Direct interdomain interactions can mediate allosterism in the thyroid receptor.
The thyroid (TR) and retinoid X receptors (RXR) belong to the nuclear receptor (NR) superfamily of ligand-mediated transcription factors. At the molecular level, TR activity is specifically modulated by interactions with the ligand 3,3',5 triiodo-l-thyronine (T3), RXR, DNA, and co-activators such as SRC1, occurring in concert or sequentially. Although binding sites for DNA and coregulators such as SRC1 are distinct and at distal regions of these receptors, cell-based and EMSA studies have suggested that these molecules can regulate binding of each other to the receptor. We present evidence of direct, DNA-dependent, communication between the DNA and ligand binding domains (DBD and LBD) that can allosterically regulate interactions with SRC1 and DNA, respectively, using isothermal titration calorimetry (ITC) and cell-based assays. Additionally, we note that interdomain communication is affected by RXR in RXR:TR. We also noticed a DNA-dependent cross-talk between RXR and TR within RXR:TR. Finally, we suggest that differences in transactivation on different TRE may be the consequence of different affinities between TRE and RXR:TR.
Putcha
Balananda-Dhurjati K
BD
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.
Fernandez
Elias J
EJ
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D002151:Calorimetry; D002645:Chickens; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D013961:Thyroid Gland / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014284:Triiodothyronine