Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators

EMBO J. 1998 Jun 15;17(12):3398-412. doi: 10.1093/emboj/17.12.3398.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • COS Cells / cytology
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Estrogen Receptor alpha
  • Gene Expression Regulation
  • Histone-Lysine N-Methyltransferase
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / metabolism
  • Receptors, Retinoic Acid / metabolism*
  • Receptors, Thyroid Hormone / metabolism
  • Retinoic Acid Receptor alpha
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Tretinoin / metabolism*
  • Yeasts


  • Carrier Proteins
  • Estrogen Receptor alpha
  • Nuclear Proteins
  • Rara protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • Retinoic Acid Receptor alpha
  • Tretinoin
  • Histone-Lysine N-Methyltransferase
  • Nsd1 protein, mouse

Associated data

  • GENBANK/AF064553