McCoy Mark A, Gesell Jennifer J, Senior Mary M, Wyss Daniel F
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1645-8. doi: 10.1073/pnas.0334477100. Epub 2003 Jan 27.
The stabilization of p53 against Mdm2-mediated degradation is an important event in DNA damage response. Initial models of p53 stabilization focused on posttranslational modification of p53 that would disrupt the p53-Mdm2 interaction. The N-terminal regions of both p53 and Mdm2 are modified in vivo in response to cellular stress, suggesting that modifications to Mdm2 also may affect the p53-Mdm2 interaction. Our NMR studies of apo-Mdm2 have found that, in addition to Mdm2 residues 25-109 that form the well ordered p53-binding domain that was observed in the p52-Mdm2 complex, Mdm2 residues 16-24 form a lid that closes over the p53-binding site. The Mdm2 lid, which is strictly conserved in mammals, may help to stabilize apo-Mdm2. It also competes weakly with peptidic and nonpeptidic antagonists. Modifications to the Mdm2 lid may disrupt p53-Mdm2 binding leading to p53 stabilization. Mdm2 and Mdm4 possess nearly identical p53-binding domains but different lids suggesting that lid modifications may select for p53 binding.
p53 对 Mdm2 介导的降解的稳定作用是 DNA 损伤反应中的一个重要事件。最初的 p53 稳定模型集中在 p53 的翻译后修饰上，这种修饰会破坏 p53-Mdm2 相互作用。p53 和 Mdm2 的 N 端区域在体内会因细胞应激而发生修饰，这表明对 Mdm2 的修饰也可能影响 p53-Mdm2 相互作用。我们对无配体 Mdm2 的核磁共振研究发现，除了在 p52-Mdm2 复合物中观察到的形成有序 p53 结合结构域的 Mdm2 残基 25 - 109 外，Mdm2 残基 16 - 24 形成一个覆盖 p53 结合位点的盖子。Mdm2 盖子在哺乳动物中严格保守，可能有助于稳定无配体 Mdm2。它与肽类和非肽类拮抗剂的竞争较弱。对 Mdm2 盖子的修饰可能会破坏 p53-Mdm2 结合，导致 p53 稳定。Mdm2 和 Mdm4 具有几乎相同的 p53 结合结构域，但盖子不同，这表明盖子修饰可能会选择与 p53 结合。
