title: Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1.
abstract: Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members-mouse and human SF-1 and human LRH-1-which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.
authors.affiliation: Department of Physiology, University of California, San Francisco, California 94143, USA.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krylova
authors.forename: Elena P
authors.initials: EP
authors.lastname: Sablin
authors.forename: Jamie
authors.initials: J
authors.lastname: Moore
authors.forename: Robert X
authors.initials: RX
authors.lastname: Xu
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Waitt
authors.forename: J Andrew
authors.initials: JA
authors.lastname: MacKay
authors.forename: Dalia
authors.initials: D
authors.lastname: Juzumiene
authors.forename: Jane M
authors.initials: JM
authors.lastname: Bynum
authors.forename: Kevin
authors.initials: K
authors.lastname: Madauss
authors.forename: Valerie
authors.initials: V
authors.lastname: Montana
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Lebedeva
authors.forename: Miyuki
authors.initials: M
authors.lastname: Suzawa
authors.forename: Jon D
authors.initials: JD
authors.lastname: Williams
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: Rodney K
authors.initials: RK
authors.lastname: Guy
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Thornton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Holly A
authors.initials: HA
authors.lastname: Ingraham
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D019143:Evolution, Molecular; D018398:Homeodomain Proteins; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism*; D010802:Phylogeny; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008024:Ligands; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse