Ma Buyong, Pan Yongping, Gunasekaran K, Venkataraghavan R Babu, Levine Arnold J, Nussinov Ruth
Basic Research Program, SAIC-Frederick, Inc., Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):3988-93. doi: 10.1073/pnas.0500215102. Epub 2005 Feb 28.
p53, the tumor suppressor protein, functions as a dimer of dimers. However, how the tetramer binds to the DNA is still an open question. In the crystal structure, three copies of the p53 monomers (containing chains A, B, and C) were crystallized with the DNA-consensus element. Although the structure provides crucial data on the p53-DNA contacts, the active oligomeric state is unclear because the two dimeric (A-B and B-C) interfaces present in the crystal cannot both exist in the tetramer. Here, we address the question of which of these two dimeric interfaces may be more biologically relevant. We analyze the sequence and structural properties of the p53-p53 dimeric interfaces and carry out extensive molecular dynamics simulations of the crystal structures of the human and mouse p53 dimers. We find that the A-B interface residues are more conserved than those of the B-C. Molecular dynamics simulations show that the A-B interface can provide a stable DNA-binding motif in the dimeric state, unlike B-C. Our results indicate that the interface between chains A-B in the p53-DNA complex constitutes a better candidate for a stable biological interface, whereas the B-C interface is more likely to be due to crystal packing. Thus, they have significant implications toward our understanding of DNA binding by p53 as well as p53-mediated interactions with other proteins.
肿瘤抑制蛋白p53以二聚体的二聚体形式发挥作用。然而，四聚体如何与DNA结合仍是一个悬而未决的问题。在晶体结构中，三个p53单体拷贝（包含A、B和C链）与DNA共有元件一起结晶。尽管该结构提供了关于p53与DNA接触的关键数据，但由于晶体中存在的两个二聚体（A - B和B - C）界面不可能同时存在于四聚体中，所以活性寡聚状态尚不清楚。在此，我们探讨这两个二聚体界面中哪一个可能在生物学上更具相关性。我们分析了p53 - p53二聚体界面的序列和结构特性，并对人和小鼠p53二聚体的晶体结构进行了广泛的分子动力学模拟。我们发现A - B界面的残基比B - C界面的残基更保守。分子动力学模拟表明，与B - C界面不同，A - B界面在二聚体状态下可以提供一个稳定的DNA结合基序。我们的结果表明，p53 - DNA复合物中A - B链之间的界面构成了一个更适合作为稳定生物学界面的候选者，而B - C界面更可能是由于晶体堆积所致。因此，它们对于我们理解p53与DNA的结合以及p53介导的与其他蛋白质的相互作用具有重要意义。
