Structural Basis for Ca2+-induced Activation and Dimerization of Estrogen Receptor α by Calmodulin

Zhang, Yonghong; Li, Zhigang; Sacks, David B.; Ames, James B.

doi:10.1074/jbc.m111.334797

Cited by 38 publications

(58 citation statements)

References 56 publications

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“…Although the dimerization domain of ER␣ is outside the hinge region, IQGAP1 could enhance ER␣ dimerization, analogous to that produced by calmodulin. Detailed structural analysis reveals that binding of calmodulin to the hinge region of ER␣ promotes dimerization of ER␣ (45). These possible mechanisms are not mutually exclusive, and more than one may be responsible for the effects we observed with IQGAP1.…”

Section: Discussionmentioning

confidence: 78%

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Erdemir¹,

Sacks

2014

Journal of Biological Chemistry

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Background: IQGAP1 is a scaffold protein that modulates diverse signaling pathways. Results: IQGAP1 binds to estrogen receptor-␣ (ER␣) and ER␤, and knockdown of IQGAP1 impairs 17␤-estradiol (E 2 )-stimulated transcriptional activation in human breast epithelial cells. Conclusion: IQGAP1 modulates ER␣ function and is required for maximal E 2 function. Significance: IQGAP1 might be a therapeutic target for patients with breast carcinoma.

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Section: Discussionmentioning

confidence: 78%

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

Erdemir¹,

Sacks

2014

Journal of Biological Chemistry

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“…have sensitivity to estrogens, the candidate receptor might be the E. granulosus SR. Calcium-dependent activation of H. sapiens ER is mediated by CaM, and CaM antagonists prevent 17␤-estradiol from stimulating the transcription (39,40). CaM binds to H. sapiens ER in the hinge domain (residues 248 to 317) and contributes to the ER dimerization and to the ER transcriptional activity in combination with 17␤-estradiol and calcium (39,40). The E. granulosus SR conserves this hydrophobic region in the LBD involved in association with the CaM ER (Fig.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

Nicolao

Elissondo

Denegri

et al. 2014

Antimicrob Agents Chemother

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Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestodeEchinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore thein vitroandin vivoeffects of tamoxifen (TAM) againstE. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival ofE. granulosusprotoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment.

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“…Two helices connected by CaM have been observed or inferred in several instances (Schumacher et al, 2001;Yap et al, 2003;Houdusse et al, 2006;Wang et al, 2008;Fallon et al, 2009;Zhang et al, 2012;Sarhan et al, 2012), although the functional relevance of this engulfing arrangement has on occasion been brought into question (Kim et al, 2010). An organization of this kind is crucial for Ca 2+ -CaM mediated gating of small conductance Ca 2+ -activated K + channels (Schumacher et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Cooperativity between calmodulin-binding sites in Kv7.2 channels

Alaimo

Alberdi

Gomis-Pérez

et al. 2013

Journal of Cell Science

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SummaryAmong the multiple roles assigned to calmodulin (CaM), controlling the surface expression of Kv7.2 channels by binding to two discontinuous sites is a unique property of this Ca 2+ binding protein.Mutations that interfere with CaM binding or the sequestering of CaM prevent this M-channel component from exiting the endoplasmic reticulum (ER), which reduces M-current density in hippocampal neurons, enhancing excitability and offering a rational mechanism to explain some forms of benign familial neonatal convulsions (BFNC). Previously, we identified a mutation (S511D) that impedes CaM binding while allowing the channel to exit the ER, hinting that CaM binding may not be strictly required for Kv7.2 channel trafficking to the plasma membrane. Alternatively, this interaction with CaM might escape detection and, indeed, we now show that the S511D mutant contains functional CaM-binding sites that are not detected by classical biochemical techniques. Surface expression and function is rescued by CaM, suggesting that free CaM in HEK293 cells is limiting and reinforcing the hypothesis that CaM binding is required for ER exit. Within the CaM-binding domain formed by two sites (helix A and helix B), we show that CaM binds to helix B with higher apparent affinity than helix A, both in the presence and absence of Ca 2+ , and that the two sites cooperate. Hence, CaM can bridge two binding domains, anchoring helix A of one subunit to helix B of another subunit, in this way influencing the function of Kv7.2 channels.

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Structural Basis for Ca2+-induced Activation and Dimerization of Estrogen Receptor α by Calmodulin

Cited by 38 publications

References 56 publications

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

IQGAP1 Binds to Estrogen Receptor-α and Modulates Its Function

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

Cooperativity between calmodulin-binding sites in Kv7.2 channels

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