scholarly journals Nuclear Hormone Receptor Architecture - Form and Dynamics: The 2009 FASEB Summer Conference on Dynamic Structure of the Nuclear Hormone Receptors

2009 ◽  
Vol 7 (1) ◽  
pp. nrs.07011 ◽  
Author(s):  
Iain J. McEwan ◽  
Ann M. Nardulli
Keyword(s):  
Hormone Receptors ◽  
Structural Information ◽  
Dynamic Structure ◽  
Structural Features ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Fatty Acid Derivatives ◽  
Agonist And Antagonist

Nuclear hormone receptors (NHRs) represent a large and diverse family of ligand-activated transcription factors involved in regulating development, metabolic homeostasis, salt balance and reproductive health. The ligands for these receptors are typically small hydrophobic molecules such as steroid hormones, thyroid hormone, vitamin D3 and fatty acid derivatives. The first NHR structural information appeared ∼20 years ago with the solution and crystal structures of the DNA binding domains and was followed by the structure of the agonist and antagonist bound ligand binding domains of different NHR members. Interestingly, in addition to these defined structural features, it has become clear that NHRs also possess significant structural plasticity. Thus, the dynamic structure of the NHRs was the topic of a recent stimulating and informative FASEB Summer Research Conference held in Vermont.

Spectroscopic Determination of the Binding Affinity of Zinc to the DNA-Binding Domains of Nuclear Hormone Receptors†

Biochemistry ◽  
2003 ◽  
Vol 42 (48) ◽  
pp. 14214-14224 ◽  
Author(s):  
John C. Payne ◽  
Brian W. Rous ◽  
Adam L. Tenderholt ◽  
Hilary Arnold Godwin
Keyword(s):  
Dna Binding ◽  
Binding Affinity ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptors ◽  
Spectroscopic Determination ◽  
Dna Binding Domains ◽  
Binding Domains

scholarly journals PSF Is a Novel Corepressor That Mediates Its Effect through Sin3A and the DNA Binding Domain of Nuclear Hormone Receptors

2001 ◽  
Vol 21 (7) ◽  
pp. 2298-2311 ◽  
Author(s):  
Mukul Mathur ◽  
Philip W. Tucker ◽  
Herbert H. Samuels
Keyword(s):  
Dna Binding ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Binding Domains ◽  
Polypyrimidine Tract Binding Protein

ABSTRACT Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54 nrb . Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.

scholarly journals Mapping and analysis of Caenorhabditis elegans transcription factor sequence specificities

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Kamesh Narasimhan ◽  
Samuel A Lambert ◽  
Ally WH Yang ◽  
Jeremy Riddell ◽  
Sanie Mnaimneh ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Dna Binding ◽  
Regulatory Elements ◽  
Nuclear Hormone Receptor ◽  
Binding Motifs ◽  
T Box ◽  
C Elegans ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Protein Binding Microarray

Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (∼40%). These data highlight the diversification of binding motifs for the nuclear hormone receptor and C2H2 zinc finger families and reveal unexpected diversity of motifs for T-box and DM families. Motif enrichment in promoters of functionally related genes is consistent with known biology and also identifies putative regulatory roles for unstudied TFs.

scholarly journals Alien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily

1999 ◽  
Vol 19 (5) ◽  
pp. 3383-3394 ◽  
Author(s):  
Uwe Dressel ◽  
Dorit Thormeyer ◽  
Boran Altincicek ◽  
Achim Paululat ◽  
Martin Eggert ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Specific Interaction ◽  
Gene Activation ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Reporter Assays

ABSTRACT Some members of nuclear hormone receptors, such as the thyroid hormone receptor (TR), silence gene expression in the absence of the hormone. Corepressors, which bind to the receptor’s silencing domain, are involved in this repression. Hormone binding leads to dissociation of corepressors and binding of coactivators, which in turn mediate gene activation. Here, we describe the characteristics of Alien, a novel corepressor. Alien interacts with TR only in the absence of hormone. Addition of thyroid hormone leads to dissociation of Alien from the receptor, as shown by the yeast two-hybrid system, glutathioneS-transferase pull-down, and coimmunoprecipitation experiments. Reporter assays indicate that Alien increases receptor-mediated silencing and that it harbors an autonomous silencing function. Immune staining shows that Alien is localized in the cell nucleus. Alien is a highly conserved protein showing 90% identity between human and Drosophila. Drosophila Alien shows similar activities in that it interacts in a hormone-sensitive manner with TR and harbors an autonomous silencing function. Specific interaction of Alien is seen with Drosophila nuclear hormone receptors, such as the ecdysone receptor and Seven-up, the Drosophila homologue of COUP-TF1, but not with retinoic acid receptor, RXR/USP, DHR 3, DHR 38, DHR 78, or DHR 96. These properties, taken together, show that Alien has the characteristics of a corepressor. Thus, Alien represents a member of a novel class of corepressors specific for selected members of the nuclear hormone receptor superfamily.

