Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family
Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family
复制标题
DOI：
10.1038/cdd.2016.75
复制
发表时间：
2016-12-01
影响因子：
12.4
通讯作者：
Doetsch, Volker
中科院分区：
文献类型：
--
作者：
Kehrloesser, Sebastian;Osterburg, Christian;Doetsch, Volker
癌症中发现的高比例p53错义突变归因于突变获得性致癌功能的获得。这些肿瘤促进功能的不同方面是由抑制p53家族成员p63和p73的转录活性引起的。经常发生的p53突变的一个子集导致DNA结合结构域（DBD）的热力学不稳定，使该结构域高度不稳定。这些构象突变体（如p53 R175 H）已被认为是直接结合p63和p73通过共聚集机制介导的DBD。虽然p63和p73的DBD事实上不足以如前所示的相互作用，但我们在此证明，p63和p73的α-同种型特异性C末端内的反式激活抑制（TI）结构域对于与p53 R175 H的结合是必需的。因此，使TI结构域不可接近的无活性TAp 63 α的闭合二聚体构象阻止了有效的相互作用。我们进一步表明，p53 R175 H的结合与四聚体α-同种型的内在聚集倾向相关，所述四聚体α-同种型由可开放访问的TI结构域赋予，再次支持通过共聚集机制的相互作用。
The high percentage of p53 missense mutations found in cancer has been attributed to mutant acquired oncogenic gain of functions. Different aspects of these tumour-promoting functions are caused by repression of the transcriptional activity of p53 family members p63 and p73. A subset of frequently occurring p53 mutations results in thermodynamic destabilisation of the DNA-binding domain (DBD) rendering this domain highly unstable. These conformational mutants (such as p53R175H) have been suggested to directly bind to p63 and p73 via a co-aggregation mechanism mediated by their DBDs. Although the DBDs of p63 and p73 are in fact not sufficient for the interaction as shown previously, we demonstrate here that the transactivation inhibitory (TI) domains within the alpha-isoform-specific C termini of p63 and p73 are essential for binding to p53R175H. Hence, the closed dimeric conformation of inactive TAp63 alpha that renders the TI domain inaccessible prevents efficient interaction. We further show that binding to p53R175H correlates with an intrinsic aggregation propensity of the tetrameric alpha-isoforms conferred by an openly accessible TI domain again supporting interaction via a co-aggregation mechanism.