A Signature Motif in Transcriptional Co-Activators Mediates Binding to Nuclear Receptors

Nature. 1997 Jun 12;387(6634):733-6. doi: 10.1038/42750.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • CREB-Binding Protein
  • Conserved Sequence
  • DNA / metabolism
  • Histone Acetyltransferases
  • Humans
  • Ligands
  • Mice
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Interacting Protein 1
  • Protein Structure, Secondary
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Trans-Activators*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Ligands
  • NCOA2 protein, human
  • Ncoa2 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Interacting Protein 1
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • transcriptional intermediary factor 1
  • DNA
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1