Crystal Structure of a Multidomain Human p53 Tetramer Bound to the Natural CDKN1A (p21) p53-Response Element
Crystal Structure of a Multidomain Human p53 Tetramer Bound to the Natural CDKN1A (p21) p53-Response Element
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DOI：
10.1158/1541-7786.mcr-11-0351
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发表时间：
2011-11-01
影响因子：
5.2
通讯作者：
Halazonetis, Thanos D.
中科院分区：
文献类型：
--
作者：
Emamzadah, Soheila;Tropia, Laurence;Halazonetis, Thanos D.
p53肿瘤抑制蛋白是一种序列特异性DNA结合转录因子。p53与DNA结合的结构已被描述，但迄今为止，尚未确定p53与天然p53反应元件结合的结构。我们在这里描述的人p53同源四聚体的结构，包括DNA结合和同源寡聚化结构域与天然p53反应元件存在的CDKN 1A（p21）基因的启动子上游的复合物。与我们先前描述的结合到人工共有DNA位点的人p53四聚体的结构类似，p53 DNA结合通过诱导配合机制进行，其中两个亚基的环L1采用凹陷构象。有趣的是，涉及环L1的构象变化甚至比以前观察到的人工共有DNA位点的构象变化更极端。事实上，先前确定的环L1构象似乎是非DNA结合和CDKN 1A结合状态之间的过渡中间体。因此，新的结构进一步支持了我们的模型，即p53对特定DNA的识别与p53的DNA结合结构域内的构象变化有关。Mol Cancer Res; 9（11）; 1493-9. (C)2011年AACR。
The p53 tumor suppressor protein is a sequence-specific DNA-binding transcription factor. Structures of p53 bound to DNA have been described, but, so far, no structure has been determined of p53 bound to a natural p53-response element. We describe here the structure of a human p53 homotetramer encompassing both the DNA-binding and homo-oligomerization domains in complex with the natural p53-response element present upstream of the promoter of the CDKN1A (p21) gene. Similar to our previously described structures of human p53 tetramers bound to an artificial consensus DNA site, p53 DNA binding proceeds via an induced fit mechanism with loops L1 of two subunits adopting recessed conformations. Interestingly, the conformational change involving loop L1 is even more extreme than the one previously observed with the artificial consensus DNA site. In fact, the previously determined loop L1 conformation seems to be a transition intermediate between the non-DNA-bound and CDKN1A-bound states. Thus, the new structure further supports our model that recognition of specific DNA by p53 is associated with conformational changes within the DNA-binding domain of p53. Mol Cancer Res; 9(11); 1493-9. (C) 2011 AACR.