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The MDM2-binding region in the transactivation domain of p53 also acts as a Bcl-X(L)-binding motif

Huibin Xu1, Hong Ye, Nur Eliza Osman

  • 1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.

Biochemistry
|November 18, 2009
PubMed

Insights

The p53 transactivation domain (p53TAD) directly binds to Bcl-X(L), a protein involved in apoptosis. This interaction occurs at a specific region (SN15) and involves a conformational change, revealing a shared binding motif with MDM2.

Area of Science:

  • Molecular Biology
  • Protein-Protein Interactions
  • Apoptosis Signaling

Background:

  • The tumor suppressor protein p53 has known transcription-dependent and independent roles in apoptosis.
  • Bcl-2 and Bcl-X(L) are key regulators of apoptosis that interact with p53.
  • Previous studies identified interactions between p53 domains and Bcl-X(L), but the precise binding site and mechanism were unclear.

Purpose of the Study:

  • To elucidate the specific binding interaction between the p53 N-terminal domain and Bcl-X(L).
  • To identify the precise region within p53 responsible for binding to Bcl-X(L) and inducing transcription-independent apoptosis.
  • To characterize the structural basis of the p53-Bcl-X(L) interaction.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to study protein-peptide interactions.
  • Identification of binding sites using peptide mapping and structural analysis.
  • Structural modeling of the Bcl-X(L)/p53 peptide complex.

Main Results:

  • The transactivation domain of p53 (p53TAD), specifically the SN15 region (residues S15-N29), directly binds to Bcl-X(L).
  • The binding interface on Bcl-X(L) is a hydrophobic pocket within the BH1, BH2, and BH3 domains, similar to the binding site for Bak/Bad BH3 peptides.
  • NMR studies revealed that the SN15 peptide undergoes an alpha-helical conformational change upon binding to Bcl-X(L).

Conclusions:

  • The p53 transactivation domain (p53TAD) directly mediates transcription-independent apoptosis by binding to Bcl-X(L).
  • The SN15 region of p53TAD binds to a conserved hydrophobic pocket on Bcl-X(L), suggesting a shared binding motif with other Bcl-2 family proteins and MDM2.
  • Structural insights into the Bcl-X(L)/SN15 complex provide a mechanistic understanding of p53's role in apoptosis regulation.

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