title: A signature motif in transcriptional co-activators mediates binding to nuclear receptors.
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.
authors.affiliation: Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Heery
authors.forename: E
authors.initials: E
authors.lastname: Kalkhoven
authors.forename: S
authors.initials: S
authors.lastname: Hoare
authors.forename: M G
authors.initials: MG
authors.lastname: Parker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D050882:CREB-Binding Protein; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D000078723:Nuclear Receptor Interacting Protein 1; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008024:Ligands; C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D000078723:Nuclear Receptor Interacting Protein 1; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1; D004247:DNA; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1