Abstract

Tripartite Motif Protein 72 (TRIM72, also named MG53) mediates membrane damage repair through membrane fusion and exocytosis. During injury, TRIM72 molecules form intermolecular disulfide bonds in response to the oxidative environment and TRIM72 oligomers are proposed to connect vesicles to the plasma membrane and promote membrane fusion in conjunction with other partners like dysferlin and caveolin. However, the detailed mechanism of TRIM72 oligomerization and action remains unclear. Here we present the crystal structure of TRIM72 B-box-coiled-coil-SPRY domains (BCC-SPRY), revealing the molecular basis of TRIM72 oligomerization, which is closely linked to disulfide bond formation. Through structure-guided mutagenesis, we have identified and characterized key residues that are important for the membrane repair function of TRIM72. Our results also demonstrate that TRIM72 interacts with several kinds of negatively charged lipids in addition to phosphatidylserine. Our work provides a structural foundation for further mechanistic studies as well as the clinical application of TRIM72.