Calmodulin Lobes Facilitate Dimerization and Activation of Estrogen Receptor-α.
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.
From the Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
Zhigang
Z
Li
the Department of Chemistry, University of Texas Rio Grande Valley, Edinburgh, Texas 78539, and.
Yonghong
Y
Zhang
From the Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
Andrew C
AC
Hedman
the Department of Chemistry, University of California, Davis, California 95616 jbames@ucdavis.edu.
James B
JB
Ames
From the Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892, david.sacks2@nih.gov.
David B
0000-0003-3100-0735
DB
Sacks
D002147:Calmodulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D055503:Protein Multimerization; D015533:Transcriptional Activation; D014162:Transfection
D002147:Calmodulin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens
breast cancer; calmodulin (CaM); estrogen receptor; receptor structure-function; signaling; structure-function; transcription