Calmodulin Lobes Facilitate Dimerization and Activation of Estrogen Receptor-?.

ABSTRACT: Estrogen receptor ? (ER-?) 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-? is modulated by Ca2+ via calmodulin (CaM). Here we present the NMR structure of Ca2+-CaM bound to two molecules of ER-? (residues 287-305). The two lobes of CaM bind to the same site on two separate ER-? molecules (residues 292, 296, 299, 302, and 303), which explains why CaM binds two molecules of ER-? in a 1:2 complex and stabilizes ER-? dimerization. Exposed glutamate residues in CaM (Glu-11, Glu-14, Glu-84, and Glu-87) form salt bridges with key lysine residues in ER-? (Lys-299, Lys-302, and Lys-303), which is likely to prevent ubiquitination at these sites and inhibit degradation of ER-?. Transfection of cells with full-length CaM slightly increased the ability of estrogen to enhance transcriptional activation by ER-? 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-? is required for estrogen-stimulated transcriptional activation by the receptor. In light of the critical role of ER-? in breast carcinoma, our data suggest that small molecules that selectively disrupt the interaction of ER-? with CaM may be useful in the therapy of breast carcinoma.

SUBMITTER: Li Z 

PROVIDER: S-EPMC5377777 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature