A Dissection of Oligomerization by the TRIM28 Tripartite Motif and the Interaction with Members of the Krab-ZFP Family

Sun, Yunyuan; Keown, J.R.; Black, Moyra M.; Raclot, Charlène; Demarais, Nicholas J.; Trono, Didier; Turelli, Priscilla; Goldstone, David C.

doi:10.1016/j.jmb.2019.05.002

Cited by 26 publications

(52 citation statements)

References 67 publications

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“…Until recently, the assembly of TRIM proteins was thought to be facilitated by the formation of an antiparallel coiled coil, and in some cases further dimeric or trimeric assembly via a Bbox1 or Bbox2 domain (Sun et al, 2019;. This was thought to allow the RING domains to be held as inactive monomers until the TRIM protein had reached a sufficiently high local concentration that the Bbox domains assembled, resulting in RING dimerization and activation.…”

Section: The Trim69 Ring Domain Promotes N-terminal Domain Assemblymentioning

confidence: 99%

“…Interestingly, the RING domain from TRIM32 is dimeric when a complete RING domain is purified, but the removal of residues outside the core reduces it to a monomer (Koliopoulos et al, 2016). The Bbox domain from some TRIM proteins has been shown to facilitate assembly, often with lowmicromolar affinities Sun et al, 2019). The interface used for this assembly is variable and, as is seen for the TRIM5 Bbox domain, regions outside the core Bbox domain can be required for complete reconstitution of the biological interface .…”

Section: Introductionmentioning

confidence: 99%

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The RING domain of TRIM69 promotes higher-order assembly

Keown

Yang

Black

et al. 2020

Acta Cryst Sect D Struct Biol

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Members of the TRIM protein family have been shown to inhibit a range of viral infections. Recently, TRIM69 was identified as a potent inhibitor of Vesicular stomatitis Indiana virus infection, with its inhibition being dependent upon multimerization. Using SEC-MALLS analysis, it is demonstrated that the assembly of TRIM69 is mediated through the RING domain and not the Bbox domain as has been shown for other TRIM proteins. Using X-ray crystallography, the structure of the TRIM69 RING domain has been determined to a resolution of 2.1 Å, the oligomerization interface has been identified and regions outside the four-helix bundle have been observed to form interactions that are likely to support assembly.

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Section: The Trim69 Ring Domain Promotes N-terminal Domain Assemblymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The RING domain of TRIM69 promotes higher-order assembly

Keown

Yang

Black

et al. 2020

Acta Cryst Sect D Struct Biol

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“…TRIM28 belongs to the tripartite motif family, containing N-terminal Ring finger, B boxes, and coiled-coil leucine zipper (RBCC) domain. RBCC is necessary for interaction with Krüppel-associated box (KRAB)-containing zinc-finger proteins (ZFPs) to silence genes and form oligomers [ 1 , 2 , 3 , 4 ]. The mechanism of TRIM28-mediated gene repression is through the recruitment of histone deacetylase (HDAC) complex NuRD (nucleosome remodeling deacetylase) and histone H3 lysine 9-specific methyltransferase SETDB1 by C-terminal PHD and bromodomain [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

TRIM28 Regulates Dlk1 Expression in Adipogenesis

Lin

Chen

et al. 2020

IJMS

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The tripartite motif-containing protein 28 (TRIM28) is a transcription corepressor, interacting with histone deacetylase and methyltransferase complexes. TRIM28 is a crucial regulator in development and differentiation. We would like to investigate its function and regulation in adipogenesis. Knockdown of Trim28 by transducing lentivirus-carrying shRNAs impairs the differentiation of 3T3-L1 preadipocytes, demonstrated by morphological observation and gene expression analysis. To understand the molecular mechanism of Trim28-mediated adipogenesis, the RNA-seq was performed to find out the possible Trim28-regulated genes. Dlk1 (delta-like homolog 1) was increased in Trim28 knockdown 3T3-L1 cells both untreated and induced to differentiation. Dlk1 is an imprinted gene and known as an inhibitor of adipogenesis. Further knockdown of Dlk1 in Trim28 knockdown 3T3-L1 would rescue cell differentiation. The epigenetic analysis showed that DNA methylation of Dlk1 promoter and differentially methylated regions (DMRs) was not altered significantly in Trim28 knockdown cells. However, compared to control cells, the histone methylation on the Dlk1 promoter was increased at H3K4 and decreased at H3K27 in Trim28 knockdown cells. Finally, we found Trim28 might be recruited by transcription factor E2f1 to regulate Dlk1 expression. The results imply Trim28-Dlk1 axis is critical for adipogenesis.

