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

  • Daniel P. Teufel
    MRC Centre for Protein Engineering and Department of Chemistry, Cambridge University, MRC Centre, Hills Road,Cambridge CB2 2QH, United Kingdom
  • Stefan M. Freund
    MRC Centre for Protein Engineering and Department of Chemistry, Cambridge University, MRC Centre, Hills Road,Cambridge CB2 2QH, United Kingdom
  • Mark Bycroft
    MRC Centre for Protein Engineering and Department of Chemistry, Cambridge University, MRC Centre, Hills Road,Cambridge CB2 2QH, United Kingdom
  • Alan R. Fersht
    MRC Centre for Protein Engineering and Department of Chemistry, Cambridge University, MRC Centre, Hills Road,Cambridge CB2 2QH, United Kingdom

抄録

<jats:p> 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 ( <jats:italic>K</jats:italic> <jats:sub>D</jats:sub> ) in the 100 μM 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 ( <jats:italic>K</jats:italic> <jats:sub>D</jats:sub> = 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. </jats:p>

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