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 alpha-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 alpha-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.
Huang
N
N
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, Strasbourg, France.
vom Baur
E
E
Garnier
J M
JM
Lerouge
T
T
Vonesch
J L
JL
Lutz
Y
Y
Chambon
P
P
Losson
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells / Q000166:cytology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014212:Tretinoin / Q000378:metabolism*; D015003:Yeasts
D002352:Carrier Proteins; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; C000607072:Rara protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase; C491867:Nsd1 protein, mouse