Dynamic and Ligand-Selective Interactions of Vitamin D Receptor with Retinoid X Receptor and Cofactors in Living Cells

Choi, Mihwa; Yamada, Sachiko; Makishima, Makoto

doi:10.1124/mol.111.074138

Cited by 26 publications

(25 citation statements)

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“…pCMX-FLAG-VDR, pCMX-VP16-VDR, pCMX-GAL4-SRC-1, pC-MX-GAL4-N-CoR, pCMX-GAL4-SMRT, Spp×3-tk-LUC, hCYP3A4-ER6×3-tk-LUC, and MH100 (UAS)×4-tk-LUC were previously reported. 3,6,16) Mutations were introduced into pCMX-FLAG-VDR using a QuikChange Site-Directed Mutagenesis kit (Agilent Technologies, Santa Clara, CA, U.S.A.) and pCMX-FLAG-VDR mutants were sequenced before use to verify DNA sequence fidelity.…”

Section: Methodsmentioning

confidence: 99%

“…3) Although the role of VDR in mediating the biological effects of 1,25(OH) 2 D 3 has been investigated for decades, an understanding of the biology of VDR regulation by LCA is only now emerging.…”

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confidence: 99%

“…1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes. 2,3) While corepressors bind to the VDR-RXR heterodimer in the absence of ligand, the ligand binding reduces the affinity of corepressors and increases the affinity for coactivators, a structural transition that induces transcription of specific genes. The VDR-RXR heterodimer binds preferentially to a DNA response element that consists of a two hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides (DR3).…”

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confidence: 99%

“…3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 .…”

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confidence: 99%

“…Vitamin D receptor (VDR; NR1I1) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], in numerous physiological and pharmacological processes, including bone and calcium metabolism, cellular growth and differentiation, immunity, and cardiovascular function. 1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes.…”

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confidence: 99%

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Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

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1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes.2,3) While corepressors bind to the VDR-RXR heterodimer in the absence of ligand, the ligand binding reduces the affinity of corepressors and increases the affinity for coactivators, a structural transition that induces transcription of specific genes. The VDR-RXR heterodimer binds preferentially to a DNA response element that consists of a two hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides (DR3).4) The DR3 VDRbinding element has been identified in the regulatory regions of many target genes, including cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), cathelicidin antimicrobial peptide (CAMP), and osteopontin.2,4) An everted repeat of the hexanucleotide motif separated by six nucleotides (ER6) is another VDR-binding element that regulates expression of the human CYP3A4 gene.2) Dynamic and coordinated interactions of VDR with RXR and cofactor complexes are required for the efficient regulation of transcription.3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 . 9) Indeed, LCA induces the interaction of VDR with RXR, steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in a manner distinct from 1,25(OH) 2 D 3 in cells.3)Although the role of VDR in mediating the biological effects of 1,25(OH) 2 D 3 has been investigated for decades, an understanding of the biology of VDR regulation by LCA is only now emerging.Hairless (HR) is a nuclear protein that functions as a corepressor of nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors and VDR.10-12) HR interacts with VDR via multiple protein-protein interfaces in the absence of ligand and represses VDR transactivation by 1,25(OH) 2 D 3 and LCA.12,13) Interestingly, LCA but not 1,25(OH) 2 D 3 enhances the interaction, 12) suggesting that LCA induces a conformation of the VDR-RXR heterodimer with enhanced affinity for HR binding. In both mice and humans, mutation of HR results in hair-loss phenotypes similar to VDR mutation, suggesting a functional interaction of HR and VDR in vivo. 14) In contrast to the in vitro interaction, 1,25(OH) 2 D 3 treatment decreases HR binding to VDR in keratinocytes. 15) Although the in vivo role of HR in VDR function remains ...

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Section: Methodsmentioning

confidence: 99%

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