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Title: Towards understanding the molecular mechanism of MHCII regulation
Author: Drake, A. C. B.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The adaptive immune system relies upon the presentation of antigens to T cells on major histocompatibility complex molecules (MHC) to regulate the immune response. The expression of MHC class II (MHCII) molecules is tightly controlled and generally confined to the professional antigen presenting cells and those stimulated with interferon gamma. This regulation is achieved by 3 specific transcription factors that bind to the 5’ X-box of all MHCII genes called RFX5, RFXANK and RFXAP, and a signal non DNA binding transcriptional transactivator, CIITA, which interacts with the RFX genes and the ubiquitously expressed cellular transcriptional machinery and its regulators. CIITA was analysed and shown to be unsuitable for bacterial expression. In addition computational analysis allowed the identification of two distinct domains the C-terminal containing RNI leucine rich repeats in the C-terminus of the protein. This could offer a possible mechanism for nuclear localization. RFXAP was bacterially expressed and biophysical characterization and crystal trials were undertaken. With the support of computational evidence this data supported RFXAP being an unstructured protein which only folded into an active from in the presence of is binding partners. RFXANK was bacterially expressed and analysed using biophysical techniques as well as crystallography. The computational identification of unannotated ankyrin repeats in the N-terminus of the protein has lead to the hypothesis that RFXANK is an non DNA binding adaptor vital for the assembly of the enhancesome complex. RFX5 was computationally analysed but no significant observations were made.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available