Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53.

ABSTRACT: 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 muM 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.

SUBMITTER: Teufel DP 

PROVIDER: S-EPMC1855428 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature