Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans

Linke, K; Mace, P D; Smith, C A; Vaux, D L; Silke, J; Day, C L

doi:10.1038/sj.cdd.4402309

Cited by 288Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans

Linke, K, Mace, P D, Smith, C A, Vaux, D L, Silke, J, Day, C L·2008·Cell Death & Differentiation

DOI 10.1038/sj.cdd.4402309

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Abstract

MDM2, a ubiquitin E3-ligase of the RING family, has a key role in regulating p53 abundance. During normal non-stress conditions p53 is targeted for degradation by MDM2. MDM2 can also target itself and MDMX for degradation. MDMX is closely related to MDM2 but the RING domain of MDMX does not possess intrinsic E3-ligase activity. Instead, MDMX regulates p53 abundance by modulating the levels and activity of MDM2. Dimerization, mediated by the conserved C-terminal RING domains of both MDM2 and MDMX, is critical to this activity. Here we report the crystal structure of the MDM2/MDMX RING domain heterodimer and map residues required for functional interaction with the E2 (UbcH5b). In both MDM2 and MDMX residues C-terminal to the RING domain have a key role in dimer formation. In addition we show that these residues are part of an extended surface that is essential for ubiquitylation in trans. This study provides a molecular basis for understanding how heterodimer formation leads to stabilization of MDM2, yet degradation of p53, and suggests novel targets for therapeutic intervention.

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Structural studies of the homo- and heterodimer are consistent with interaction between the C-terminus of one partner and the RING domain of the other.
“However, structural studies of the homo- and heterodimer are consistent with interaction between the C- terminus of one partner and the RING domain of the other [8,20].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [20]
The binding mode of E2s appears to be similar for the Mdm2-Mdmx heterodimer.
“This binding mode of E2 s appears to be similar for the Mdm2–Mdmx heterodimer [8,20].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [20]

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Authors: Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L.
Affiliations: University of Otago (NZ)
Stanford Synchrotron Radiation Lightsource (US)
La Trobe University (AU)
Corresponding author: Day, C L
ORCID: Mace, P D
Smith, C A
Vaux, D L
Silke, J
Day, C L
Venue: Cell Death & Differentiation
Publisher: Springer Science and Business Media LLC
Published: 2008-01-25
Volume: 15
Issue: 5
Pages: 841-848
ISSN: 1350-9047 (ISSN-L)
1476-5403
DOI: 10.1038/sj.cdd.4402309
OpenAlex: W2161828378
Cited by: 288
References: 41
Citations by year: 2026: 11 · 2025: 8 · 2024: 12 · 2023: 14 · 2022: 14 · 2021: 16 · 2020: 18 · 2019: 7 · 2018: 3 · 2017: 14 · 2016: 21 · 2015: 18 · 2014: 25 · 2013: 14 · 2012: 24
FWCI: 12.14
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Cell Death and Differentiation (publishedVersion)
PubMed (publishedVersion)
Funders: University of Otago
National Institutes of Health (RR001209)
Marsden Fund
National Center for Research Resources (P41RR001209)
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, RING domain, heterodimer, protein dimerization, E3 ubiquitin ligase, p53 degradation, UbcH5b, crystal structure, protein stability
MeSH terms: Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Tumor Suppressor Protein p53, Sequence Alignment, Crystallography, X-Ray, Dimerization, Protein Structure, Quaternary, Ubiquitin, Proto-Oncogene Proteins c-mdm2

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Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans

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