A new family of nuclear receptor coregulators that integrate nuclear receptor signaling through CREB-binding protein.
We describe the cloning and characterization of a new family of nuclear receptor coregulators (NRCs) which modulate the function of nuclear hormone receptors in a ligand-dependent manner. NRCs are expressed as alternatively spliced isoforms which may exhibit different intrinsic activities and receptor specificities. The NRCs are organized into several modular structures and contain a single functional LXXLL motif which associates with members of the steroid hormone and thyroid hormone/retinoid receptor subfamilies with high affinity. Human NRC (hNRC) harbors a potent N-terminal activation domain (AD1), which is as active as the herpesvirus VP16 activation domain, and a second activation domain (AD2) which overlaps with the receptor-interacting LXXLL region. The C-terminal region of hNRC appears to function as an inhibitory domain which influences the overall transcriptional activity of the protein. Our results suggest that NRC binds to liganded receptors as a dimer and this association leads to a structural change in NRC resulting in activation. hNRC binds CREB-binding protein (CBP) with high affinity in vivo, suggesting that hNRC may be an important functional component of a CBP complex involved in mediating the transcriptional effects of nuclear hormone receptors.
Mahajan
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Division of Clinical and Molecular Endocrinology, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
Samuels
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D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein; D003001:Cloning, Molecular; D019281:Dimerization; D017405:Herpes Simplex Virus Protein Vmw65 / Q000737:chemistry / Q000378:metabolism; D006728:Hormones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D056918:Nuclear Receptor Coactivators; D011487:Protein Conformation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D017405:Herpes Simplex Virus Protein Vmw65; D006728:Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C486559:NCOA6 protein, human; C486560:Ncoa6 protein, rat; D009687:Nuclear Proteins; D056918:Nuclear Receptor Coactivators; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494365:Crebbp protein, rat