Abstract
p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects.
Highlights
We find that p53 Lys120-DNA interactions can change dramatically depending on the bp at positions 1-3 of the quarter site, which in turn affects the Arg280 binding. We find that such binding pattern changes at the DNA-protein interface have allosteric effects in terms of the p53 tetrameric organization and the fluctuations of residues on the p53 surface away from the DNA binding site. We propose that this combined allosteric effect could hold the key to selective transcriptional activation by the degenerate p53-response element (RE) and can serve as a paradigm for selective activation of transcription factors [13]
The results show that (a) with a quarter site whose sequence conforms to the consensus, Lys120 interacted mainly with the central G or A base, as in the crystal structures (Table 1: 14-3-3s Q1 and Q4, Gadd45 Q2, Noxa Q1 and Q2, p21-5 Q1 and Q2, p53R2 Q2, Q3 and Q4, puma Q2 and Q4); the representative structure in Fig 2A shows that all four hydrogen bonds are well maintained
We show that subtle conformational changes elicited by DNA sequences which can differ by as little as a single bp can result in altered p53 core domain organization and protein surface dynamics
Summary
P53-response elements (p53-REs) are two 10-bp palindromic DNA segments with the consensus sequence of 59-Pu1Pu2Pu3C4(A/T)5(A/T)59G49Py39Py29Py19-39 for each of the two half sites, where Pu and Py stand for purine and pyrimidine bases, respectively [1,2]. Hundreds of p53-REs have been identified [2,5], and the numbers continue to grow [7] Many of these are known to be related to regulation of genes involved in cellular pathways such as apoptosis, cell cycle arrest and senescence [8,9]. P53-RE binding is affected by chromatin packaging epigenetic events known to be a key factor in RE occupancy [24,25]. In the glucocorticoid receptor (GR) [40,41], single bp changes were shown to allosterically affect GR conformational changes. These were amplified by ligand binding and propagated to the co-regulator binding site. DNA methylation can lead to packing of the genome, making the PLoS Computational Biology | www.ploscompbiol.org p53-p53RE Allosteric Effects
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