Corepressor recruitment by agonist-bound nuclear receptors.
Members of the nuclear receptor superfamily are ligand-regulated transcription factors that are composed of a series of conserved domains. These receptors are targets of a wide range of lipophilic signaling molecules that modulate many aspects of physiology and metabolism. Binding of cognate ligands to receptors induces a conformational change in the ligand binding domain (LBD) that creates a pocket for recruitment of coregulatory proteins, which are essential for ligand-dependent regulation of transcription. Several coregulatory proteins that interact with hormone-bound receptors contain characteristic helical LXXLL motifs, known as nuclear receptor (NR) boxes. Generally, ligand binding to receptors is associated with activation of transcription, and most of the NR box-containing proteins characterized to date are coactivators. However, a full understanding of the function of hormone-bound receptors must also incorporate their recruitment of corepressors. The recent identification of ligand-dependent corepressor (LCoR) is a case in point. LCoR contains a single NR box that mediates its hormone-dependent interaction with several nuclear receptors. It functions as a molecular scaffold that recruits several proteins that function in transcriptional repression. Remarkably, although the two proteins share only very limited homology, LCoR and another NR box-containing corepressor RIP140 recruit similar cofactors implicated in transcriptional repression, suggesting many parallels in their mechanisms of action. Corepressors such as LCoR and RIP140 may function in negative feedback loops to attenuate hormone-induced transactivation, act more transiently as part of a cycle of cofactors recruited to target promoters by ligand-bound receptors, or function in hormone-induced target gene repression.
White
John H
JH
Department of Physiology, McGill University, McIntyre Medical Sciences Bldg, Montreal, Quebec H3G 1Y6, Canada.
Fernandes
Isabelle
I
Mader
Sylvie
S
Yang
Xiang-Jiao
XJ
D048868:Adaptor Proteins, Signal Transducing; D000429:Alcohol Oxidoreductases; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009687:Nuclear Proteins / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D000078723:Nuclear Receptor Interacting Protein 1; D010750:Phosphoproteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C472166:LCOR protein, human; D008024:Ligands; C539130:NCOR2 protein, human; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D000078723:Nuclear Receptor Interacting Protein 1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D006655:Histone Deacetylases