Thyroid Hormone Response Element Organization Dictates the Composition of Active Receptor

Velasco, L.; Togashi, Marie; Walfish, Paul G.; Pessanha, Rutineia de Paula; Moura, Fanny N.; Barra, Gustavo Barcelos; Nguyen, Phuong; Rebong, Rachelle; Yuan, Chaoshen; Simeoni, Luiz Alberto; Ribeiro, Ralff C. J.; Baxter, John D.; Webb, Paul; Neves, Francisco Assis Rocha

doi:10.1074/jbc.m610700200

Cited by 66 publications

(60 citation statements)

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“…DNA and/or additional transcription factors may play a role in this preselection process. DNA may also play a role in the allosteric control of coactivator binding and dimerization as suggested for TR where the binding of the SRC-1 RID is influenced by the nature of the DNA response elements (10,33). An allosteric communication between SRC-1 and DNA was reported for RXR-TR (34) and RXR-VDR (35).…”

Section: Discussionmentioning

confidence: 99%

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Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.allostery | structure T he superfamily of nuclear receptors (NRs) comprises liganddependent transcription factors involved in the regulation of gene expression. They constitute key drug targets for human diseases such as cancer, osteoporosis, obesity, or type II diabetes (1-2). NRs share a common structural organization with a variable amino-terminal domain, a conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) linked by a flexible hinge peptide. In addition to the ligand-binding pocket, the LBD comprises dimerization surfaces and the sites for coregulator interactions. In the classic mode of action, in absence of ligand, some NRs are associated with corepressors (NCoRs) that harbor histone-deacetylase activity to maintain the chromatin in a transcriptionally silent state (3-4). Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).The vast majority of NRs functions as dimers. RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8-10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 c...

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Section: Discussionmentioning

confidence: 99%

“…RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8)(9)(10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 coactivator (11).…”

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confidence: 99%

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The primary sequence and 3D structure of TRα1 and TRβ1 are very similar, although differences are observed for key amino acids in the DNA-binding domain (9)(10)(11)(12). In most in vitro and cellular assays, they behave equally, even if TRα1 has a slightly higher affinity for T3 and is less prone to form homodimers in the absence of ligand (13). By contrast, genetic data indicate that the two receptors have very different functions in vivo.…”

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confidence: 99%

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

Chatonnet

Guyot

Galand

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

109

100

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TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.

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“…In other assays, however, T 4 has been found to be of lower potency than T 3 and TRIAC (5,7,8). Because various NRs, including estrogen and glucocorticoid receptors and TRs, undergo specific conformational changes upon binding to different response elements, resulting in selective recruitment of coactivator/corepressor proteins and ultimately altering the transcriptional response to a particular ligand (25,35,(46)(47)(48)(49), we wondered whether the higher relative potency of T 4 in our hands might be due to a selective stabilizing effect of the heterodimer partner RXR, the TRE, or the coactivator components on the TR-T 4 complex relative to the TR-T 3 complex.From ligand dissociation rate measurements, we found that the rapid T 4 dissociation from TR was moderated to some extent by the addition of TRE, but T 3 dissociation was unaffected. Given the fact that circulating levels of free T 4 is ~7-times higher than that of T 3 in humans (50), this suggests that T 4 might have greater effectiveness in vivo, despite its lower affinity for TR.…”

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confidence: 99%

Quantification of Ligand-Regulated Nuclear Receptor Corepressor and Coactivator Binding, Key Interactions Determining Ligand Potency and Efficacy for the Thyroid Hormone Receptor

et al. 2008

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The potency and efficacy of ligands for nuclear receptors (NR) result both from the affinity of the ligand for the receptor and the affinity that various coregulatory proteins have for ligand-receptor complexes; the latter interaction, however, is rarely quantified. To understand the molecular basis for ligand potency and efficacy, we developed dual time-resolved fluorescence resonance energy transfer (tr-FRET) assays and quantified both ligand and coactivator/corepressor binding to the thyroid hormone receptor (TR). Promoter-bound TR exerts dual transcriptional regulatory functions, recruiting corepressor proteins and repressing transcription in absence of thyroid hormones (THs), and shedding corepressors in favor of coactivators upon binding agonists, activating transcription. Our tr-FRET assays involve a TRE sequence labeled with terbium (fluorescence donor), TRβ•RXRα heterodimer and fluorescein-labeled NR interaction domains of coactivator SRC3 or corepressor NCoR (fluorescence acceptors). Through coregulator titrations, we could determine the affinity of SRC3 or NCoR for TRE-bound TR•RXR heterodimers, unliganded or saturated with different THs. Alternatively, through ligand titrations, we could determine the relative potencies of different THs. TR agonist potencies were GC-1~T 3~T RIAC~T 4 >>rT 3 , for both coactivator recruitment and corepressor dissociation; the affinity of SRC3 binding to TR-ligand complexes followed a similar trend. This highlights that the low activity of rT 3 derives both from its low affinity for TR and the low affinity of SRC for the TR-rT 3 complex. The TR antagonist NH-3 failed to induce SRC3 recruitment but did effect NCoR dissociation. These assays provide quantitative information on the affinity of two key interactions that are determinants of NR ligand potency and efficacy.Our evolving understanding of the processes by which nuclear receptors (NRs) regulate gene transcription has revealed an increasing number of protein partners with which a receptor interacts to alter chromatin architecture and nucleosome structure, and to regulate the activity of RNA polymerase II. The best characterized proximal protein partners of the NRs are the p160 coactivators, exemplified by the steroid receptor coactivator 3 (SRC3), and corepressors, exemplified by nuclear receptor corepressor (NCoR). Both of these proteins interact with the NRs through specific nuclear receptor interaction domains (NRID) in a ligand-dependent manner, with the corepressor binding to unliganded or antagonist-liganded NR states that Address Correspondence to: John A. Katzenellenbogen, Department of Chemistry and University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801, USA, 217 333 6310 (phone), 217 333 7325 (fax), jkatzene@uiuc.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 October 28. Published in final edited form as:Biochemistry. While in general, the potency of a NR ligand is related to the affinity with which it binds to its cognate receptor, poten...

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Thyroid Hormone Response Element Organization Dictates the Composition of Active Receptor

Cited by 66 publications

References 57 publications

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

Quantification of Ligand-Regulated Nuclear Receptor Corepressor and Coactivator Binding, Key Interactions Determining Ligand Potency and Efficacy for the Thyroid Hormone Receptor

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