Structure and activation of the RING E3 ubiquitin ligase TRIM72 on the membrane
Si Hoon Park, Juhyun Han, Byung‐Cheon Jeong, Ju Han Song, Se Hwan Jang, Hyeongseop Jeong, Bong Heon Kim, Young‐Gyu Ko, Zee‐Yong Park, Kyung Eun Lee, Jaekyung Hyun, Hyun Kyu Song
Abstract
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.