2 DISTINCT NUCLEAR RECEPTOR INTERACTION DOMAINS IN NSD1, A NOVEL SET PROTEIN THAT EXHIBITS CHARACTERISTICS OF BOTH COREPRESSORS AND COACTIVATORS

NSD1, a novel 2588 amino acid mouse nuclear protein that interacts dir ectly with the ligand-binding domain (LBD) of several nuclear receptor s (NRs), has been identified and characterized. NSD1 contains a SET do main and multiple PHD fingers. In addition to these conserved domains found in both positive and negative Drosophila chromosomal regulators, NSD1 contains two distinct NR interaction domains, NID-L and NID+L th at exhibit binding properties of NIDs found in NR corepressors and coa ctivators, respectively. NID-L, but not NID+L, interacts with the unli ganded LBDs of retinoic acid receptors (RAR) and thyroid hormone recep tors (TR), and this interaction is severely impaired by mutations in t he LED alpha-helix 1 that prevent binding of corepressors and transcri ptional silencing by apo-NRs, NID+L, but not NID-L, interacts with the liganded LBDs of RAR, TR, retinoid X receptor (RXR), and estrogen rec eptor (ER), and this interaction is abrogated by mutations in the LED alpha-helix 1 that prevent binding of coactivators of the ligand-induc ed transcriptional activation function AF-2, A novel variant (FxxLL) o f the NR box motif (LxxLL) is present in NID+L and is required for the binding of NSD1 to holo-LBDs. Interestingly, NSD1 contains separate r epression and activation domains. Thus, NSD1 may define a novel class of bifunctional transcriptional intermediary factors playing distinct roles in both the presence and absence of ligand.