Distinct Ligand-Dependent And Independent Modes Of Thyroid Hormone Receptor (Tr)/Pgc-1 Alpha Interaction

Thyroid hormone receptor (TR)/peroxisome proliferator activated receptor coactivator (PGC-1 alpha) interactions are required for T-3-dependent transcriptional responses involved in adaptive thermogenesis and liver. Thus, it is important to define TR/PGC-1 alpha contact modes and to understand their significance in gene expression. Previous studies have shown that TR beta 1 recruits PGC-1 alpha to target promoters via contacts between the hormone-dependent TR beta 1 activation function 2 (AF-2) in the C-terminal ligand binding domain (LBD) and a major PGC-1 alpha 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 TR beta 1 also binds PGC-1 alpha in a second ligand and LxxLL motif independent mode and show that this interaction requires the TR beta 1 N-terminal domain (NTD) and the PGC-1 alpha N-terminal activation domain (AD) at amino acids 1-130. Transfection assays suggest that optimal PGC-1 alpha coactivation requires the TR beta 1 NTD and that these contacts are needed for utilization of the PGC-1 alpha C-terminal AD, which does not bind TR and is implicated in basal transcription machinery contacts. We propose that TR AF-1/PGC-1 alpha contacts are needed for transition between activities of PGC-1 alpha N-and C-terminal ADs in gene expression. Our findings provide insights into possible roles for TR and NR AF-1 in gene expression. (C) 2012 Elsevier Ltd. All rights reserved.