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Coordinated regulation of bile acid biosynthesis, the predominant pathway for hepatic cholesterol catabolism, is mediated by few key nuclear receptors including the orphan receptors liver receptor homolog 1 (LRH-1), hepatocyte nuclear factor 4[alpha] (HNF4[alpha]), small heterodimer partner (SHP), and the bile acid receptor FXR (farnesoid X receptor). Activation of FXR initiates a feedback regulatory loop via induction of SHP, which suppresses LRH-1- and HNF4[alpha]-dependent expression of cholesterol 7[alpha] hydroxylase (CYPTA1) and sterol12[alpha] hydroxylase (CYP8B1), the two major pathway enzymes. Here we dissect the transcriptional network governing bile acid biosynthesis in human liver by identifying GPS2, a stoichiometric subunit of a conserved corepressor complex, as a differential coregulator of CYP7A1 and CYP8B1 expression. Direct interactions of GPS2 with SHP, LRH-1, HNF4[alpha], and FXR indicate alternative coregulator recruitment strategies to cause differential transcriptional outcomes. In addition, species-specific differences in the regulation of bile acid biosynthesis were uncovered by identifying human CYP8B1 as a direct FXR target gene, which has implications for therapeutic approaches in bile acid-related human disorders. cholesterol 7[alpha] hydroxylase | sterol 12[alpha] hydroxylase | farnesoid X receptor | small heterodimer partner

Recent studies have identified a series of estrogen receptor (ER)-interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER[alpha]-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-[Angstrom] crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the [beta]-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences, In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER[alpha], particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity. coregulator | phage display | structure