Coactivators PGC-1β and SRC-1 interact functionally to promote the agonist activity of the selective estrogen receptor modulator tamoxifen

PGC-1β is a transcriptional coactivator that enhances strongly and in a hormone-dependent manner the activity of the estrogen receptor α (ERα) while having only weak effects on similar steroid hormone receptors, such as ERβ or the glucocorticoid receptor. Notably, PGC-1β enhances ERα 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-1β to act selectively on ERα and to promote the agonist activity of tamoxifen. We show that receptor selectivity is achieved by PGC-1β 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 ERα, which are less well conserved. PGC-1β 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 ERα surfaces and SRC-1 collectively enable efficient coactivation by PGC-1β. Similar ERα surfaces and interactions enable PGC-1β to coactivate transcription by tamoxifen-bound ERα. Surprisingly, PGC-1β coactivation of tamoxifen-bound ERα depends partially on one of the LXXLL motifs of PGC-1β and on Lys ³⁶² of the ERα LBD (i.e. surfaces implicated in agonist-dependent interactions). Our findings suggest that tamoxifen-induced changes in the ERα LBD promote interactions with the coactivator PGC-1β, which then cooperates with SRC-1 to enable tamoxifen agonism.