Kitayner Malka, Rozenberg Haim, Kessler Naama, Rabinovich Dov, Shaulov Lihi, Haran Tali E, Shakked Zippora
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100.
Department of Biology, Technion, Technion City, Haifa 32000, Israel.
Mol Cell. 2006 Jun 23;22(6):741-753. doi: 10.1016/j.molcel.2006.05.015.
The tumor-suppressor protein p53 is among the most effective of the cell's natural defenses against cancer. In response to cellular stress, p53 binds as a tetramer to diverse DNA targets containing two decameric half-sites, thereby activating the expression of genes involved in cell-cycle arrest or apoptosis. Here we present high-resolution crystal structures of sequence-specific complexes between the core domain of human p53 and different DNA half-sites. In all structures, four p53 molecules self-assemble on two DNA half-sites to form a tetramer that is a dimer of dimers, stabilized by protein-protein and base-stacking interactions. The protein-DNA interface varies as a function of the specific base sequence in correlation with the measured binding affinities of the complexes. The new data establish a structural framework for understanding the mechanisms of specificity, affinity, and cooperativity of DNA binding by p53 and suggest a model for its regulation by regions outside the sequence-specific DNA binding domain.
肿瘤抑制蛋白p53是细胞对抗癌症最有效的天然防御机制之一。响应细胞应激时，p53以四聚体形式结合到含有两个十聚体半位点的多种DNA靶点上，从而激活参与细胞周期停滞或凋亡的基因表达。在此，我们展示了人类p53核心结构域与不同DNA半位点之间序列特异性复合物的高分辨率晶体结构。在所有结构中，四个p53分子在两个DNA半位点上自组装形成一个四聚体，该四聚体是由蛋白质-蛋白质和碱基堆积相互作用稳定的二聚体。蛋白质-DNA界面根据特定碱基序列而变化，这与复合物的测量结合亲和力相关。这些新数据为理解p53与DNA结合的特异性、亲和力和协同性机制建立了结构框架，并提出了一种由序列特异性DNA结合结构域之外的区域对其进行调控的模型。
