Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 17, Pages 7009-7014Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0702010104
Keywords
AD1; cAMP response element binding protein-binding protein; IBiD homology domain; Mdm4; SRC-1
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Funding
- Medical Research Council [MC_U105474168, MC_U105459896] Funding Source: researchfish
- MRC [MC_U105459896, MC_U105474168] Funding Source: UKRI
- Medical Research Council [MC_U105474168, MC_U105459896] Funding Source: Medline
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The transcriptional coactivator p300 binds to and mediates the transcriptional functions of the tetrameric tumor suppressor p53. Both proteins consist of independently folded domains linked by intrinsically disordered sequences. A well studied short sequence of the p53 transactivation domain, p53(15-29), binds weakly to four folded domains of p300[Taz1/cysteine-histidine-rich region 1 (CH1), Kix, Taz2/CH3, IBiD], with dissociation constants (K-D) in the 100 mu M region. However, we found that a longer N-terminal transactivation domain construct p53(1-57) bound tightly to each p300 domain. Taz2/CH3 had the greatest affinity (K-D = 27 nM) and competes with the N-terminal domain of Mdm2 for the p53 N terminus. p300 thus can protect the N terminus of p53 against the binding of other proteins. Mutations of p53 that abrogate transactivation (L22Q/W23S, W53Q/F54S) greatly weakened binding to each p300 domain, linking phenotypic defects to weakened coactivator binding. We propose a complex between tetrameric p53 and p300 in which four domains of p300 wrap around the four transactivation domains of p53.
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