The nuclear corepressors recognize distinct nuclear receptor complexes

The thyroid hormone receptor (TR) and retinoic acid receptor (RAR) isoforms have the capacity to silence gene expression in the absence of their ligan ds on target response elements. This active repression is mediated by the a bility of the corepressors, nuclear receptor corepressor (NCoR) and silenci ng mediator of retinoid and thyroid hormone receptors (SMRT), to recruit a complex containing histone deacetylase activity. Interestingly, NCoR and SM RT share significant differences in the their two nuclear receptor-interact ing domains (IDs), suggesting that they may recruit receptors with differen t affinities. In addition, the role of the receptor complex bound to a resp onse element has not: been fully evaluated in its ability to recruit separa te corepressors. We demonstrate in this report that the proximal ID in NCoR and SMRT, which share only 23% homology, allows preferential recognition o f nuclear receptors, such that Tn prefers to recruit NCoR, and RAR prefers to recruit SMRT, to DNA response elements. However, mutations in the TR fou nd in the syndromes of resistance to thyroid hormone can change the corepre ssor recruited by changing the complex (homodimer or heterodimer) formed on the TRE. These results demonstrate that the corepressor complex recruited can be both nuclear receptor- and receptor complex-specific.