Activity of MDM2, a ubiquitin Ligase, toward p53 or itself is dependent on the RING finger domain of the ligase
Activity of MDM2, a ubiquitin Ligase, toward p53 or itself is dependent on the RING finger domain of the ligase
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DOI：
10.1038/sj.onc.1203464
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发表时间：
2000-03-09
期刊：
影响因子：
8
通讯作者：
Yasuda, H
中科院分区：
文献类型：
--
作者：
Honda, R;Yasuda, H
我们在之前的研究中发现，肿瘤蛋白MDM2对肿瘤抑制因子p53具有泛素连接酶活性，在这篇论文中，我们发现MDM2与E6AP （HECT结构域）之间的羧基末端具有非常弱的同源性。我们突变了与E6AP泛素连接酶活性相对应的半胱氨酸残基（C464），该突变降低了MDM2的连接酶活性。上述半胱氨酸残基也是构成MDM2环指结构域的半胱氨酸残基之一。我们试图找出突变导致的活性减弱是否归因于无名指结构域的破坏。当MDM2环指结构域被删除时，截断突变体不具有泛素连接酶活性。当我们突变MDM2环指结构域羧基端的7个半胱氨酸残基时，环指结构域中每个残基的破坏完全降低了MDM2对MDM2本身和肿瘤抑制因子p53的泛素连接酶活性。这些数据表明，MDM2中的环指结构域对于其针对p53和自身的泛素连接酶活性至关重要。
We previously showed that oncoprotein MDM2 has ubiquitin ligase activity toward tumor suppressor p53, In that paper, we showed very weak homology in the carboxyl terminal portion between MDM2 and E6AP (HECT domain). We mutated the cysteine residue (C464) corresponding to the residue essential for the ubiquitin ligase activity of E6AP and this mutation diminished the ligase activity of MDM2. The cysteine residue described above is also one of the cysteine residues that form the RING finger domain of MDM2. We tried to find out whether the diminishing of the activity by the mutation is attributable to the disruption of the RING finger domain or not. When the ring finger domain of MDM2 was deleted, the truncation mutant did not have the ubiquitin ligase activity. When we mutated the seven cysteine residues of RING finger domain of MDM2 in the carboxyl terminus, the disruption of each residue in the RING finger completely diminished the ubiquitin ligase activity of MDM2 toward MDM2 itself and toward tumor suppressor p53. These data indicate that the RING finger domain in MDM2 is essential for its ubiquitin ligase activity toward p53 and itself.