The DNA-binding domain mediates both nuclear and cytosolic functions of p53

Nat Struct Mol Biol. 2014 Jun;21(6):535-43. doi: 10.1038/nsmb.2829. Epub 2014 May 11.


Under conditions of genotoxic stress, human p53 activates the apoptotic effectors BAX or BAK to result in mitochondrial outer-membrane permeabilization and apoptosis. Antiapoptotic BCL-2 family member BCL-xL opposes this activity by sequestering cytosolic p53 via association with its DNA-binding domain, an interaction enhanced by p53 tetramerization. Here we characterized the BCL-xL-p53 complex by NMR spectroscopy and modulated it through mutagenesis to determine the relative contributions of BCL-xL's interactions with p53 or other BCL-2 family proteins to the BCL-xL-dependent inhibition of UV irradiation-induced apoptosis. Under our experimental conditions, one-third of the antiapoptotic activity of BCL-xL was mediated by p53 sequestration and the remaining two-thirds through sequestration of proapoptotic BCL-2 family members. Our studies define the contributions of cytosolic p53 to UV irradiation-induced apoptosis and provide opportunities to explore its contributions to other p53-dependent apoptotic signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / radiation effects
  • Binding Sites
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • Humans
  • Models, Molecular
  • Mutagenesis
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Interaction Mapping
  • Protein Multimerization
  • Signal Transduction
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology
  • Ultraviolet Rays
  • bcl-X Protein / chemistry*
  • bcl-X Protein / metabolism
  • bcl-X Protein / physiology


  • BCL2L1 protein, human
  • Tumor Suppressor Protein p53
  • bcl-X Protein

Associated data

  • PDB/2ME8
  • PDB/2ME9
  • PDB/2MEJ