Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors.
An alpha-helical motif containing the sequence LXXLL is required for the ligand-dependent binding of transcriptional co-activators to nuclear receptors. By using a peptide inhibition assay, we have defined the minimal "core" LXXLL motif as an 8-amino acid sequence spanning positions -2 to +6 relative to the primary conserved leucine residue. In yeast two-hybrid assays, core LXXLL motif sequences derived from steroid receptor co-activator (SRC1), the 140-kDa receptor interacting protein (RIP140), and CREB-binding protein (CBP) displayed differences in selectivity and affinity for nuclear receptor ligand binding domains. Although core LXXLL motifs from SRC1 and RIP140 mediated strong interactions with steroid and retinoid receptors, three LXXLL motifs present in the global co-activator CBP were found to have very weak affinity for these proteins. Core motifs with high affinity for steroid and retinoid receptors were generally found to contain a hydrophobic residue at position -1 relative to the first conserved leucine and a nonhydrophobic residue at position +2. Our results indicate that variant residues in LXXLL core motifs influence the affinity and selectivity of co-activators for nuclear receptors.
Heery
D M
DM
Department of Biochemistry, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom.dh37@le.ac.uk
Hoare
S
S
Hussain
S
S
Parker
M G
MG
Sheppard
H
H
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein; D002467:Cell Nucleus / Q000378:metabolism; D051548:Histone Acetyltransferases; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D000078723:Nuclear Receptor Interacting Protein 1; D017433:Protein Structure, Secondary; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D047488:Retinoid X Receptors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1