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CD Spectroscopy to Study DNA-Protein Interactions
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MDMX contains an autoinhibitory sequence element.

Michal Bista1, Miriana Petrovich, Alan R Fersht

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|October 16, 2013
PubMed
Summary
This summary is machine-generated.

MDMX protein has a self-inhibitory element that masks its p53 binding. Removing this element enhances MDMX

Keywords:
HDMXIDPMDM4MDMX-STROSY

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Area of Science:

  • Molecular Biology
  • Protein Structure and Function
  • Biochemistry

Background:

  • MDM2 and MDMX are homologous proteins that regulate p53 activity.
  • Both proteins feature folded domains and intrinsically disordered regions.
  • Prior research focused on isolated folded domains, not full-length proteins.

Purpose of the Study:

  • Investigate the binding affinity of full-length MDMX to p53.
  • Identify regulatory mechanisms governing MDMX activity.
  • Explore the role of a novel self-inhibitory element in MDMX.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Binding studies
  • Site-directed mutagenesis

Main Results:

  • Full-length MDMX exhibits ~100-fold weaker affinity for p53TAD than its isolated N-terminal domain.
  • MDMX contains a disordered self-inhibitory element (WWW element) that competes for p53TAD binding.
  • Deletion or mutation of the WWW element significantly increases MDMX binding affinity.

Conclusions:

  • MDMX functions via an allosteric, self-inhibitory mechanism, existing in a latent state.
  • A regulatory protein is required to activate MDMX.
  • The WWW element's function may explain the oncogenic potential of MDMX splice variants lacking it.