A Biophysical Understanding of Mutations in the Human Thyroid Hormone Receptor Alpha

Thyroid Hormone Receptor alpha (TRα) is a transcription factor involved in the regulation of the T3 target genes expression in response to T3. TRα plays multiple critical roles in development and growth in addition to regulate the metabolism in adult organisms. TRα regulates the transcription of T3 target genes by recruiting corepressor or coactivator factors to the promoters of the target genes in response to T3. Corepressors such as SMRT are recruited by unliganded TRα, whereas coactivators such as GRIP1 are recruited in response to T3 binding to the receptors. Several mutations in the THRA1 gene have been recently identified in patients showing symptoms of tissue-specific hypothyroidism, delayed growth and development, and severe constipation. These mutations lead to a disorder called Resistance to Thyroid Hormone due to mutations in TRα (RTHα) whose degree of impairment depends on the location and severity of the mutation. Three mutations affecting the C-terminal or AF-2 domain of the TRα generate truncated TRα proteins that show aberrant interactions with coregulator proteins and a complete absence of T3 response. The aims of this thesis are to understand the molecular pathology of the mutant TRα as well as to obtain a deeper insight into the structural basis for repression by the mutant TRα using structural and biochemical approaches. The biophysical characterization demonstrates that mutant TRα impairment is mainly due to the inability of the mutant TRα to recruit coactivators in response to T3. Consequently, TRα mutants are constitutively bound to corepressors and repress T3 target gene transcription. X-rays structural data indicated that TRα mutants are able to bind and accommodate T3 in the hydrophobic pocket in an identical place and conformation as in the WT