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Title: Structural and functional analysis of the amino-terminal transactivation domain of the human androgen receptor
Author: Reid, James Arthur
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2001
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The androgen receptor (AR) belongs to the steroid/nuclear receptor family of ligand-activated transcription factors. Most of these receptors activate transcription through two distinct regions known as activation functions (AF). The first, AF-1, is located within the variable amino-terminal domain (NTD) and the second, AF-2, within the ligand binding domain (LBD). However, the AR is unusual amongst the steroid receptor family in that an independent AF-2 function has not been demonstrated. Transactivation by the AR is therefore dependent primarily upon AF-1. Previous work in our laboratory has shown that an amino-terminal fragment of the AR (amino acids 142 to 485) is able to interact specifically with RAP74, the large subunit of general transcription factor TFIIF. Using a series of deletion constructs, two distinct AR binding sites have been identified with RAP74, one at the amino-terminus and one at the carboxyl-terminus of the protein. Functional analyses of these interactions suggest that the interaction between the AR and the carboxyl-terminus of RAP74 is the most significant with respect to transcriptional activation by the receptor. Mutational analysis of the AR-NTD identified a six amino acid motif, PSTLSL, as being involved in RAP74 binding. In addition to RAP74, an interaction has been identified between the p160 coactivator protein SRC-1a and amino acids 142-485 of the AR. Interestingly, another high related p160 coactivator protein, TIF2, showed little or no binding to this region of the receptor. Structural analysis, using circular dichroism and fluorescence spectroscopy and sensitivity to protease digestion, indicates that the AR-NTD exists in an extended conformation in aqueous solution but retains a propensity to fold into a more ordered structure in the presence of the hydrophobic solvent trifluoroethanolor the osmolyte trimethylamine-N-oxide. Significantly, RAP74 also confers protection to trypsin digestion, consistent with folding of the AR-NTD (aa 142 to 485) upon interaction with a target factor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available