Structure and activation of the RING E3 ubiquitin ligase TRIM72 on the membrane

Defects in plasma membrane repair can lead to muscle and heart diseases in humans. Tripartite motif-containing protein (TRIM)72 (mitsugumin 53; MG53) has been determined to rapidly nucleate vesicles at the site of membrane damage, but the underlying molecular mechanisms remain poorly understood. Here we present the structure of Mus musculus TRIM72, a complete model of a TRIM E3 ubiquitin ligase. We demonstrated that the interaction between TRIM72 and phosphatidylserine-enriched membranes is necessary for its oligomeric assembly and ubiquitination activity. Using cryogenic electron tomography and subtomogram averaging, we elucidated a higher-order model of TRIM72 assembly on the phospholipid bilayer. Combining structural and biochemical techniques, we developed a working molecular model of TRIM72, providing insights into the regulation of RING-type E3 ligases through the cooperation of multiple domains in higher-order assemblies. Our findings establish a fundamental basis for the study of TRIM E3 ligases and have therapeutic implications for diseases associated with membrane repair. The authors present the full-length dimeric TRIM72 E3 ubiquitin ligase and the architecture of its high-order assembly bound to a phosphatidylserine-enriched membrane, providing insights into its role in membrane repair and ubiquitylation.

Automated summary

By studying TRIM72 protein, we have revealed the importance of its interaction with phosphatidylserine-enriched membranes for its function. We have also proposed a molecular model of TRIM72, providing further insights into its role in cell membrane repair and ubiquitination.