Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation.
Ligand-dependent activation of gene transcription by nuclear receptors is dependent on the recruitment of coactivators, including a family of related NCoA/SRC factors, via a region containing three helical domains sharing an LXXLL core consensus sequence, referred to as LXDs. In this manuscript, we report receptor-specific differential utilization of LXXLL-containing motifs of the NCoA-1/SRC-1 coactivator. Whereas a single LXD is sufficient for activation by the estrogen receptor, different combinations of two, appropriately spaced, LXDs are required for actions of the thyroid hormone, retinoic acid, peroxisome proliferator-activated, or progesterone receptors. The specificity of LXD usage in the cell appears to be dictated, at least in part, by specific amino acids carboxy-terminal to the core LXXLL motif that may make differential contacts with helices 1 and 3 (or 3') in receptor ligand-binding domains. Intriguingly, distinct carboxy-terminal amino acids are required for PPARgamma activation in response to different ligands. Related LXXLL-containing motifs in NCoA-1/SRC-1 are also required for a functional interaction with CBP, potentially interacting with a hydrophobic binding pocket. Together, these data suggest that the LXXLL-containing motifs have evolved to serve overlapping roles that are likely to permit both receptor-specific and ligand-specific assembly of a coactivator complex, and that these recognition motifs underlie the recruitment of coactivator complexes required for nuclear receptor function.
McInerney
E M
EM
Howard Hughes Medical Institute, Department and School of Medicine, University of California at San Diego, La Jolla, California 92093-0648 USA.
Rose
D W
DW
Flynn
S E
SE
Westin
S
S
Mullen
T M
TM
Krones
A
A
Inostroza
J
J
Torchia
J
J
Nolte
R T
RT
Assa-Munt
N
N
Milburn
M V
MV
Glass
C K
CK
Rosenfeld
M G
MG
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology; D056920:Nuclear Receptor Coactivator 1; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D017433:Protein Structure, Secondary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology*
D009687:Nuclear Proteins; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1