The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1
Year: 2014
Type: article
Abstract: The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, U.S. Department of Energy, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1229526393, INHIBITION OF PANCREATIC CANCER CELL PROLIFERATION BY LRH-1 INHIBITORS, G1239756754, G1286251239, Mapping Hypothalamic Neurocircuits Controlling Physical Activity, G1831385526, G1984473900, G2300450775, G2371548206, Mechanisms of regulation of LRH-1, Nanog and SF-1 by DAX-1, G262532246, G303061748, G315621713, G3175282201, G4047395780, G4119534169, G4235786860, G4581610328, G495301720, G498139845, G501232126, G510075810, G5570207115, G5850682332, G6550344761, G7283024673, Structures of Protein Complexes Regulating Transcription in Enbryonic Stem Cells, G8382000481, Diabetes Research Center, Cancer cell signaling through lipids complexed to proteins, G8925327636, G9000069621, G9000140088, G9000327983, G9000331358, G9000346532, G911061179, G941334431, G969889393
OpenAlex ID: W2024955650