The MDM2-binding Region in the Transactivation Domain of p53 Also Acts as a Bcl-X(L)-binding Motif

Biochemistry. 2009 Dec 29;48(51):12159-68. doi: 10.1021/bi901188s.

Abstract

While the transcription-dependent mechanism of p53 has been extensively studied, recently the transcription-independent apoptotic activity of p53 has also been described. Bcl-2 and Bcl-X(L) interact with p53 and induce apoptosis. Initially, the p53 DNA-binding domain (p53DBD) was found to bind to Bcl-2 and Bcl-X(L). Later, the p53 N-terminal domain (p53NTD) was reported to be sufficient for inducing the transcription-independent apoptotic activity of p53 and also shown to interact with Bcl-X(L). Here, we further document that the transactivation domain of p53 (p53TAD) in p53NTD alone binds to Bcl-X(L). We demonstrated that the MDM2-binding region (residues S15 to N29, herein referred to as SN15) in p53TAD is the binding site for Bcl-X(L). The binding interface on Bcl-X(L) was identified at the hydrophobic pocket formed by the BH1, BH2, and BH3 domains, which also binds to the Bak/Bad BH3 peptides, suggesting Bcl-X(L) and MDM2 share a common binding motif in p53TAD. Our NMR structural studies have shown that the SN15 peptide undergoes a conformational change upon binding to Bcl-X(L). A Bcl-X(L)/SN15 complex structural model suggests that the SN15 peptide adopts an extended alpha-helical structure to bind to the hydrophobic pocket on the Bcl-X(L), which is similar to the mode of binding between BH3 peptides and Bcl-X(L).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Humans
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-X Protein / chemistry*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Proto-Oncogene Proteins c-mdm2