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J Biol Chem. 2012 Mar 16;287(12):9336-44. doi: 10.1074/jbc.M111.334797. Epub 2012 Jan 23.

Structural basis for Ca2+-induced activation and dimerization of estrogen receptor α by calmodulin.

Author information

1
Department of Chemistry, University of California, Davis, California 95616, USA.

Abstract

The estrogen receptor α (ER-α) regulates expression of target genes implicated in development, metabolism, and breast cancer. Calcium-dependent regulation of ER-α is critical for activating gene expression and is controlled by calmodulin (CaM). Here, we present the NMR structures for the two lobes of CaM each bound to a localized region of ER-α (residues 287-305). A model of the complete CaM·ER-α complex was constructed by combining these two structures with additional data. The two lobes of CaM both compete for binding at the same site on ER-α (residues 292, 296, 299, 302, and 303), which explains why full-length 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 are likely to prevent ubiquitination at these sites and inhibit degradation of ER-α. Mutants of ER-α at the CaM-binding site (W292A and K299A) weaken binding to CaM, and I298E/K299D disrupts estrogen-induced transcription. CaM facilitates dimerization of ER-α in the absence of estrogen, and stimulation of ER-α by either Ca(2+) and/or estrogen may serve to regulate transcription in a combinatorial fashion.

PMID:
22275375
PMCID:
PMC3308758
DOI:
10.1074/jbc.M111.334797
[Indexed for MEDLINE]
Free PMC Article

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