Regulation of the Activity in the p53 Family Depends on the Organization of the Transactivation Domain

Structure. 2018 Aug 7;26(8):1091-1100.e4. doi: 10.1016/j.str.2018.05.013. Epub 2018 Jun 28.


Despite high sequence homology among the p53 family members, the regulation of their transactivation potential is based on strikingly different mechanisms. Previous studies revealed that the activity of TAp63α is regulated via an autoinhibitory mechanism that keeps inactive TAp63α in a dimeric conformation. While all p73 isoforms are constitutive tetramers, their basal activity is much lower compared with tetrameric TAp63. We show that the dimeric state of TAp63α not only reduces DNA binding affinity, but also suppresses interaction with the acetyltransferase p300. Exchange of the transactivation domains is sufficient to transfer the regulatory characteristics between p63 and p73. Structure determination of the transactivation domains of p63 and p73 in complex with the p300 Taz2 domain further revealed that, in contrast to p53 and p73, p63 has a single transactivation domain. Sequences essential for stabilizing the closed dimer of TAp63α have evolved into a second transactivation domain in p73 and p53.

Keywords: CBP; autoinhibition; oligomerization; p300; p53 family; p63; p73.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Cloning, Molecular
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • E1A-Associated p300 Protein / chemistry*
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Humans
  • Models, Molecular
  • Neurons
  • Osteoblasts
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Thermodynamics
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation*
  • Tumor Protein p73 / chemistry*
  • Tumor Protein p73 / genetics
  • Tumor Protein p73 / metabolism
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • Recombinant Proteins
  • TP63 protein, human
  • TP73 protein, human
  • Transcription Factors
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • DNA
  • E1A-Associated p300 Protein
  • EP300 protein, human