Structure and Dynamics of the Liver Receptor Homolog 1-PGC1? Complex.

ABSTRACT: Peroxisome proliferator-activated gamma coactivator 1-? (PGC1?) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1? binding partners is liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1? is known to bind and activate LRH-1, mechanisms through which PGC1? changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1? complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1? with higher affinity than to the coactivator, nuclear receptor coactivator-2 (Tif2), in coregulator peptide recruitment assays. We present the first crystal structure of the LRH-1-PGC1? complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1? induced correlated atomic motion throughout the entire LRH-1 activation function surface, which was dependent on charge-clamp formation. In contrast, Tif2 induced weaker signaling at the activation function surface than PGC1? but promoted allosteric signaling from the helix 6/?-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1? interaction and may illuminate strategies for selective therapeutic targeting of PGC1?-dependent LRH-1 signaling pathways.

SUBMITTER: Mays SG 

PROVIDER: S-EPMC5452058 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature