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首页> 外文期刊>Nucleic Acids Research >Deconstructing nucleotide binding activity of the Mdm2 RING domain
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Deconstructing nucleotide binding activity of the Mdm2 RING domain

机译：解构Mdm2 RING域的核苷酸结合活性

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摘要

Mdm2, a central negative regulator of the p53 tumor suppressor, possesses a Really Interesting New Gene (RING) domain within its C-terminus. In addition to E3 ubiquitin ligase activity, the Mdm2 RING preferentially binds adenine base nucleotides, and such binding leads to a conformational change in the Mdm2 C-terminus. Here, we present further biochemical analysis of the nucleotide-Mdm2 interaction. We have found that MdmX, an Mdm2 family member with high sequence homology, binds adenine nucleotides with similar affinity and specificity as Mdm2, suggesting that residues involved in nucleotide binding may be conserved between the two proteins and adenosine triphosphate (ATP) binding may have similar functional consequences for both Mdm family members. By generating and testing a series of proteins with deletions and substitution mutations within the Mdm2 RING, we mapped the specific adenine nucleotide binding region of Mdm2 to residues 429-484, encompassing the minimal RING domain. Using a series of ATP derivatives, we demonstrate that phosphate coordination by the Mdm2 P-loop contributes to, but is not primarily responsible for, ATP binding. Additionally, we have identified the 2' and 3' hydroxyls of the ribose and the C6 amino group of the adenine base moiety as being essential for binding.
机译：Mdm2是p53肿瘤抑制因子的中央负调控因子，在其C端拥有一个真正有趣的新基因（RING）域。除了E3泛素连接酶活性外，Mdm2 RING还优先结合腺嘌呤碱基核苷酸，这种结合导致Mdm2 C末端发生构象变化。在这里，我们提出核苷酸-Mdm2相互作用的进一步生化分析。我们发现，MdmX是具有高度序列同源性的Mdm2家族成员，其结合的腺嘌呤核苷酸的亲和力和特异性与Mdm2相似，这表明参与核苷酸结合的残基可能在两种蛋白质之间保守，而三磷酸腺苷（ATP）的结合可能具有相似性Mdm家庭成员的功能后果。通过生成和测试一系列在Mdm2 RING内具有缺失和取代突变的蛋白质，我们将Mdm2的特定腺嘌呤核苷酸结合区定位到残基429-484，其中包含最小的RING域。使用一系列的ATP衍生物，我们证明Mdm2 P环的磷酸配位有助于但不主要负责ATP结合。此外，我们已经确定了核糖的2'和3'羟基以及腺嘌呤碱基部分的C6氨基对于结合至关重要。

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