Coactivators PGC-1beta and SRC-1 interact functionally to promote the agonist activity of the selective estrogen receptor modulator tamoxifen.
PGC-1beta is a transcriptional coactivator that enhances strongly and in a hormone-dependent manner the activity of the estrogen receptor alpha (ERalpha) while having only weak effects on similar steroid hormone receptors, such as ERbeta or the glucocorticoid receptor. Notably, PGC-1beta enhances ERalpha transcriptional activity not only in response to agonist ligands, such as estradiol, but also to selective ER modulators, such as tamoxifen. Here, we dissect the molecular mechanisms underlying the ability of PGC-1beta to act selectively on ERalpha and to promote the agonist activity of tamoxifen. We show that receptor selectivity is achieved by PGC-1beta interactions with not just the ligand binding domain (LBD), which is highly conserved among nuclear receptors, but also the N-terminal domain and the hinge/AF-2a region of ERalpha, which are less well conserved. PGC-1beta interacts directly with the hinge/AF-2a and LBD regions but indirectly and via the coactivator SRC-1 with the N-terminal domain. The three ERalpha surfaces and SRC-1 collectively enable efficient coactivation by PGC-1beta. Similar ERalpha surfaces and interactions enable PGC-1beta to coactivate transcription by tamoxifen-bound ERalpha. Surprisingly, PGC-1beta coactivation of tamoxifen-bound ERalpha depends partially on one of the LXXLL motifs of PGC-1beta and on Lys(362) of the ERalpha LBD (i.e. surfaces implicated in agonist-dependent interactions). Our findings suggest that tamoxifen-induced changes in the ERalpha LBD promote interactions with the coactivator PGC-1beta, which then cooperates with SRC-1 to enable tamoxifen agonism.
Kressler
Dieter
D
Division of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
Hock
M Benjamin
MB
Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037.
Kralli
Anastasia
A
Division of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland; Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037. Electronic address: kralli@scripps.edu.
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000737:chemistry / Q000502:physiology; D051548:Histone Acetyltransferases / Q000502:physiology*; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000502:physiology*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D020845:Selective Estrogen Receptor Modulators; D014157:Transcription Factors; D013629:Tamoxifen; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1