title: The N-Terminal A/B domain of the thyroid hormone receptor-beta2 isoform influences ligand-dependent recruitment of coactivators to the ligand-binding domain.
abstract: Thyroid hormone receptors (TRs), expressed as TRalpha1, TRbeta1, and TRbeta2 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-alpha, 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 TRbeta2 exhibits higher ligand-independent transcriptional activity than the A/B regions of TRalpha1 or TRbeta1. Thus, we examined the role of the A/B domain and the LBD of rat TRbeta2 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 TRbeta2 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 TRbeta2. Our studies document the interplay between the A/B domain and the LBD of TRbeta2 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 TRbeta2.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Henghe
authors.initials: H
authors.lastname: Tian
authors.forename: Muktar A
authors.initials: MA
authors.lastname: Mahajan
authors.forename: Chun Tung
authors.initials: CT
authors.lastname: Wong
authors.forename: Ioanis
authors.initials: I
authors.lastname: Habeos
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
mesh_terms: D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D009154:Mutation / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D020033:Protein Isoforms; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1