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Structure of the wild-type human BCL6 POZ domain.

ABSTRACT: BCL6 is a transcriptional repressor that is overexpressed in diffuse large B-cell lymphoma and follicular lymphoma. The N-terminal POZ domain of BCL6 interacts with transcriptional corepressors and targeting these associations is a promising therapeutic strategy. Previous structural studies of the BCL6 POZ domain have used a mutant form because of the low solubility of the wild-type recombinant protein. A method for the purification and crystallization of the wild-type BCL6 POZ domain is described and the crystal structure to 2.1 A resolution is reported. This will be relevant for the design of therapeutics that target BCL6 POZ-domain interaction interfaces.

SUBMITTER: Stead MA

PROVIDER: S-EPMC2593701 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Structure of the wild-type human BCL6 POZ domain.

Stead Mark A MA Rosbrook Gareth O GO Hadden Jonathan M JM Trinh Chi H CH Carr Stephen B SB Wright Stephanie C SC

Acta crystallographica. Section F, Structural biology and crystallization communications 20081128 Pt 12

BCL6 is a transcriptional repressor that is overexpressed in diffuse large B-cell lymphoma and follicular lymphoma. The N-terminal POZ domain of BCL6 interacts with transcriptional corepressors and targeting these associations is a promising therapeutic strategy. Previous structural studies of the BCL6 POZ domain have used a mutant form because of the low solubility of the wild-type recombinant protein. A method for the purification and crystallization of the wild-type BCL6 POZ domain is describ ...[more]

PMID: 19052359

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Backbone resonance assignment of the BCL6-BTB/POZ domain.

Project description:BCL6 is a transcriptional repressor. Two domains of the protein, the N-terminal BTB-POZ domain and the RD2 domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ domains, including BCL6 have been determined. The BTB-POZ domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ domain despite having very different primary sequences. Since both peptides and small molecules have been shown to bind to the co-repressor binding site it would suggest that the BTB_POZ domain is a suitable target for drug discovery. Here we report near complete backbone 15N, 13C and 1H assignments for the BTB-POZ domain of BCL6 to assist in the analysis of binding modes for small molecules.

| S-EPMC5869878 | biostudies-literature

Structure of the human Nac1 POZ domain.

Project description:Nac1 is a POZ-domain transcription factor that is involved in the self-renewal of embryonic stem cells. It is overexpressed in ovarian serous carcinoma and targeting the interactions of its POZ domain is a potential therapeutic strategy. Nac1 lacks a zinc-finger DNA-binding domain and thereby differs from most other POZ-domain transcription factors. Here, the crystal structure of the Nac1 POZ domain at 2.1 A resolution is reported. The Nac1 POZ domain crystallized as a dimer in which the interaction interfaces between subunits resemble those found in the POZ-zinc finger transcription factors. The organization of the Nac1 POZ-domain core resembles reported POZ-domain structures, whereas the C-terminus differs markedly. The C-terminal alpha-helix of the Nac1 POZ domain is shorter than that observed in most other POZ-domain transcription factors; variation in the organization of this region may be a general feature of POZ-domain structures.

| S-EPMC2675581 | biostudies-literature

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain.

Project description:BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ?40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor.

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Structures of heterodimeric POZ domains of Miz1/BCL6 and Miz1/NAC1.

Project description:The POZ domain is an evolutionarily conserved protein-protein interaction domain that is found in approximately 40 mammalian transcription factors. POZ domains mediate both homodimerization and the heteromeric interactions of different POZ-domain transcription factors with each other. Miz1 is a POZ-domain transcription factor that regulates cell-cycle arrest and DNA-damage responses. The activities of Miz1 are altered by its interaction with the POZ-domain transcriptional repressors BCL6 and NAC1, and these interactions have been implicated in tumourigenesis in B-cell lymphomas and in ovarian serous carcinomas that overexpress BCL6 and NAC1, respectively. A strategy for the purification of tethered POZ domains that form forced heterodimers is described, and crystal structures of the heterodimeric POZ domains of Miz1/BCL6 and of Miz1/NAC1 are reported. These structures will be relevant for the design of therapeutics that target POZ-domain interaction interfaces.

| S-EPMC4259219 | biostudies-literature

Crystal structure of wild-type human procathepsin K.

Project description:Cathepsin K is a lysosomal cysteine protease belonging to the papain superfamily. It has been implicated as a major mediator of osteoclastic bone resorption. Wild-type human procathepsin K has been crystallized in a glycosylated and a deglycosylated form. The latter crystals diffract better, to 3.2 A resolution, and contain four molecules in the asymmetric unit. The structure was solved by molecular replacement and refined to an R-factor of 0.194. The N-terminal fragment of the proregion forms a globular domain while the C-terminal segment is extended and shows substantial flexibility. The proregion interacts with the enzyme along the substrate binding groove and along the proregion binding loop (residues Ser138-Asn156). It binds to the active site in the opposite direction to that of natural substrates. The overall binding mode of the proregion to cathepsin K is similar to that observed in cathepsin L, caricain, and cathepsin B, but there are local differences that likely contribute to the specificity of these proregions for their cognate enzymes. The main observed difference is in the position of the short helix alpha3p (67p-75p), which occupies the S' subsites. As in the other proenzymes, the proregion utilizes the S2 subsite for anchoring by placing a leucine side chain there, according to the specificity of cathepsin K toward its substrate.

| S-EPMC2144248 | biostudies-other

The dimeric structure of wild-type human glycosyltransferase B4GalT1.

