Jean-Luc Vonesch

Two 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 directly with the ligand‐binding domain (LBD) of several nuclear receptors (NRs), has been identified and characterized. NSD1 contains a SET domain 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, that exhibit binding properties of NIDs found in NR corepressors and coactivators, respectively. NID−L, but not NID+L, interacts with the unliganded LBDs of retinoic acid receptors (RAR) and thyroid hormone receptors (TR), and this interaction is severely impaired by mutations in the LBD α‐helix 1 that prevent binding of corepressors and transcriptional silencing by apo‐NRs. NID+L, but not NID−L, interacts with the liganded LBDs of RAR, TR, retinoid X receptor (RXR), and estrogen receptor (ER), and this interaction is abrogated by mutations in the LBD α‐helix 12 that prevent binding of coactivators of the ligand‐induced transcriptional activation function AF‐2. A novel variant (FxxLL) of 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 repression 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.