Cited by 42Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysProtein Structure and Dynamics

Structural and Functional Comparison of the RING Domains of Two p53 E3 Ligases, Mdm2 and Pirh2

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Shloush, Jonathan, Vlassov, John E., Engson, Ian, Duan, Shili, Saridakis, Vivian, Dhe-paganon, Sirano, Raught, Brian, Sheng, Yi +1 more·2011·Journal of Biological Chemistry

Abstract

The tumor suppressor p53 maintains genome stability and prevents malignant transformation by promoting cell cycle arrest and apoptosis. Both Mdm2 and Pirh2 have been shown to ubiquitylate p53 through their RING domains, thereby targeting p53 for proteasomal degradation. Using structural and functional analyses, here we show that the Pirh2 RING domain differs from the Mdm2 RING domain in its oligomeric state, surface charge distribution, and zinc coordination scheme. Pirh2 also possesses weaker E3 ligase activity toward p53 and directs ubiquitin to different residues on p53. NMR and mutagenesis studies suggest that whereas Pirh2 and Mdm2 share a conserved E2 binding site, the seven C-terminal residues of the Mdm2 RING directly contribute to Mdm2 E3 ligase activity, a feature unique to Mdm2 and absent in the Pirh2 RING domain. This comprehensive analysis of the Pirh2 and Mdm2 RING domains provides structural and mechanistic insight into p53 regulation by its E3 ligases.

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Crossref · 10.1074/jbc.m110.157669

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Authors
Shloush, J., Vlassov, J. E., Engson, I., Duan, S., Saridakis, V., Dhe-paganon, S., Raught, B., Sheng, Y., & Arrowsmith, C. H.
Affiliations
York University (CA)
Corresponding author
  • Sheng, Yi
  • Arrowsmith, Cheryl H.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2011-02
Volume
286
Issue
6
Pages
4796-4808
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2074600331
Cited by
42
References
63
Citations by year
2026: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 2 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 3
FWCI
2.22
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 › Protein Structure and Dynamics
Keywords
p53, MDM2, Pirh2, RING domain, E3 ubiquitin ligase, p53 ubiquitination, proteasomal degradation, zinc coordination, oligomeric state, surface charge distribution, E2 binding sites, tumor suppressor regulation
MeSH terms
Binding Sites, Humans, Structure-Activity Relationship, Tumor Suppressor Protein p53, Mutagenesis, Nuclear Magnetic Resonance, Biomolecular, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-mdm2, RING Finger Domains, Protein Multimerization

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