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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites / physiology
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Cell Line, Tumor
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism*
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Evolution, Molecular
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Homeodomain Proteins
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Humans
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Ligands
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Mice
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Models, Molecular
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Phosphatidylinositol Phosphates / chemistry
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Phosphatidylinositol Phosphates / metabolism
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Phosphatidylinositols / chemistry
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Phosphatidylinositols / metabolism*
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Phylogeny
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Protein Binding / physiology
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Protein Structure, Tertiary / physiology
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Receptors, Cytoplasmic and Nuclear / chemistry*
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction / physiology
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Steroidogenic Factor 1
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Transcription Factors / chemistry*
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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Homeodomain Proteins
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Ligands
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NR5A1 protein, human
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NR5A2 protein, human
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Phosphatidylinositol Phosphates
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Phosphatidylinositols
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Receptors, Cytoplasmic and Nuclear
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Steroidogenic Factor 1
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Transcription Factors
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steroidogenic factor 1, mouse
Associated data
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PDB/1YMT
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PDB/1YOK
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PDB/1YOW