Rsk2 allosterically activates estrogen receptor α by docking to the hormone-binding domain

We describe a novel mechanism for transcriptional regulation, in which docking of p90 ribosomal S6 kinase 2 (Rsk2) to the hormone-binding domain (HBD) of estrogen receptor alpha (ER alpha) induces a conformational change that enhances the transcriptional activation function contained in the HBD. A constitutively active mutant of Rsk2 specifically enhances ER alpha -mediated transcription by phosphorylation of Ser167 in ER alpha and by physically associating with residues 326-394 of the ER alpha HBD, The anti-estrogen 4-hydroxytamoxifen blocks Rsk2-mediated activation of ERa, by inducing a conformation of ER alpha in which the Rsk2 docking site is masked. Transcriptional activation and docking are specific for ER alpha and do not occur with the related isoform, ER beta. ER alpha phosphorylation, docking and transcriptional activation are regulated by the Rsk2 N-terminal kinase domain. The allosteric regulation of a target protein, independent of phosphorylation, may be paradigmatic of a general function for protein kinase docking sites.