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Title: Structural analysis of the BTB domains of the Bach and BCL6 transcriptional repressors
Author: Rosbrook, Gareth Owen
ISNI:       0000 0004 2714 8187
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2010
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The BTB domain is a protein-protein interaction domain found in a number of protein families including the BTB-zinc finger and BTB-basic leucine zipper (bZip) transcription factors. The domain directs the specific recruitment of transcriptional co-repressors to the BTB- transcription factors and mediates homodimerisation and the formation of specific heteromeric BTB-BTB complexes. A number of BTB-transcription factors are implicated in human cancers, such as BCL6 in B-cell lymphomas, Bach2 in ovarian cancer and PLZF in acute promyelocytic leukaemias. BCL6 and Bach2 are expressed during early B-cell development and synergistically inhibit differentiation of the germinal centre B-cells. Both BCL6 and Bach2 interact with the BTB domain of the BTB- transcription factor MIZ-1; while the BCL6/MIZ-1 complex is known to inhibit DNA-damage induced cellular arrest of developing germinal centre B-cells, the role of the Bach2/MIZ-1 complex remains to be elucidated. This work presents the structure of the Bach2 BTB domain in two different states to 2.1 A (form I) and 2.2 A (form 11) resolution. Structural analysis of the BTB domain of Bach2 identified a unique intra-dimeric disulphide bond not previously reported in BTB structures of the BTB- transcription factors. The presence of this disulphide bond was confirmed in-vivo. Further investigation is required to identify the roles of this disulphide bond in regulating Bach2 activity. Current therapeutic strategies target the interactions of the BCL6 BTB domain with transcriptional co-repressors, and are based on the crystal structures of a mutant BTB domain. These mutations may affect the interaction interface that mediates heteromeric interactions of BTB domains with each other. This thesis also presents the methodology for the expression, , purification and crystallisation of the human wild-type BCL6 BTB domain, and the solved structure to 2.1A resolution. This wild-type structure will assist in the rational design of therapeutics that target BCL6 activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available