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From Proteopedia
Solution NMR-derived structure of calmodulin N-lobe bound with ER alpha peptide
Structural highlights
FunctionCALM1_XENLA Calmodulin mediates the control of a large number of enzymes, ion channels and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases. Publication Abstract from PubMedThe estrogen receptor alpha (ER-alpha) regulates expression of target genes implicated in development, metabolism, and breast cancer. Calcium-dependent regulation of ER-alpha 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-alpha (residues 287-305). A model of the complete CaM.ER-alpha 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-alpha (residues 292, 296, 299, 302, and 303), which explains why full-length CaM binds two molecules of ER-alpha in a 1:2 complex and stabilizes ER-alpha dimerization. Exposed glutamate residues in CaM (Glu(11), Glu(14), Glu(84), and Glu(87)) form salt bridges with key lysine residues in ER-alpha (Lys(299), Lys(302), and Lys(303)), which are likely to prevent ubiquitination at these sites and inhibit degradation of ER-alpha. Mutants of ER-alpha at the CaM-binding site (W292A and K299A) weaken binding to CaM, and I298E/K299D disrupts estrogen-induced transcription. CaM facilitates dimerization of ER-alpha in the absence of estrogen, and stimulation of ER-alpha by either Ca(2+) and/or estrogen may serve to regulate transcription in a combinatorial fashion. Structural basis for Ca2+-induced activation and dimerization of estrogen receptor alpha by calmodulin.,Zhang Y, Li Z, Sacks DB, Ames JB J Biol Chem. 2012 Mar 16;287(12):9336-44. Epub 2012 Jan 23. PMID:22275375[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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