Protein backbone stability resonance12/16/2023 Uniformly 15N, 13C/ 15N and 2H/ 13C/ 15N labelled samples were grown in modified Spizizen’s media with 1.0 g/L of 15N ammonium chloride and 4 g/L of 13C-glucose (99%, Sigma Aldrich) as the sole nitrogen and carbon sources. 2014)), and the recombinant protein was over expressed in E. The BCL6-BTB/POZ domain (residues 7–128, with the following mutations C8Q, C67R and C84N) was cloned into an expression vector (as described previously (Evans et al. There are also suggestions that these agents can specifically cause apoptosis of BCL6 dependent B-cell lines and primary human B-cell lymphomas and this site on the BTB-POZ domain is, therefore, a validated target for drug discovery. Peptide or small molecule binders to the co-repressor binding site have been shown to abrogate the effects of BCL6 in normal B-cells. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ domain despite having different primary sequences (Ahmad et al. The binding of co-repressors, SMRT, NCOR and BCOR, have been studied in detail. The BTB-POZ domain mediates dimerisation but is also responsible for recruitment of co-repressors. The BTB-POZ domain is found in a large family of proteins and crystal structures of several members, including BCL6 have been produced. Gene expression studies have shown that relatively high BCL6 mRNA expression is a feature of the germinal centre (GC) type of high grade B-cell lymphoma, and is again associated with good prognosis, whereas the activated B-cell (ABC) type of lymphoma has relatively low BCL6 expression and poorer clinical outlook.īCL6 is a transcriptional repressor and the N-terminal BTB-POZ domain is responsible for the recruitment of co-repressor molecules and histone deacetylases (Dhordain et al. The presence of the t(3 14) translocation was associated with improved prognosis. More recently BCL6 has been shown to be essential for the differentiation of the follicular helper CD4 T-cell subset.īCL6 is also important as a prognostic marker in high grade B-cell lymphoma. On the other hand, mice bearing homozygous disruptions of the BCL6 locus do not have germinal centres and are unable to produce high affinity antibodies in response to immunisation. The enforced expression of BCL6 prevents terminal B-cell differentiation to plasma cells in vitro and in vivo is sufficient to promote lymphomagenesis in mice (Cattoretti et al. 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.īCL6 is a zinc finger transcription factor and regulator of lymphocyte differentiation. 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. Interestingly both SMRT and BCOR bind to the same site within the BCL6 BTB-POZ domain despite having very different primary sequences. 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. Crystal structures of several BTB-POZ domains, including BCL6 have been determined. The BTB-POZ domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. 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.
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