Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors

Ligand-dependent exchange of coactivators and corepressors is the fundament al regulator of nuclear hormone receptor (NHR) function. The interaction su rfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR an d SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferre d corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR in teracts almost exclusively with CoRNR2. Second, the NHR preference for N-Co R or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepress or interaction and preference suggest that repression is regulated by the p ermissibility of selected receptor-CoRNR-corepressor combinations. Interest ingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, s uggesting a model to explain corepressor binding to NHR heterodimers.