Calmodulin Lobes Facilitate Dimerization and Activation of Estrogen Receptor-α

Abstract

Estrogen receptor α (ER-α) is a nuclear hormone receptor that controls selected genes, thereby regulating proliferation and differentiation of target tissues, such as breast. Gene expression controlled by ER-α is modulated by Ca via calmodulin (CaM). Here we present the NMR structure of Ca-CaM bound to two molecules of ER-α (residues 287-305). The two lobes of CaM bind to the same site on two separate ER-α molecules (residues 292, 296, 299, 302, and 303), which explains why CaM binds two molecules of ER-α in a 1:2 complex and stabilizes ER-α dimerization. Exposed glutamate residues in CaM (Glu-11, Glu-14, Glu-84, and Glu-87) form salt bridges with key lysine residues in ER-α (Lys-299, Lys-302, and Lys-303), which is likely to prevent ubiquitination at these sites and inhibit degradation of ER-α. Transfection of cells with full-length CaM slightly increased the ability of estrogen to enhance transcriptional activation by ER-α of endogenous estrogen-responsive genes. By contrast, expression of either the N- or C-lobe of CaM abrogated estrogen-stimulated transcription of the estrogen responsive genes pS2 and progesterone receptor. These data suggest that CaM-induced dimerization of ER-α is required for estrogen-stimulated transcriptional activation by the receptor. In light of the critical role of ER-α in breast carcinoma, our data suggest that small molecules that selectively disrupt the interaction of ER-α with CaM may be useful in the therapy of breast carcinoma.

Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects?

“…By interacting with ERα, CaM plays a key role in the stabilization and transcriptional activity of ERα dimers at the ERE. The agonistic effect of genistein and apigenin in this interaction may also account for the anti-tumor origin of these compounds against ER-positive breast cancers [ 129 , 130 ]. It is, therefore, essential to continue advances in the understanding diverse signaling pathways activated by phytoestrogens, to fully exploit their anticancer properties and/or their potential roles in estrogen-related diseases.…”

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…The anti-estrogenic action of tamoxifen may be explained at least in part by its antagonistic action on CaM, as the estrogen receptor binds and is activated by CaM [327] (reviewed in [328]). In this context, the pineal hormone melatonin has been described as having anti-metastatic properties by interfering with the interaction between CaM and the estrogen receptor preventing its activation (reviewed in [329]).…”

Dynamic NHE1-Calmodulin complexes of varying stoichiometry and structure regulate Ca2+-dependent NHE1 activation

“…CaM-mediated oligomerization has been reported for both soluble and membrane proteins. Examples of the former include the ERα, two of which bind to one Ca 2+ -CaM, one ERα in each lobe, to maximally activate transcription [13,55]. The affinity of ERα for one CaM lobe is almost 100 fold lower than what we see here for NHE1, further supporting a unique role of the 1:1 NH1:CaM complex.…”