The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity
Open accessAbstract
Mdm2, a key negative regulator of the p53 tumor suppressor, is a RING-type E3 ubiquitin ligase. The Mdm2 RING domain can be biochemically fractionated into two discrete species, one of which exists as higher order oligomers that are visible by electron microscopy, whereas the other is a monomer. Both fractions are ATP binding and E3 ligase activity competent, although the oligomeric fraction exhibits lower dependence on the E2 component of ubiquitin polymerization reactions. The extreme C-terminal five amino acids of Mdm2 are essential for E3 ligase activity in vivo and in vitro, as well as for oligomeric assembly of the protein. A single residue (phenylalanine 490) in that sequence is critical for both properties. Interestingly, the C-terminus of the Mdm2 homologue, MdmX (itself inert as an E3 ligase), can fully substitute for the equivalent segment of Mdm2 and restore its E3 activity. We further show that the Mdm2 C-terminus is involved in intramolecular interactions and can set up a platform for direct protein-protein interactions with the E2.
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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 [28]
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 [28]
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 [28]
The MDM2 RING domain has greater E3 ligase activity in vitro when it oligomerizes.
“Oligomerization of MDM2 RING domain increases its E3 ligase activity in vitro (Poyurovsky et al, 2007).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Poyurovsky et al, 2007
RING domains commonly form high-order oligomers.
“Formation of high-order oligomers is a common feature of RING domains (Kentsis et al, 2002;Poyurovsky et al, 2007).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Poyurovsky et al, 2007
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- Authors
- Poyurovsky, M. V., Priest, C., Kentsis, A., Borden, K. L., Pan, Z., Pavletich, N., & Prives, C.
- Affiliations
- Columbia University (US)
- New York University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Prives, Carol
- ORCID
- Venue
- The EMBO Journal
- Published
- 2006-12-14
- Volume
- 26
- Issue
- 1
- Pages
- 90-101
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1782380
- OpenAlex
- W2123242499
- Cited by
- 203
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 12 · 2022: 3 · 2021: 11 · 2020: 14 · 2019: 6 · 2018: 6 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 18
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA58316, CA87497)
- National Cancer Institute (R37CA058316, CA-87497, P01CA087497, R01CA058316, CA 58316)
- 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 › TGF-β signaling in diseases
- Keywords
- MDM2, RING domain, E3 ubiquitin ligase, protein oligomerization, supramolecular self-assembly, C-terminal domain, p53 regulation, MDMX, E2 ubiquitin-conjugating enzyme, intramolecular interactions, protein-protein interaction, ubiquitination
- MeSH terms
- Adenosine Triphosphate, Escherichia coli, Humans, Microscopy, Electron, Models, Biological, Nuclear Proteins, Phenylalanine, Protein Binding, Protein Conformation, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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