title: Distinct ligand-dependent and independent modes of thyroid hormone receptor (TR)/PGC-1α interaction.
abstract: Thyroid hormone receptor (TR)/peroxisome proliferator activated receptor coactivator (PGC-1α) interactions are required for T(3)-dependent transcriptional responses involved in adaptive thermogenesis and liver. Thus, it is important to define TR/PGC-1α contact modes and to understand their significance in gene expression. Previous studies have shown that TRβ1 recruits PGC-1α to target promoters via contacts between the hormone-dependent TRβ1 activation function 2 (AF-2) in the C-terminal ligand binding domain (LBD) and a major PGC-1α nuclear receptor (NR) interaction box (consensus LxxLL) at amino acids 142-146. While our studies verify the existence and importance of this interaction, we present evidence that TRβ1 also binds PGC-1α in a second ligand and LxxLL motif independent mode and show that this interaction requires the TRβ1 N-terminal domain (NTD) and the PGC-1α N-terminal activation domain (AD) at amino acids 1-130. Transfection assays suggest that optimal PGC-1α coactivation requires the TRβ1 NTD and that these contacts are needed for utilization of the PGC-1α C-terminal AD, which does not bind TR and is implicated in basal transcription machinery contacts. We propose that TR AF-1/PGC-1α contacts are needed for transition between activities of PGC-1α N-and C-terminal ADs in gene expression. Our findings provide insights into possible roles for TR and NR AF-1 in gene expression.
authors.affiliation: University of California Medical Center, Diabetes Center, San Francisco, CA 94122, USA.
authors.forename: Chaoshen
authors.initials: C
authors.lastname: Yuan
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D002460:Cell Line; D015870:Gene Expression; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D006360:Heat-Shock Proteins; D008024:Ligands; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011994:Recombinant Proteins; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine