Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 15, Pages 4624-4629Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420833112
Keywords
MDMX; p53; intramolecular; acidic domain; protease
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Funding
- Chemical Biology Core Facility at the H. Lee Moffitt Cancer Center & Research Institute
- National Cancer Institute-designated Comprehensive Cancer Center [P30-CA076292]
- National Institutes of Health [CA141244, CA109636]
- Florida Department of Health [4BB14]
- National Science Foundation [MCB-0939014]
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The p53 inhibitor MDMX is controlled by multiple stress signaling pathways. Using a proteolytic fragment release (PFR) assay, we detected an intramolecular interaction in MDMX that mechanistically mimics the interaction with p53, resulting in autoinhibition of MDMX. This mimicry is mediated by a hydrophobic peptide located in a long disordered central segment of MDMX that has sequence similarity to the p53 transactivation domain. NMR spectroscopy was used to show this hydrophobic peptide interacts with the N-terminal domain of MDMX in a structurally analogous manner to p53. Mutation of two critical tryptophan residues in the hydrophobic peptide disrupted the intramolecular interaction and increased p53 binding, providing further evidence for mechanistic mimicry. The PFR assay also revealed a second intramolecular interaction between the RING domain and central region that regulates MDMX nuclear import. These results establish the importance of intramolecular interactions in MDMX regulation, and validate a new assay for the study of intramolecular interactions in multidomain proteins with intrinsically disordered regions.
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