Project description:Most glycosyltransferases, including B4GalT1 (EC 2.4.1.38), are known to assemble into enzyme homomers and functionally relevant heteromers in vivo. However, it remains unclear why and how these enzymes interact at the molecular/atomic level. Here, we solved the crystal structure of the wild-type human B4GalT1 homodimer. We also show that B4GalT1 exists in a dynamic equilibrium between monomer and dimer, since a purified monomer reappears as a mixture of both and as we obtained crystal forms of the monomer and dimer assemblies in the same crystallization conditions. These two crystal forms revealed the unliganded B4GalT1 in both the open and the closed conformation of the Trp loop and the lid regions, responsible for donor and acceptor substrate binding, respectively. The present structures also show the lid region in full in an open conformation, as well as a new conformation for the GlcNAc acceptor loop (residues 272-288). The physiological relevance of the homodimer in the crystal was validated by targeted mutagenesis studies coupled with FRET assays. These showed that changing key catalytic amino acids impaired homomer formation in vivo. The wild-type human B4GalT1 structure also explains why the variant proteins used for crystallization in earlier studies failed to reveal the homodimers described in this study.

| S-EPMC6198961 | biostudies-literature

Crystal structure of wild-type and mutant human Ap4A hydrolase.

Project description:Ap4A hydrolase (asymmetrical diadenosine tetraphosphate hydrolase, EC 3.6.1.17), an enzyme involved in a number of biological processes, is characterized as cleaving the polyphosphate chain at the fourth phosphate from the bound adenosine moiety. This paper presents the crystal structure of wild-type and E58A mutant human Ap4A hydrolase. Similar to the canonical Nudix fold, human Ap4A hydrolase shows the common ???-sandwich architecture. Interestingly, two sulfate ions and one diphosphate coordinated with some conserved residues were observed in the active cleft, which affords a better understanding of a possible mode of substrate binding.

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Nac1 interacts with the POZ-domain transcription factor, Miz1.

Project description:Nac1 (nucleus accumbens 1) is a POZ (poxvirus and zinc finger)-domain transcriptional repressor that is expressed at high levels in ovarian serous carcinoma. Here we identify Nac1 as a novel interacting partner of the POZ-domain transcriptional activator, Miz1 (Myc-interacting zinc-finger protein 1), and using chemical crosslinking we show that this association is mediated by a heterodimeric interaction of the Nac1 and Miz1 POZ domains. Nac1 is found in discrete bodies within the nucleus of mammalian cells, and we demonstrate the relocalization of Miz1 to these structures in transfected HeLa cells. We show that siRNA (small interfering RNA)-mediated knockdown of Nac1 in ovarian cancer cells results in increased levels of the Miz1 target gene product, p21Cip1. The interaction of Nac1 with Miz1 may thus be relevant to its mechanism of tumourigenesis in ovarian cancer.

| S-EPMC4046208 | biostudies-literature

Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer.

Project description:The transcriptional corepressors BCOR, SMRT, and NCoR are known to bind competitively to the BCL6 BTB domain despite the fact that BCOR has no detectable sequence similarity to the other two corepressors. We have identified a 17 residue motif from BCOR that binds directly to the BCL6 BTB domain and determined the crystal structure of the complex to a resolution of 2.6 A. Remarkably, the BCOR BCL6 binding domain (BCOR(BBD)) peptide binds in the same BCL6 binding site as the SMRT(BBD) peptide despite the lack of any significant sequence similarity between the two peptides. Mutations of critical BCOR(BBD) residues cause the disruption of the BCL6 corepression activities of BCOR, and a BCOR(BBD) peptide blocks BCL6-mediated transcriptional repression and kills lymphoma cells.

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BTB/POZ zinc finger protein ZBTB16 inhibits breast cancer proliferation and metastasis through upregulating ZBTB28 and antagonizing BCL6/ZBTB27.

Project description:BackgroundBreast cancer remains in urgent need of reliable diagnostic and prognostic markers. Zinc finger and BTB/POZ domain-containing family proteins (ZBTBs) are important transcription factors functioning as oncogenes or tumor suppressors. The role and regulation of ZBTB16 in breast cancer remain to be established.MethodsReverse-transcription PCR and methylation-specific PCR were applied to detect expression and methylation of ZBTB16 in breast cancer cell lines and tissues. The effects of ZBTB16 in breast cancer cells were examined via cell viability, CCK8, Transwell, colony formation, and flow cytometric assays. Xenografts and immunohistochemistry analyses were conducted to determine the effects of ZBTB16 on tumorigenesis in vivo. The specific mechanisms of ZBTB16 were further investigated using Western blot, qRT-PCR, luciferase assay, and co-IP.ResultsZBTB16 was frequently downregulated in breast cancer cell lines in correlation with its promoter CpG methylation status. Restoration of ZBTB16 expression led to induction of G2/M phase arrest and apoptosis, inhibition of migration and invasion, reversal of EMT, and suppression of cell proliferation, both in vitro and in vivo. Furthermore, ectopically expressed ZBTB16 formed heterodimers with ZBTB28 or BCL6/ZBTB27 and exerted tumor suppressor effects through upregulation of ZBTB28 and antagonistic activity on BCL6.ConclusionsLow expression of ZBTB16 is associated with its promoter hypermethylation and restoration of ZBTB16 inhibits tumorigenesis. ZBTB16 functions as a tumor suppressor through upregulating ZBTB28 and antagonizing BCL6. Our findings also support the possibility of ZBTB16 being a prognostic biomarker for breast cancer.

| S-EPMC7285556 | biostudies-literature

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