The RING domain of TRIM69 promotes higher-order assembly

Keown, J.R.; Yang, Joy X.; Black, Moyra M.; Goldstone, David C.

doi:10.1107/s2059798320010499

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…Finally, we investigated the activation mechanism of Ub transfer in the higher-order TRIM72 assembly on the membrane. Speci cally, we revealed that the RING domain can be dimerized for activation, similar to other known TRIM RINGs 43,[61][62][63] . Although the monomeric TRIM72 RING domains are nearly 20 nm apart from each other in the dimer model, it is likely that the RINGs are dimerized transiently since they are located close to each other in the higher-order TRIM72 assembly on the membrane (Fig.…”

Section: Resultssupporting

confidence: 61%

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

Song¹,

Park

Jeong

et al. 2023

Preprint

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Plasma membrane repair defects cause human muscle and heart diseases. In the early stage of membrane repair, TRIM72/MG53 nucleates vesicles to the damaged site within seconds. Despite the therapeutic potential of TRIM72/MG53, the molecular mechanisms are poorly understood. Here, we present the structure of TRIM72, the first complete model of a TRIM E3 ligase. Structure-guided functional analysis revealed a unique phospholipid recognition mode in which a pair of PRYSPRY domains interacts with negatively charged membranes. In subsequent biochemical analyses, the interaction between TRIM72 and the phosphatidylserine-enriched membrane was shown to be critical for both the oligomeric assembly and ubiquitination activity of TRIM72. We elucidated a higher-order model of TRIM72 assembly on the phospholipid bilayer using cryogenic electron tomography followed by subtomogram averaging. We developed a working molecular model of TRIM72 through integrated structural and biochemical techniques. The findings provide a fundamental basis for the study of TRIM E3 ligases, which share a conserved molecular architecture, and provide further insights into the general regulation of RING-type E3 ligases through the cooperation of multiple domains like those in higher-order assemblies.

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Section: Resultssupporting

confidence: 61%

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

Song¹,

Park

Jeong

et al. 2023

Preprint

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“…The arrangement of the TRIM2 RING dimer is reminiscent of other TRIM dimeric RING structures, such as the constitutive dimers TRIM32 (5FEY) and TRIM69 (6YXE) or those of TRIM25 (5FER) and TRIM5α (4TKP) that show minimal self-association in solution but crystallized as dimers in complex with E2~Ub conjugates (Fig. 2c) 31,33,34 . The calculated gain in solvation free energy of TRIM2 RING dimerization is −19.8 kcal/mol, a value larger than that calculated for the constitutive RING dimers of TRIM32 (−14.7 kcal/mol) and TRIM69 (−12.5 kcal/mol) 30,33 .…”

Section: Structure Of the Active Trim2 Ring/ Ube2d1~ub Complexmentioning

confidence: 89%

Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity

et al. 2022

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Tripartite motif (TRIM) proteins constitute a large family of RING-type E3 ligases that share a conserved domain architecture. TRIM2 and TRIM3 are paralogous class VII TRIM members that are expressed mainly in the brain and regulate different neuronal functions. Here we present a detailed structure-function analysis of TRIM2 and TRIM3, which despite high sequence identity, exhibit markedly different self-association and activity profiles. We show that the isolated RING domain of human TRIM3 is monomeric and inactive, and that this lack of activity is due to a few placental mammal-specific amino acid changes adjacent to the core RING domain that prevent self-association but not E2 recognition. We demonstrate that the activity of human TRIM3 RING can be restored by substitution with the relevant region of human TRIM2 or by hetero-dimerization with human TRIM2, establishing that subtle amino acid changes can profoundly affect TRIM protein activity. Finally, we show that TRIM2 and TRIM3 interact in a cellular context via their filamin and coiled-coil domains, respectively.

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“…1e ) 46 . This dimerization mode is highly conserved in the TRIM family as it has now been observed in all known crystal structures of TRIM RINGs (TRIM5α: 4TKP 46 , TRIM37: 3LRQ, TRIM69: 6YXE 55 , TRIM23: 5VZW 56 , TRIM32: 5FEY 47 , TRIM25: 5EYA 47 , 48 , TRIM21: 6S53 54 and possibly others).…”

Section: Resultsmentioning

confidence: 58%

Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation

Herkules

Taylor

et al. 2022

Nat Commun

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TRIM5α is an E3 ubiquitin ligase of the TRIM family that binds to the capsids of primate immunodeficiency viruses and blocks viral replication after cell entry. Here we investigate how synthesis of K63-linked polyubiquitin is upregulated by transient proximity of three RING domains in honeycomb-like assemblies formed by TRIM5α on the surface of the retroviral capsid. Proximity of three RINGs creates an asymmetric arrangement, in which two RINGs form a catalytic dimer that activates E2-ubiquitin conjugates and the disordered N-terminus of the third RING acts as the substrate for N-terminal autoubiquitylation. RING dimerization is required for activation of the E2s that contribute to the antiviral function of TRIM5α, UBE2W and heterodimeric UBE2N/V2, whereas the proximity of the third RING enhances the rate of each of the two distinct steps in the autoubiquitylation process: the initial N-terminal monoubiquitylation (priming) of TRIM5α by UBE2W and the subsequent extension of the K63-linked polyubiquitin chain by UBE2N/V2. The mechanism we describe explains how recognition of infection-associated epitope patterns by TRIM proteins initiates polyubiquitin-mediated downstream events in innate immunity.

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The RING domain of TRIM69 promotes higher-order assembly

Cited by 11 publications

References 32 publications

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

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

Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity

Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation

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