THE TRAP220 COMPONENT OF A THYROID-HORMONE RECEPTOR-ASSOCIATED PROTEIN (TRAP) COACTIVATOR COMPLEX INTERACTS DIRECTLY WITH NUCLEAR RECEPTORSIN A LIGAND-DEPENDENT FASHION

Cognate cDNAs are described for 2 of the 10 thyroid hormone receptor-a ssociated proteins (TRAPs) that are immunopurified with thyroid hormon e receptor alpha (TR alpha) from ligand-treated HeLa (alpha-2) cells. Both TRAP220 and TRAP100 contain LXXLL domains found in other nuclear receptor-interacting proteins and both appear to reside in a single co mplex with other TRAPs tin the absence of TR), However, only TRAP220 s hows a direct ligand-dependent interaction with TRa, and these interac tions are mediated through the C terminus of TR alpha and (at least in part) the LXXLL domains of TRAP220, TRAP220 also interacts with other nuclear receptors [vitamin D receptor, retinoic acid receptor alpha, retinoid X receptor alpha, peroxisome proliferation-activated receptor (PPAR) alpha, PPAR gamma and, to a lesser extent, estrogen receptor] in a ligand-dependent manner, whereas TRAP100 shows only marginal inte ractions with estrogen receptor, retinoid X receptor alpha, PPAR alpha , and PPAR gamma. Consistent with these results, TRAP220 moderately st imulates human TR alpha-mediated transcription in transfected cells, w hereas a fragment containing the LXXLL motifs acts as a dominant negat ive inhibitor of nuclear receptor-mediated transcription both in trans fected cells (TRa) and in cell free transcription systems (TRa and vit amin D receptor). These studies indicate that TRAP220 plays a major ro le in anchoring other TRAPs to TR alpha during the function of the TR alpha-TRAP complex and, further, that TRAP220 (possibly along with oth er TRAPs) may be a global coactivator for the nuclear receptor superfa mily.