ArticleProceedings of the National Academy of Sciences of the United States of America2013
MDMX contains an autoinhibitory sequence element.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- Mechanistic Role of the Mdm2/MdmX Lid Domain in Regulating Their Interactions with p53.Biomolecules · 2025Review
- Long-Read MDM4 Sequencing Reveals Aberrant Isoform Landscape in Metastatic Melanomas.International journal of molecular sciences · 2024Article
- Structural Adaptation of Secondary p53 Binding Sites on MDM2 and MDMX.Journal of molecular biology · 2024Article
- MDMX in Cancer: A Partner of p53 and a p53-Independent Effector.Biologics : targets & therapy · 2024Review
- TP53 and its Regulatory Genes as Prognosis of Cutaneous Melanoma.Cancer informatics · 2023Article
- The MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX.Journal of molecular biology · 2022Article
- Connecting sequence features within the disordered C-terminal linker ofProceedings of the National Academy of Sciences of the United States of America · 2022Article
- MDM4 alternative splicing and implication in MDM4 targeted cancer therapies.American journal of cancer research · 2021Review
- Dissecting the Functional Contributions of the Intrinsically Disordered C-terminal Tail of Bacillus subtilis FtsZ.Journal of molecular biology · 2020Article
- Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges.Frontiers in oncology · 2020Review
- Mutual regulation of MDM4 and TOP2A in cancer cell proliferation.Molecular oncology · 2019Article
- Interaction between p53 N terminus and core domain regulates specific and nonspecific DNA binding.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A Single Conserved Amino Acid Residue as a Critical Context-Specific Determinant of the Differential Ability of Mdm2 and MdmX RING Domains to Dimerize.Frontiers in physiology · 2019Article
- MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Imaging and kinetics of the bimolecular complex formed by the tumor suppressor p53 with ubiquitin ligase COP1 as studied by atomic force microscopy and surface plasmon resonance.International journal of nanomedicine · 2018Article
- Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity.Nature structural & molecular biology · 2017Article
- Optimal Affinity Enhancement by a Conserved Flexible Linker Controls p53 Mimicry in MdmX.Biophysical journal · 2017Article
- Tumorigenesis promotes Mdm4-S overexpression.Oncotarget · 2017Article
- Targeting MDM4 Splicing in Cancers.Genes · 2017Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
MDM2 and MDMX are homologous proteins that bind to p53 and regulate its activity. Both contain three folded domains and ~70% intrinsically disordered regions. Previous detailed structural and biophysical studies have concentrated on the isolated folded domains. The N-terminal domains of both exhibit high affinity for the disordered N-terminal of p53 (p53TAD) and inhibit its transactivation function. Here, we have studied full-length MDMX and found a ~100-fold weaker affinity for p53TAD than does its isolated N-terminal domain. We found from NMR spectroscopy and binding studies that MDMX (but not MDM2) contains a conserved, disordered self-inhibitory element that competes intramolecularly for binding with p53TAD. This motif, which we call the WWW element, is centered around residues Trp200 and Trp201. Deletion or mutation of the element increased binding affinity of MDMX to that of the isolated N-terminal domain level. The self-inhibition of MDMX implies a regulatory, allosteric mechanism of its activity. MDMX rests in a latent state in which its binding activity with p53TAD is masked by autoinhibition. Activation of MDMX would require binding to a regulatory protein. The inhibitory function of the WWW element may explain the oncogenic effects of an alternative splicing variant of MDMX that does not contain the WWW element and is found in some aggressive cancers.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.