An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity
An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity
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DOI：
10.1038/emboj.2011.127
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发表时间：
2011-06-01
期刊：
影响因子：
11.4
通讯作者：
Halazonetis, Thanos D.
中科院分区：
文献类型：
--
作者：
Petty, Tom J.;Emamzadah, Soheila;Halazonetis, Thanos D.
p53肿瘤抑制基因是人类癌症中最常突变的基因，编码一种转录因子，含有序列特异性DNA结合和同源四聚化结构域。有趣的是，p53对特异性和非特异性DNA位点的亲和力仅相差一个数量级，这使得很难理解这种蛋白质如何在体内识别其特异性DNA靶标。我们在这里描述的结构的p53多肽含有DNA结合和寡聚化结构域与DNA的复合物。该结构揭示了序列特异性DNA结合通过诱导配合机制进行，该机制涉及p53 DNA结合结构域的L1环中的构象转换。环L1突变体的分析表明，构象开关允许DNA结合解离速率独立于亲和力进行调节。这些结果可以解释普遍流行的序列特异性DNA结合蛋白的构象转换，并建议蛋白质，如p53更多地依赖于结合解离速率的差异，而不是亲和力的差异，以识别其特定的DNA位点。The EMBO Journal（2011）30，2167-2176. doi：10.1038/daj.2011.127; 2011年4月26日在线发布
The p53 tumour suppressor gene, the most frequently mutated gene in human cancer, encodes a transcription factor that contains sequence-specific DNA binding and homo-tetramerization domains. Interestingly, the affinities of p53 for specific and non-specific DNA sites differ by only one order of magnitude, making it hard to understand how this protein recognizes its specific DNA targets in vivo. We describe here the structure of a p53 polypeptide containing both the DNA binding and oligomerization domains in complex with DNA. The structure reveals that sequence-specific DNA binding proceeds via an induced fit mechanism that involves a conformational switch in loop L1 of the p53 DNA binding domain. Analysis of loop L1 mutants demonstrated that the conformational switch allows DNA binding off-rates to be regulated independently of affinities. These results may explain the universal prevalence of conformational switching in sequence-specific DNA binding proteins and suggest that proteins like p53 rely more on differences in binding off-rates, than on differences in affinities, to recognize their specific DNA sites. The EMBO Journal (2011) 30, 2167-2176. doi: 10.1038/emboj.2011.127; Published online 26 April 2011