Biologjia Online

Vertebrate nuclear receptors SF-1 and LRH-1 regulate crucial aspects of development, endocrine homeostasis, and metabolism. Both have been categorized as orphan receptors since their corresponding ligands have thus far not been identified. Here Krylova et al. present structural analyses revealing that these receptors bind phospholilpids. Further studies show that phosphatidyl inositol phosphates are candidate ligands and are required for optimal receptor activity. Intriguingly, evolutionary analysis indicates that ligand binding is the ancestral state of these receptors but was uniquely diminished or altered in the rodent LRH-1 lineage. These results identify SF-1 and LRH-1 as novel mediators of phospholipid signaling.