Phosphatidylinositols as Ligands for Orphan Nuclear Receptors?

Abstract

Phosphatidylinositol lipids are implicated in a broad range of signaling processes, from organization of signaling pathways to vesicle trafficking and control of the actin cytoskeleton. Now, structural studies by Krylova et al . strongly suggest that these lipids may also serve as activating ligands for a class of orphan (so-called because no regulatory ligand was known) nuclear receptors. The authors focused on members of the nuclear receptor 5A subfamily and obtained crystal structures of family members, including mouse mSF-1 and the human proteins hSF-1 and hLRH-1. The proteins showed protein folds characteristic of the ligand-binding domains of other nuclear receptors that are regulated by known ligands. Electron density in the ligand-binding pocket revealed that the bacterially expressed proteins contained lipids. The authors therefore tested binding to lipids from eukaryotic cells and detected preferential binding to phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. Although biological regulation by such lipids remains to be fully explored, mutant proteins designed to disrupt lipid binding had decreased transcriptional activity in a luciferase reporter assay in human HepG2 cells. The rodent receptor appears to have lost ligand binding, and the authors' evolutionary analysis indicated that the most parsimonious hypothesis is that ancestral proteins did bind lipid ligands and that this property was later lost in the rodent protein. The authors note that an ancestral orphan receptor may not have gained ligand binding over the course of evolution, as previously proposed, but rather there may have been repeated loss of ligand binding from a ligand-regulated ancestral protein. I. N. Krylova, E. P. Sablin, J. Moore, R. X. Xu, G. M. Waitt, J. A. MacKay, D. Juzumiene, J. M. Bynum, K. Madauss, V. Montana, L. Lebedeva, M. Suzawa, J. D. Williams, S. P. Williams, R. K. Guy, J. W. Thornton, R. J. Fletterick, T. M. Willson, H. A. Ingraham, Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120 , 343-355 (2005). [PubMed]