Structural and Functional Correlations of the Thyroid Hormone Receptor.

[摘要] Thyroid hormones (THs) play essential roles in numerous critical physiological processes. The crucial functions of TH are exerted through binding to the thyroid hormone receptor (TR). TRs can specifically regulate gene transcription in response to TH binding. The two major functional domains, the DNA binding domain and the ligand binding domain, in the TRs are the key player working in collaboration to exert TR function. Although the overall procedures of TR actions have been revealed, the molecular mechanisms managing the fine-tuning of different aspects in the course of the transactivation have yet to be defined.The DNA binding domain (DBD) of TR is responsible for recognizing and binding to different classes of the DNA response elements in the promoter regions of target genes. We report here the first crystal structure of a homodimer TR DBD in complex with a inverted repeat type of thyroid response element (F2 TRE). The structure reveals a nearly symmetric structure of the TR DBD assembled on the F2 TRE. The T-box regions of the DBDs in the structure exhibit their function as a structural hinge that enables a large degree of flexibility in positioning of the C-terminal extension, which connects the DBD to the ligand binding domain (LBD). The C-terminal tail regions have also been shown to assist the cooperative homodimeric assembly of the TR DBD on the F2 TRE. The TR LBD is responsible for the ligand-dependent coregulator recruiting and transcription activation. In contrary to the common assumption that ligand binding induces a dramatic conformation change in the C-terminal helix of the TR LBD, our data from computational homology modeling and molecular dynamic simulations support that the PPAR-based apo TR LBD model in which the helix 12 adopts a relatively stable conformation mimicking the active holo TR LBD structure. Thus the corepressor binding to the apo TR LBD is an induced fit process. From in silicon studies on the TR LBDs with the corepressor peptides, we have further identified the crucial components determining the TR preference on the nuclear receptor corepressor (NCoR).

[发布机构] University of Michigan

[效力级别] Biological Chemistry

[关键词] Thyroid Hormone Receptor;Biological Chemistry;Science;Biophysics