The MDM2 RING and central acidic domains play distinct roles in MDM2 homodimerization and MDM2-MDMX heterodimerization [Signal Transduction]

March 25th, 2015 by Leslie, P. L., Ke, H., Zhang, Y.

ABSTRACT The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein MDMX, both of which are thought to occur through their respective C-terminal RING (Really Interesting New Gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms, as MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with wild-type (WT) MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model whereby MDM2-MDMX heterodimerization requires the extreme C-terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C-terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization.