Document Type
Article
Publication Date
3-17-2017
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 Ca2+ via calmodulin (CaM). Here we present the NMR structure of Ca2+-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.
Recommended Citation
Li, Zhigang, Yonghong Zhang, Andrew C. Hedman, James B. Ames, and David B. Sacks. "Calmodulin lobes facilitate dimerization and activation of estrogen receptor-α." Journal of Biological Chemistry 292, no. 11 (2017): 4614-4622. https://doi.org/10.1074/jbc.M116.754804
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Journal of Biological Chemistry
DOI
10.1074/jbc.M116.754804
Comments
© 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. Under http://creativecommons.org/licenses/by/4.0/ license.