An essential function of the extreme C-terminus of MDM2 can be provided by MDMX
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MDM2 (HDM2) is a ubiquitin ligase that can target the p53 tumor suppressor protein for degradation. The RING domain is essential for the E3 activity of MDM2, and we show here that the extreme C-terminal tail of MDM2 is also critical for efficient E3 activity. Loss of E3 function in MDM2 mutants deleted of the C-terminal tail correlated with a failure of these mutants to oligomerize with MDM2, or with the related protein MDMX (HDMX). However, MDM2 containing point mutations within the C-terminus that inactivated E3 function retained the ability to oligomerize with the wild-type MDM2 RING domain and MDMX, and our results indicate that oligomers containing both wild-type MDM2 and a C-terminal mutant protein retain E3 function both in auto-degradation and degradation of p53. Interestingly, the E3 activity of C-terminal point mutants of MDM2 can also be supported by interaction with wild-type MDMX, suggesting that MDMX can directly contribute to E3 function.
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Aromatic residues are conserved in the Mdmx C-terminal tail and can act in trans to reactivate E3 ligase function in Mdm2 C-terminal mutants.
“Aromatic residues are conserved in the Mdmx C-terminal tail, and can also act in trans to reactivate E3 ligase function in Mdm2 C-terminal mutants [27,28].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [27]
Aromatic residues Y489 and F490 outside the RING domain at the extreme C-terminus are critical for Mdm2 ligase activity.
“Intriguingly, their data show that aromatic residues (Y489 and F490) outside the RING domain at the extreme C-terminus are also critical for Mdm2 ligase activity.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [27]
Oligomeric Mdm2 is a more effective p53 ubiquitin ligase than monomeric Mdm2.
“Work from both the Vousden and Prives laboratories indicatesthat oligomeric Mdm2is a more effectivep53 ubiquitin ligase than is monomeric Mdm2 [27,28].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [27]
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References 49 · Cited by 170
- Authors
- Uldrijan, S., Pannekoek, W., & Vousden, K. H.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Corresponding author
- Vousden, Karen H
- Venue
- The EMBO Journal
- Published
- 2006-12-14
- Volume
- 26
- Issue
- 1
- Pages
- 102-112
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1782374
- OpenAlex
- W2039288045
- Cited by
- 170
- References
- 49
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 12 · 2012: 16
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, MDMX, C-terminal tail, E3 ubiquitin ligase activity, RING domain, p53 degradation, protein oligomerization, ubiquitination, tumor suppressor regulation
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Transfection, Tumor Suppressor Protein p53, Mutagenesis, Point Mutation, Protein Structure, Tertiary, Cell Cycle Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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