Pavletich的小组（2）报道了一个c-Cbl片段的结构，该片段含有RING指基序和变体SH 2（TKB）结构域，该结构域与UbcH 7（一种E2）和酪氨酸磷酸化肽（模拟蛋白质底物中的结合位点）结合。该结构揭示了c-Cbl家族蛋白质的新特征，并提示其他RING E3如何与E2酶结合。在哺乳动物细胞中，c-Cbl RING E3是表皮生长因子受体、血小板衍生生长因子受体和集落刺激因子-1受体泛素化的限速酶。这种活性需要高度保守的RING指基序和SH 2结构域的存在：前者募集E2，后者靶向活化的受体酪氨酸激酶进行泛素化和降解（3-5）。事实上，在70 Z3 Cbl癌基因（分离自前B细胞淋巴瘤）中发现的17个氨基酸缺失（包括RING基序中的第一个半胱氨酸）消除了c-Cbl促进受体酪氨酸激酶泛素化的能力。
The addition of a ubiquitin tag to proteins (ubiquitination), which targets them for degradation, is an essential step in many cellular processes including signal transduction, transcription, and control of the cell cycle. Three enzymes are required for ubiquitination—E1 (the ubiquitin-activator), E2 (the ubiquitin-conjugator), and E3 (the ubiquitin-protein ligase). Many E3 ligases are RING finger proteins containing a zinc-stabilized RING finger motif that binds to E2 and a domain that binds to the protein substrate to be degraded (1). One particularly interesting RING E3 is the c-Cbl proto-oncoprotein, which shuts down the signaling of activated growth factor receptor tyrosine kinases by inducing their ubiquitination. Exactly how c-Cbl interacts with both E2 and the receptor tyrosine kinase to be ubiquitinated is unclear. Now, in a recent issue of Cell, Pavletich's group (2) reports the structure of a c-Cbl fragment—containing the RING finger motif and the variant SH2 (TKB) domain—bound to both UbcH7 (an E2) and a tyrosine-phosphorylated peptide (that mimics the binding site in the protein substrate). The structure reveals new features of c-Cbl family proteins and suggests how other RING E3s may bind to E2 enzymes.In mammalian cells, the c-Cbl RING E3 is a rate-limiting enzyme for the ubiquitination of epidermal growth factor receptor, platelet-derived growth factor receptor, and colony-stimulating factor-1 receptor. This activity requires the presence of the highly conserved RING finger motif and SH2 domain: The former recruits the E2 and the latter targets activated receptor tyrosine kinases for ubiquitination and degradation (3-5). Indeed, the 17-amino acid deletion found in the 70Z3 Cbl oncogene (isolated from a pre-B cell lymphoma), which includes the first cysteine in the RING motif, abolishes the ability of c-Cbl to promote ubiquitination of receptor tyrosine kinases.