title: RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity.
abstract: The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect the E3 ligase activity of MDM2. We report that the E3 ligase activity requires the RING domain-dependent complex formation. In vivo, MDM2 and MDMX hetero-RING complexes are the predominant form versus the MDM2 homo-RING complex. Importantly, the MDM2/MDMX hetero-RING complexes exhibit a greater E3 ligase activity than the MDM2 homo-RING complexes. Disruption of the binding between MDM2 and MDMX resulted in a marked increase in both abundance and activity of p53, emphasizing the functional importance of this heterocomplex in p53 control.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kawai
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lopez-Pajares
authors.forename: Mihee M
authors.initials: MM
authors.lastname: Kim
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D003433:Crosses, Genetic; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases