Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1.
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.
Krylova
Irina N
IN
Department of Physiology, University of California, San Francisco, California 94143, USA.
Sablin
Elena P
EP
Moore
Jamie
J
Xu
Robert X
RX
Waitt
Gregory M
GM
MacKay
J Andrew
JA
Juzumiene
Dalia
D
Bynum
Jane M
JM
Madauss
Kevin
K
Montana
Valerie
V
Lebedeva
Lioudmila
L
Suzawa
Miyuki
M
Williams
Jon D
JD
Williams
Shawn P
SP
Guy
Rodney K
RK
Thornton
Joseph W
JW
Fletterick
Robert J
RJ
Willson
Timothy M
TM
Ingraham
Holly A
HA
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*
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