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Autoinhibition of MDMX by intramolecular p53 mimicry

Lihong Chen1, Wade Borcherds2, Shaofang Wu1

  • 1Departments of Molecular Oncology and.

Proceedings of the National Academy of Sciences of the United States of America
|April 1, 2015
PubMed

Insights

The p53 inhibitor MDMX protein regulates itself through an internal interaction that mimics its binding to p53. This discovery reveals new insights into MDMX regulation and protein interaction studies.

Area of Science:

  • Molecular Biology
  • Protein Biochemistry
  • Cell Signaling

Background:

  • The p53 inhibitor MDMX (also known as MDM4) plays a crucial role in cancer suppression.
  • MDMX activity is tightly regulated by various cellular stress pathways.

Purpose of the Study:

  • To investigate the intramolecular interactions governing MDMX function and regulation.
  • To validate a novel assay for studying intramolecular interactions in complex proteins.

Main Methods:

  • Proteolytic Fragment Release (PFR) assay to detect intramolecular interactions.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to elucidate structural details.
  • Site-directed mutagenesis to probe functional significance.

Main Results:

  • Identified an intramolecular interaction in MDMX that mimics p53 binding, leading to autoinhibition.
  • A hydrophobic peptide in the central disordered region mediates this mimicry, interacting with the N-terminal domain.
  • Mutating key tryptophan residues in this peptide abolished autoinhibition and enhanced p53 binding.
  • Discovered a second intramolecular interaction involving the RING domain regulating nuclear import.

Conclusions:

  • Intramolecular interactions are critical for the regulation of MDMX.
  • The PFR assay is a valuable tool for studying intramolecular interactions in multidomain proteins, including those with intrinsically disordered regions.
Keywords:
MDMXacidic domainintramolecularp53protease

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