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首页> 外文期刊>Molecular and Cellular Biology >Critical Contribution of the MDM2 Acidic Domain to p53 Ubiquitination
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Critical Contribution of the MDM2 Acidic Domain to p53 Ubiquitination

机译：MDM2酸性域对p53泛素化的关键贡献。

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MDM2 is an E3 ubiquitin ligase that targets p53 for proteasomal degradation. Recent studies have shown, however, that the ring-finger domain (RFD) of MDM2, where the ubiquitin E3 ligase activity resides, is necessary but not sufficient for p53 ubiquitination, suggesting that an additional activity of MDM2 might be required. To test this possibility, we generated a series of MDM2/MDMX chimeric proteins to assess the contribution of each domain of MDM2 to the ubiquitination process. MDMX is a close structural homolog of MDM2 that nevertheless lacks the E3 ligase activity in vivo. We demonstrate here that MDMX gains self-ubiquitination activity and becomes extremely unstable upon introduction of the MDM2 RFD, indicating that the RFD is essential for self-ubiquitination. This MDMX chimeric protein, however, is unable to ubiquitinate p53 in vivo despite its E3 ligase activity and binding to p53, separating the self-ubiquitination activity of MDM2 from its ability to ubiquitinate p53. Significantly, fusion of the central acidic domain (AD) of MDM2 to the MDMX chimeric protein renders the protein fully capable of ubiquitinating p53, and p53 ubiquitination is associated with p53 degradation and nuclear export. Moreover, the AD mini protein expressed in trans can functionally rescue the AD-lacking MDM2 mutant, further supporting a critical role for the AD in MDM2-mediated p53 ubiquitination.
机译：MDM2是E3泛素连接酶，靶向p53进行蛋白酶体降解。但是，最近的研究表明，泛素E3连接酶活性所驻留的MDM2的环指结构域（RFD）对于p53泛素化是必需的，但并不足够，这表明可能还需要MDM2的其他活性。为了测试这种可能性，我们生成了一系列MDM2 / MDMX嵌合蛋白来评估MDM2的每个结构域对泛素化过程的贡献。 MDMX是MDM2的紧密结构同源物，但在体内缺乏E3连接酶活性。我们在这里证明，MDMX获得了自我泛素化活性，并且在引入MDM2 RFD后变得极为不稳定，这表明RFD对于自我泛素化至关重要。然而，尽管这种MDMX嵌合蛋白具有E3连接酶活性并与p53结合，但它无法在体内泛素化p53，从而将MDM2的自身泛素化活性与其泛素化p53的能力分开了。重要的是，MDM2的中央酸性域（AD）与MDMX嵌合蛋白的融合使该蛋白完全能够泛素化p53，而p53泛素化与p53降解和核输出有关。此外， trans 中表达的AD微型蛋白可以在功能上拯救缺少AD的MDM2突变体，进一步支持AD在MDM2介导的p53泛素化中的关键作用。

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