Lysine120 interactions with p53 response elements can allosterically direct p53 organization.
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 fun...
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Public Library of Science (PLoS)
2010-08-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000878&type=printable |
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| author | Yongping Pan Ruth Nussinov |
| author_facet | Yongping Pan Ruth Nussinov |
| author_sort | Yongping Pan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6c3154b51b8647e89c58c79bebecff92 |
| institution | DOAJ |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2010-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-6c3154b51b8647e89c58c79bebecff922025-08-20T03:07:20ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582010-08-0168e100087810.1371/journal.pcbi.1000878Lysine120 interactions with p53 response elements can allosterically direct p53 organization.Yongping PanRuth Nussinovp53 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.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000878&type=printable |
| spellingShingle | Yongping Pan Ruth Nussinov Lysine120 interactions with p53 response elements can allosterically direct p53 organization. PLoS Computational Biology |
| title | Lysine120 interactions with p53 response elements can allosterically direct p53 organization. |
| title_full | Lysine120 interactions with p53 response elements can allosterically direct p53 organization. |
| title_fullStr | Lysine120 interactions with p53 response elements can allosterically direct p53 organization. |
| title_full_unstemmed | Lysine120 interactions with p53 response elements can allosterically direct p53 organization. |
| title_short | Lysine120 interactions with p53 response elements can allosterically direct p53 organization. |
| title_sort | lysine120 interactions with p53 response elements can allosterically direct p53 organization |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1000878&type=printable |
| work_keys_str_mv | AT yongpingpan lysine120interactionswithp53responseelementscanallostericallydirectp53organization AT ruthnussinov lysine120interactionswithp53responseelementscanallostericallydirectp53organization |