Structural and Mechanistic Insights into TRIM E3 Ubiquitin Ligase Activities

Protein ubiquitination is a post-translational modification process that regulates diverse physiological activities. The Tripartite Motif proteins (TRIM) are a family of E3 ubiquitin ligases that catalyze protein ubiquitination through multi-domain coordination. Structurally, how various domains are orientated to fulfill their E3 ligase activities remains largely enigmatic. Here we solved the crystal structure of the CC domains of TRIM29 and revealed a tetrameric structure formed by two dimers orientated in an anti-parallel fashion, which allows the substrates to directly access the ubiquitin-loaded E2. Similar structure was also observed for TRIM45 and TRIM20. We further demonstrated that the full-length TRIM proteins indeed form tetramers under physiological conditions via the CC domain and this tetrameric structure is required for their E3 activities. Thus, our results provide structural insights into the functional attributes of the TRIM family E3 ligases and offer potential therapeutic strategies in manipulating their functions.