scholarly journals Determinants of CoRNR-Dependent Repression Complex Assembly on Nuclear Hormone Receptors

2001 ◽  
Vol 21 (5) ◽  
pp. 1747-1758 ◽  
Author(s):  
Xiao Hu ◽  
Yun Li ◽  
Mitchell A. Lazar
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Complex Assembly ◽  
Acid Receptor ◽  
Repression Complex ◽  
The Individual

ABSTRACT Ligand-dependent exchange of coactivators and corepressors is the fundamental regulator of nuclear hormone receptor (NHR) function. The interaction surfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR and SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferred corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR interacts almost exclusively with CoRNR2. Second, the NHR preference for N-CoR or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepressor interaction and preference suggest that repression is regulated by the permissibility of selected receptor-CoRNR-corepressor combinations. Interestingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, suggesting a model to explain corepressor binding to NHR heterodimers.

scholarly journals Specific Structural Motifs Determine TRAP220 Interactions with Nuclear Hormone Receptors

2000 ◽  
Vol 20 (15) ◽  
pp. 5433-5446 ◽  
Author(s):  
Yunsheng Ren ◽  
Evan Behre ◽  
Zhaojun Ren ◽  
Jiachang Zhang ◽  
Qianben Wang ◽  
...  
Keyword(s):  
Single Molecule ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Site Directed Mutagenesis ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Amino Terminal ◽  
Binding Domains

ABSTRACT The TRAP coactivator complex is a large, multisubunit complex of nuclear proteins which associates with nuclear hormone receptors (NRs) in the presence of cognate ligand and stimulates NR-mediated transcription. A single subunit, TRAP220, is thought to target the entire complex to a liganded receptor through a domain containing two of the signature LXXLL motifs shown previously in other types of coactivator proteins to be essential for mediating NR binding. In this work, we demonstrate that each of the two LXXLL-containing regions, termed receptor binding domains 1 and 2 (RBD-1 and RBD-2), is differentially preferred by specific NRs. The retinoid X receptor (RXR) displays a weak yet specific activation function 2 (AF2)-dependent preference for RBD-1, while the thyroid hormone receptor (TR), vitamin D3 receptor (VDR), and peroxisome proliferator-activated receptor all exhibit a strong AF2-dependent preference for RBD-2. Using site-directed mutagenesis, we show that preference for RBD-2 is due to the presence of basic-polar residues on the amino-terminal end of the core LXXLL motif. Furthermore, we show that the presence and proper spacing of both RBD-1 and RBD-2 are required for an optimal association of TRAP220 with RXR-TR or RXR-VDR heterodimers bound to DNA and for TRAP220 coactivator function. On the basis of these results, we suggest that a single molecule of TRAP220 can interact with both subunits of a DNA-bound NR heterodimer.

scholarly journals How to overcome the ATRA resistance with the 9aaTAD activation domains in retinoic acid receptors

2018 ◽  
Author(s):  
Martin Piskacek ◽  
Marek Havelka ◽  
Andrea Knight
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptors ◽  
Activation Function ◽  
Receptor Activation ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Loss Of Function ◽  
Activation Domains ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

AbstractIn higher metazoa, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor cofactors NCoA, which are surprisingly absent in lower metazoa. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor activates transcription as a small peptide. We showed, that the 9aaTAD domains are conserved in the human nuclear hormone receptors including HNF4, RARa, VDR and PPARg. The small 9aaTAD peptides derived from these nuclear hormone receptors also effectively activated transcription and that in absence of the NCoA adaptors. We identified adjacent inhibitory domains in the human HNF4 and RARa, which hindered their activation function.In acute promyelocytic leukaemia (PML-RARa), the receptor mutations often caused all-trans retinoic acid (ATRA) resistance. The fact that almost the entire receptor is needed for ATRA mediated receptor activation, this activation pathway is highly susceptible for loss of function when mutated. Nevertheless in the most of the reported mutants, the activation domains 9aaTAD are still intact. The release of activation 9aaTAD from its dormancy by a new drug might be the sound strategy in combat the ATRA resistance in PML leukaemia.Graphical Abstract

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