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The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2

M Uesugi1, G L Verdine

  • 1Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 28, 1999
PubMed

Insights

The p53 tumor suppressor

Area of Science:

  • Molecular Biology
  • Protein Structure and Function
  • Cancer Biology

Background:

  • Transcriptional activation domains (TADs) are crucial for gene regulation but are difficult to study due to low sequence homology and lack of inherent structure.
  • The tumor suppressor p53's activity is regulated by cellular factors, including MDM2, which inhibits its function.
  • Understanding the structural basis of TADs is key to deciphering gene transcription regulation.

Purpose of the Study:

  • To characterize the structural features of the p53 activation domain and its interaction with target proteins.
  • To elucidate the mechanism by which MDM2 regulates p53 activity.
  • To identify conserved recognition motifs for transcriptional coactivators.

Main Methods:

  • Utilized a combination of biochemical assays and nuclear magnetic resonance (NMR) spectroscopy.
  • Investigated the interaction between the p53 activation domain and its target hTAF(II)31.
  • Examined the specificity of MDM2 in recognizing different activation domains.

Main Results:

  • Identified an FXXPhiPhi motif within the p53 activation domain that forms an alpha-helix upon binding to hTAF(II)31.
  • Demonstrated that MDM2 specifically recognizes and inhibits the p53 FXXPhiPhi motif, distinguishing it from similar motifs in NF-kappaB p65 and VP16.
  • Established the FXXPhiPhi sequence as a general alpha-helical recognition motif for hTAF(II)31.

Conclusions:

  • The FXXPhiPhi motif is a critical structural element in the p53 activation domain, mediating target recognition through alpha-helix formation.
  • MDM2's specific inhibition of p53 activity is based on its discrimination of the FXXPhiPhi motif.
  • These findings provide mechanistic insights into p53 regulation and highlight a conserved recognition mechanism for transcriptional activation.

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