Stoichiometric and steric principles governing repression by nuclear hormone receptors.
We have defined two principles of corepressor function that account for differences in transcriptional repression by nuclear hormone receptors (NHRs). First, we have determined that receptor stoichiometry is a crucial determinant of transcriptional repression mediated by the corepressors N-CoR and SMRT. This provides a molecular explanation for the observation that NHRs repress transcription as dimers but not monomers. Second, corepressor function is restricted by steric effects related to DNA binding in a receptor-specific manner. Thus, although N-CoR and SMRT are capable of binding to several NHRs in solution, they are highly selective about receptor binding on DNA, a context that reflects their in vivo function more accurately. These stoichiometric and steric principles govern specific interactions between corepressors and NHRs, thus providing evidence that N-CoR and SMRT do not serve redundant functions but rather contribute to receptor-specific transcriptional repression.
Zamir
I
I
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Zhang
J
J
Lazar
M A
MA
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors