Di Lello Paola, Jenkins Lisa M Miller, Jones Tamara N, Nguyen Bao D, Hara Toshiaki, Yamaguchi Hiroshi, Dikeakos Jimmy D, Appella Ettore, Legault Pascale, Omichinski James G
Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Mol Cell. 2006 Jun 23;22(6):731-740. doi: 10.1016/j.molcel.2006.05.007.
The interaction between the amino-terminal transactivation domain (TAD) of p53 and TFIIH is directly correlated with the ability of p53 to activate both transcription initiation and elongation. We have identified a region within the p53 TAD that specifically interacts with the pleckstrin homology (PH) domain of the p62 and Tfb1 subunits of human and yeast TFIIH. We have solved the 3D structure of a complex between the p53 TAD and the PH domain of Tfb1 by NMR spectroscopy. Our structure reveals that p53 forms a nine residue amphipathic alpha helix (residues 47-55) upon binding to Tfb1. In addition, we demonstrate that diphosphorylation of p53 at Ser46 and Thr55 leads to a significant enhancement in p53 binding to p62 and Tfb1. These results indicate that a phosphorylation cascade involving Ser46 and Thr55 of p53 could play an important role in the regulation of select p53 target genes.
p53的氨基末端反式激活结构域（TAD）与TFIIH之间的相互作用与p53激活转录起始和延伸的能力直接相关。我们在p53 TAD中鉴定出一个区域，该区域与人及酵母TFIIH的p62和Tfb1亚基的pleckstrin同源（PH）结构域特异性相互作用。我们通过核磁共振光谱法解析了p53 TAD与Tfb1的PH结构域之间复合物的三维结构。我们的结构显示，p53在与Tfb1结合时形成一个由九个残基组成的两亲性α螺旋（残基47 - 55）。此外，我们证明p53在Ser46和Thr55处的双磷酸化导致p53与p62和Tfb1的结合显著增强。这些结果表明，涉及p53的Ser46和Thr55的磷酸化级联反应可能在调控特定p53靶基因中起重要作用。
