Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers
Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers
复制标题
DOI：
10.4161/cc.11.5.19445
复制
发表时间：
2012-03-01
期刊：
影响因子：
4.3
通讯作者：
Uldrijan, Stjepan
中科院分区：
文献类型：
--
作者：
Dolezelova, Pavlina;Cetkovska, Katerina;Uldrijan, Stjepan
Mdm 2可以以Mdm 2同源二聚体或Mdm 2/MdmX异源二聚体的形式介导p53泛素化和降解。这些复合物的泛素连接酶活性主要存在于它们各自的RING指结构域中，并且还需要相邻的C-末端尾。到目前为止，结构研究未能显示Mdm 2 RING同源二聚体和Mdm 2/MdmX RING异源二聚体之间的显著差异。在这里，我们报告说，不仅主要的氨基酸序列，而且长度的Mdm 2的C-末端尾巴是高度保守的通过进化和Mdm 2对p53的活性中起着重要的作用。具有延伸C末端的Mdm 2突变体不泛素化p53，尽管能够通过RING-酸性结构域和RING-RING相互作用形成Mdm 2同源二聚体。所有扩展的突变体也保留了与MdmX相互作用的能力，这种相互作用导致其E3泛素连接酶活性的重新激活。与此相反，只有一个子集的扩展Mdm 2突变体被激活的Mdm 2环域的相互作用，这表明Mdm 2同源二聚体和Mdm 2/MdmX异源二聚体可能不是结构和功能完全相同。
Mdm2 can mediate p53 ubiquitylation and degradation either in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer. The ubiquitin ligase activity of these complexes resides mainly in their respective RING finger domains and also requires adjacent C-terminal tails. So far, structural studies have failed to show significant differences between Mdm2 RING homodimers and Mdm2/MdmX RING heterodimers. Here, we report that not only the primary amino acid sequence, but also the length of the C-terminal tail of Mdm2 is highly conserved through evolution and plays an important role in Mdm2 activity toward p53. Mdm2 mutants with extended C termini do not ubiquitylate p53 despite being capable of forming Mdm2 homodimers through both RING-acidic domain and RING-RING interactions. All extended mutants also retained the ability to interact with MdmX, and this interaction led to reactivation of their E3 ubiquitin ligase activity. In contrast, only a subset of extended Mdm2 mutants was activated by the interaction with Mdm2 RING domain, suggesting that Mdm2 homodimers and Mdm2/MdmX heterodimers may not be structurally and functionally fully equivalent.