The B-box 1 dimer of human promyelocytic leukemia protein

Huang, Shu Yu; Naik, Mandar T.; Chang, Chi‐Fon; Fang, Pei Ju; Wang, Ying Hui; Shih, Hsiu Ming; Huang, Tai Huang

doi:10.1007/s10858-014-9869-4

Cited by 14 publications

(22 citation statements)

References 19 publications

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“…The PML protein appears to be the primary scaffold for these bodies (Ishov et al, 1999). PML can self-assemble via elements within its Tripartite Motif (TRIM) (Antolini et al, 2003; Huang et al, 2014) and also via binding of its conserved SIM element to SUMOs conjugated at up to eight sites in the protein (Nisole et al, 2013; Shen et al, 2006). Though not strictly required for body assembly (Brand et al, 2010; Sahin et al, 2014), SUMO-SIM interactions likely contribute substantially to body architecture, as deletion of the SIM motif or perturbations to PML SUMOylation via mutagenesis, viral infection, or knockdown/overexpression of SUMO ligases/proteases can cause changes in the size, number, morphology, or dynamics of PML NBs (Best et al, 2002; Hattersley et al, 2011; He et al, 2015; Müller and Dejean, 1999; Shen et al, 2006; Weidtkamp-Peters et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Compositional Control of Phase-Separated Cellular Bodies

Banani

Rice

Peeples

et al. 2016

Cell

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1,290

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SUMMARY Cellular bodies such as P bodies and PML nuclear bodies (PML NBs) appear to be phase-separated liquids organized by multivalent interactions among proteins and RNA molecules. Although many components of various cellular bodies are known, general principles that define body composition are lacking. We modeled cellular bodies using several engineered multivalent proteins and RNA. In vitro and in cells, these scaffold molecules form phase-separated liquids that concentrate low valency client proteins. Clients partition differently depending on the ratio of scaffolds, with a sharp switch across the phase diagram diagonal. Composition can switch rapidly through changes in scaffold concentration or valency. Natural PML NBs and P bodies show analogous partitioning behavior, suggesting how their compositions could be controlled by levels of PML SUMOylation or cellular mRNA concentration, respectively. The data suggest a conceptual framework for considering the composition and control thereof of cellular bodies assembled through heterotypic multivalent interactions.

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Section: Resultsmentioning

confidence: 99%

Compositional Control of Phase-Separated Cellular Bodies

Banani

Rice

Peeples

et al. 2016

Cell

1,045

1,290

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“…However, this is inconsistent with more recent reports that TRIM5, TRIM25 and TRIM69 form antiparallel dimers, a property predicted to be conserved across the TRIM family (23)(24)(25)(26). Moreover, various TRIMs (TRIM5, PML/TRIM19, TRIM32) further 90 assemble into tetramers and higher-order oligomers, including two-dimensional lattices and molecular scaffolds (as seen in PML bodies), and these higher-order assemblies are important for their biological activities (25,(27)(28)(29). RING domains, including those of TRIM5a and TRIM32, form dimers, which contribute to E3 ligase activity by priming the associated E2 ubiquitin ligase 4 for ubiquitin transfer (28,30,31).…”

Section: Introductionmentioning

confidence: 82%

“…tetramers) led us to hypothesize that the RBCC may be able to self-associate into polymeric chains or molecular scaffold (Fig. 3G) as observed for other TRIMs (25,(27)(28)(29). We therefore investigated the possibility that KAP1 self-assembly may contribute to its transcriptional silencing function.…”

Section: Discussion 340mentioning

confidence: 97%

“…Each of the domains within the RBCC motif (RING, B-box 1, B-box 2 and coiled coil) has been reported to independently form dimers or oligomers in TRIM-family proteins (23)(24)(25)(26)(27)(28)(29). The presence of two or more domains capable of oligomerization independently can lead to polymerization of TRIMs into lattices or scaffolds (25,27,28), but it remains unclear whether this 110 applies to KAP1.…”

Section: Kap1 Forms Dimers That Self-assemble Into Higher-order Oligomentioning

confidence: 99%

“…Various TRIM proteins assemble into higher-order oligomers, two-dimensional lattices or 260 molecular scaffolds that are important for physiological function (25,(27)(28)(29). To determine whether self-assembly of KAP1 into higher-order oligomers is required for its retroelement repression, we LINE-1 reporters, despite being deficient in dimer-dimer assembly (Fig.…”

Section: Self-assembly Of Kap1 Rbcc Dimers Is Not Required For Retroementioning

confidence: 99%

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Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons

Stoll

Oda

Chong

et al. 2018

Preprint

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Transcription of transposable elements is tightly regulated to prevent genome damage. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific 15 retrotransposon sequences and recruit KAP1, inducing the assembly of an epigenetic silencing complex, with chromatin remodeling activities that repress transcription of the targeted retrotransposon and adjacent genes. Our biophysical and structural data show that the tripartite motif (TRIM) of KAP1 forms antiparallel dimers, which further assemble into tetramers and higherorder oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 20 domain prevent higher-order oligomerization without significant loss of retrotransposon silencing activity, indicating that, in contrast to other TRIM-family proteins, self-assembly is not essential for KAP1 function. The crystal structure of the KAP1 TRIM dimer identifies the KRAB domain binding site, in the coiled-coil domain near the dyad. Mutations at this site abolished KRAB binding and transcriptional silencing activity of KAP1. This work identifies the interaction interfaces in the 25 KAP1 TRIM responsible for self-association and KRAB binding and establishes their role in retrotransposon silencing. Keywords Transcriptional repressor; epigenetic silencing; endogenous retrovirus; transposable element; ubiquitin E3 ligase 30 2 Running title Structure and function of KAP1/TRIM28 Significance Retroviruses can integrate their DNA into the host-cell genome. Inherited retroviral DNA and other transposable elements account for over half of the human genome. Transposable elements must be tightly regulated to restrict their proliferation and prevent toxic gene expression. KAP1/TRIM2835 is an essential regulator of transposable element transcription. We determined the crystal structure of the KAP1 TRIM. The structure identifies a protein-protein interaction site required for recruitment of KAP1 to transposable elements. An epigenetic gene silencing assay confirms the importance of this site for KAP1-dependent silencing. We also show that KAP1 self-assembles in solution, but this self-assembly is not required for silencing. Our work provides insights into KAP1-40 dependent silencing, and tools for expanding our mechanistic understanding of this process. /body

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