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 rec eptor coregulators (NRCs) which modulate the function of nuclear hormone re ceptors in a ligand-dependent manner. NRCs are expressed as alternatively s pliced isoforms which may exhibit different intrinsic activities and recept or specificities. The NRCs are organized into several modular structures an d 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 doma in (AD1), which is as active as the herpesvirus VP16 activation domain, and a second activation domain (AD2) which overlaps with the receptor- interac ting 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 sanity in vivo , suggesting that hNRC may be an important functional component of a CBP co mplex involved in mediating the transcriptional effects of nuclear hormone receptors.