Cryo-EM structure of human MG53 homodimer

Niu, Yange; Chen, Gengjia; Lv, Fengxiang; Xiao, Rui‐Ping; Hu, Xinli; Chen, Lei

doi:10.1042/bcj20220385

Cited by 3 publications

(3 citation statements)

References 47 publications

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“…Furthermore, the B-box domain located at the end of the coiled-coil was mobile. In our structures, as well as in the cryo-TEM and crystal structures from other research groups 31,32,33 , the RING, B-box domain, and part of the coiled-coil showed no or very weak densities for chain tracing, suggesting that these peripheral parts of TRIM72 are highly dynamic. When we superimposed our TRIM72 crystal structures, it was evident that the core region comprising two PRYSPRY and nearby H1:H1′ coiled-coil domains was highly rigid (Fig.…”

Section: Flexible Nature Of the Rbcc Domainsupporting

confidence: 59%

“…As diverse as their roles, mutations in TRIM genes cause various genetic disorders, including Mulibrey Nanism (TRIM37) 16 , Sjögren's syndrome (TRIM21/Ro52) 17,18,19,20 , Opitz G/BBB syndrome (TRIM18/MID1) 21,22 , familial Mediterranean fever (TRIM20/pyrin) 23 , acute promyelocytic leukemia (TRIM19/PML) 24 , and muscular dystrophy (TRIM32) 25 . Despite the increasing number of genetic and cellular studies, biochemical and structural evidence are still limited, and only domain structures are available 26,27,28,29,30,31,32 . We recently presented dimeric and oligomeric structures of TRIM72, in which oligomerization was found to be coupled to ubiquitylation and phospholipid membrane recognition 33 .…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the role of the hendecad-repeat coiled-coil domain of TRIM72 in membrane curvature recognition

Song,

Park

2024

Preprint

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RING-type E3 ubiquitin ligases are functional multidomain proteins involved in diverse eukaryotic cellular processes. A major subfamily of RING-type ligases is the tripartite motif (TRIM)-containing protein family, whose members contain RING, B-box, coiled-coil, and variable C-terminal domains. Although the roles of individual TRIM domains are well understood, the function of the coiled-coil domain remains unclear owing to its structural complexity. In this study, we investigated the structural details of the coiled-coil domain of TRIM72 to elucidate its role in facilitating interactions with both concave and convex membranes. Cooperative interactions of the coiled-coil/coiled-coil and B-box/B-box domains were found to drive oligomerization, aiding in the recognition of phospholipid layers by the PRYSPRY domains. These insights provide a fundamental basis for understanding TRIM family E3 ligases and highlight their conserved molecular architecture and pattern recognition capabilities through higher-order assembly.

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Section: Flexible Nature Of the Rbcc Domainsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Deciphering the role of the hendecad-repeat coiled-coil domain of TRIM72 in membrane curvature recognition

Song,

Park

2024

Preprint

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“…Certain conformation changes of the B-box must take place during this process to reduce the distance between C242s from 30 Å to less than 3 Å. As shown by the recently reported 3.5 Å TRIM72 cryo-EM structure, the B-box region is highly dynamic and couldn’t be resolved in the cryo-EM map 61 . Molecular dynamics simulation of TRIM72 BCC-SPRY crystal structure showed that rotation of the B-box relative to the coiled-coil domain occurred without disintegrating the ternary structure of individual domains, which led to the exposure of C242 to the solvent (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for TRIM72 oligomerization during membrane damage repair

Ding

et al. 2023

Nat Commun

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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.

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

Park,

Han,

Jeong

et al. 2023

Nat Struct Mol Biol

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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.

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Cryo-EM structure of human MG53 homodimer

Cited by 3 publications

References 47 publications

Deciphering the role of the hendecad-repeat coiled-coil domain of TRIM72 in membrane curvature recognition

Deciphering the role of the hendecad-repeat coiled-coil domain of TRIM72 in membrane curvature recognition

Structural basis for TRIM72 oligomerization during membrane damage repair

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

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