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The N-Terminal A/B Domain of the Thyroid Hormone Receptor-ß2 Isoform Influences Ligand-Dependent Recruitment of Coactivators to the Ligand-Binding Domain

Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York 10016

Address all correspondence and requests for reprints to: Herbert H. Samuels, Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: herbert. samuels{at}med.nyu.edu

Thyroid hormone receptors (TRs), expressed as TR1, TRß1, and TRß2 isoforms, are members of the steroid hormone nuclear receptor gene superfamily, which comprises ligand-dependent transcription factors. The TR isoforms differ primarily in their N-terminal (A/B) domains, suggesting that the A/B regions mediate distinct transcriptional activation functions in a cell type-dependent or promoter-specific fashion. The nuclear receptor ligand-binding domain (LBD) undergoes a conformational change upon ligand binding that results in the recruitment of coactivators to the LBD. For glucocorticoid receptor and estrogen receptor-, the same coactivator can contact both the LBD and A/B domains, thus leading to enhanced transcriptional activation. Very little is known regarding the role of the A/B domains of the TR isoforms. The A/B domain of TRß2 exhibits higher ligand-independent transcriptional activity than the A/B regions of TR1 or TRß1. Thus, we examined the role of the A/B domain and the LBD of rat TRß2 in integrating the transcriptional activation function of the A/B and LBD domains by different coactivators. Both domains are essential for a productive functional interaction with cAMP response element-binding protein (CREB)-binding protein (CBP), and we found that CBP binds to the A/B domain of TRß2 in vitro. In contrast, steroid receptor coactivator-1a (SRC-1a) interacts strongly with the LBD but not the A/B domain. The coactivator NRC (nuclear receptor coactivator) interacts primarily with the LBD, although a weak interaction with the A/B domain further enhances ligand-dependent binding with TRß2. Our studies document the interplay between the A/B domain and the LBD of TRß2 in recruiting different coactivators to the receptor. Because NRC and SRC-1a bind CBP, and CBP enhances ligand-dependent activity, our studies suggest a model in which coactivator recruitment of NRC (or SRC-1a) occurs primarily through the LBD whereas the complex is further stabilized through an interaction of CBP with the N terminus of TRß2.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Coregulators:   CBP  |  SRC-1  |  ASC-2

Ligands:   Thyroid hormone

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