Abstract
The binding of lipophilic hormones, retinoids and vitamins to members of the nuclear-receptor superfamily modifies the DNA-binding and transcriptional properties of these receptors, resulting in the activation or repression of target genes. Ligand binding induces conformational changes in nuclear receptors and promotes their association with a diverse group of nuclear proteins, including SRC-1/p160, TIF-2/GRIP-1 and CBP/p300 which function as co-activators of transcription, and RIP-140, TIF-1 and TRIP-1/SUG-1 whose functions are unclear. Here we report that a short sequence motif LXXLL (where L is leucine and X is any amino acid) present in RIP-140, SRC-1 and CBP is necessary and sufficient to mediate the binding of these proteins to liganded nuclear receptors. We show that the ability of SRC-1 to bind the oestrogen receptor and enhance its transcriptional activity is dependent upon the integrity of the LXXLL motifs and on key hydrophobic residues in a conserved helix (helix 12) of the oestrogen receptor that are required for its ligand-induced activation function. We propose that the LXXLL motif is a signature sequence that facilitates the interaction of different proteins with nuclear receptors, and is thus a defining feature of a new family of nuclear proteins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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CREB-Binding Protein
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Conserved Sequence
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DNA / metabolism
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Histone Acetyltransferases
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Humans
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Ligands
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Mice
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nuclear Receptor Coactivator 1
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Nuclear Receptor Coactivator 2
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Nuclear Receptor Interacting Protein 1
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Protein Structure, Secondary
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Estrogen / chemistry
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Receptors, Estrogen / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Trans-Activators*
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Transcription, Genetic*
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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Ligands
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NCOA2 protein, human
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Ncoa2 protein, mouse
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Nuclear Proteins
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Nuclear Receptor Coactivator 2
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Nuclear Receptor Interacting Protein 1
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Receptors, Cytoplasmic and Nuclear
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Receptors, Estrogen
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Recombinant Fusion Proteins
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Trans-Activators
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Transcription Factors
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transcriptional intermediary factor 1
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DNA
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CREB-Binding Protein
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CREBBP protein, human
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Crebbp protein, mouse
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Histone Acetyltransferases
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NCOA1 protein, human
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Ncoa1 protein, mouse
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Nuclear Receptor Coactivator 1