UNDERSTANDING THE ROLE OF THE HINGE DOMAIN IN INTERDOMAIN COMMUNICATION IN NUCLEAR HORMONE RECEPTORS

The thyroid hormone receptor (TR), a nuclear receptor (NR), acts as a ligand-mediated transcription factor. TR activity is modulated by interactions with the ligand 3,3’,5 triiodo-L-thyronine (T3), DNA, co-activators, and other NRs such as retinoid X receptor (RXR). Allostery is increasingly recognized among NRs as a common regulatory mechanism. Ligand-binding causes conformational changes in TR, enabling the recruitment of transcriptional coactivators and interact with the pre-initiation complex (PIC) for gene expression. Attempts at characterizing these structural changes in NRs have proven futile due to the presence of intrinsically disordered regions, such as the hinge domain. The hinge domain is poorly conserved throughout the nuclear receptor family. It links the ligand-binding domain (LBD) to the DNA-binding domain (DBD). Studies have shown that the presence or absence of DNA bound to the ligand-activated NR results in ‘open’ and ‘closed’ conformations of the receptor. The role of the hinge in this interdomain communication, however, remains unknown. This research elucidates the function of the hinge domain in these transcriptionally optimal orientations of TRα using single molecule studies and cell-based assays.