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“…Our observation of reduced binding of the KRAB domain by TRIM28-K304Q, which was not the case for either mutant K266Q or K340Q, suggests that the speci c acetylation of K304 may impact the interaction between the KRAB domain and the TRIM28 homodimer (dimerization is mediated by the RBCCs). Molecular modeling failed to pinpoint the interaction at atomic resolution based on published structural studies (6,7,53,54) and our unpublished observations. As such, further structural studies are needed.…”

Section: Discussionmentioning

confidence: 94%

“…TRIM28 is composed of an N-terminal unstructured region (amino acid residues 1-62), a RBCC (RING, B1 and B2 boxes, coiled-coil domain) motif, two central unstructured regions (residues 406-623, 673-696), a PHD nger and bromo domain, and a C-terminal unstructured region (residues 813-835). The RBCC facilitates homodimerization of TRIM28 and speci cally interacts with the KRAB domain of ZNFs (6,7). TRIM28 serves as a scaffold for co-repressor proteins including DNA methyltransferases (DNMTs), the Nucleosome Remodeling and Deacetylase (NuRD) complex, the H3K9me3 MTs SETDB1, G9a (EHMT2), and HP1, and this holocomplex contributes to histone modi cations and heterochromatin formation to maintain gene silencing (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Mutation of TRIM28-Lys304 to Gln Attenuates its Interaction with KRAB-ZNFs and Promotes Differentiation of Erythroleukemic K562 Cells

Chang¹,

Lin²,

Kang³

et al. 2020

Preprint

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BackgroundTRIM28/KAP1/TIF1β is a key epigenetic modifier. Genetic ablation of trim28 is embryonic lethal although RNAi-mediated knockdown in somatic cells yields viable cells. Reduction in TRIM28 abundance at the cellular or organismal level results in polyphenism. Posttranslational modifications such as phosphorylation and sumoylation have been shown to regulate TRIM28 activity. Moreover, the methylation of DNA, RNA and histones and acetylation of histones are key epigenetic modifications that regulate gene expression. A number of lysine residues of TRIM28 are subject to acetylation, but how acetylation of TRIM28 affects its functions remains poorly understood. ResultsHere we report that, compared with wild-type TRIM28, the acetylation-mimic mutant TRIM28-K304Q has an altered interaction with Krüppel-associated box zinc-finger proteins (KRAB-ZNFs), with consequent effects on the phenotype of the erythroleukemic cell line K562. TRIM28-K304Q was comparable with its wild-type counterpart with respect to intracellular level, homodimerization, phosphorylation at S473 and S824, and interactions with heterochromatin-binding protein HP1. The expression of embryonic-related and fetal globin genes was activated in TRIM28-K304Q mutant cells. Transcriptome analysis revealed that TRIM28-K304Q and TRIM28 knockout K562 cells had similar global gene expression profiles, yet the profiles differed considerably from that of wild-type K562 cells. The gene expression ensemble of mutant K562 cells indicated a general induction of differentiation-promoting genes and attenuation of proliferation-promoting genes. ConclusionsThese results suggest that acetylation/deacetylation of K304 in TRIM28 or TRIM28-K304Q constitutes a switch for regulating its interaction with KRAB-ZNFs and alters the gene regulation of this key epigenetic modifier as demonstrated by the acetylation mimic TRIM28-K304Q.

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A Dissection of Oligomerization by the TRIM28 Tripartite Motif and the Interaction with Members of the Krab-ZFP Family

Cited by 26 publications

References 67 publications

The RING domain of TRIM69 promotes higher-order assembly

The RING domain of TRIM69 promotes higher-order assembly

TRIM28 Regulates Dlk1 Expression in Adipogenesis

Mutation of TRIM28-Lys304 to Gln Attenuates its Interaction with KRAB-ZNFs and Promotes Differentiation of Erythroleukemic K562 Cells

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