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Title: Selective interactions of nuclear receptors and cofactors: novel targets for drug discovery
Author: Fulton, Joel
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Nuclear receptors (NRs) are biomedically important transcription factors that regulate gene expression by recruitment of coactivators and corepressors (cofactors) to target gene promoters. Humans express 48 different NRs.and their isoforms, approximately half of which are orphans that have no recognised ligand. NRs can interact with more than 350 known cofactor proteins, many of which are chromatin modifying enzymes. Binding of ligand induces a conformational change in the NR that stimulates or prevents the docking of cofactors. These interactions are mediated by signature motifs (LXXLL in coactivators; or LXXXIXXXI/L in corepressors) that are essential for NR/cofactor function. To allow broader understanding of cofactor selectivity, an NR LBD interaction panel was constructed consisting of seven ligand-binding and eighteen orphan NRs. Interaction studies using LXXLL motifs from the well-characterised cofactor SRCl and the lesser-studied cofactor MEDl identified distinct patterns of interaction within Class I and Class 11 subsets of NRs. Novel motifs within the developmental regulator BCLllA, with consensus Y /FSXXLXXL/Y, were also investigated, revealing selective binding to a group of related orphan NRs consisting of the NR2E/F subfamilies. This sequence was also found to be conserved in other NR cofactors such as NSDl and was again shown to facilitate interactions with this subset of orphan NRs. As highly social transcription factors, nuclear receptors form a complex and integrated dimerisation network, binding to DNA as monomers, homodimers and heterodimers. While heterodin:terisation of nuclear receptors remains poorly understood, it is known to increase the complexity of NR-mediated transcription by integrating gene networks, mUltiple ligand inputs, cofactor selectivity, and increasing competition for other heterodimeric partners. Having determined the cofactor binding preference of the NR2E/F subfamily we profiled their dimerisation, revealing diverse dimerisation properties and several interactions of interest, including novel complexes of PNR that are likely to be of physiological consequence in the retina. ii
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available