Evolution of the thyroid hormone, retinoic acid, ecdysone and liver X receptors (original) (raw)
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Evolution of the nuclear receptor family
The EMBO Journal
Nuclear receptor genes represent a large family of genes encoding receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. This family also contains genes encoding putative receptors for unknown ligands. Nuclear receptor gene products are composed of several domains important for transcriptional activation, DNA binding (C domain), hormone binding and dinerization (E domain). It is not known whether these genes have evolved through gene duplication from a common ancestor or if their different domains came from different independent sources. To test these possibilities we have constructed and compared the phylogenetic trees derived from two different domains of 30 nuclear receptor genes. The tree built from the DNA binding C domain clearly shows a common progeny of all nuclear receptors, which can be grouped into three subfamilies: (i) thyroid hormone and retinoic acid receptors, (ii) orphan receptors and (iii) steroid honnone receptors. The tree constructed from the central part of the E domain which is implicated in transcriptional regulation and dimerization shows the same distribution in three subfamilies but two groups of receptors are in a different position from that in the C domain tree: (i) the Drosophila knirps family genes have acquired very different E domains during evolution, and (li) the vitamin D and ecdysone receptors, as well as the FTZ-F1 and the NGF1B genes, seem to have DNA binding and hormone binding domains belonging to different classes. These data suggest a complex evolutionary history for nuclear receptor genes in which gene duplication events and swapping between domains of different origins took place.
Nuclear Hormone Receptors and Evolution
Integrative and Comparative Biology, 1999
SYNOPSIS. The nuclear receptor (NR) superfamily includes, in addition to ligandactivated transcription factors, members called orphan receptors, for which no ligand has yet been identified. Phylogenetic analysis shows that the nuclear receptor superfamily can be split into six subfamilies. Interestingly, there appears to be no relationship between the position of a given liganded receptor in the tree and the chemical nature of its ligand. For example, RAR and RXR, which both recognize retinoids, belong to two different subfamilies, suggesting an independence between the evolutionary history of the receptors and their ligand binding abilities. A PCR screen for the presence of NR genes in several phyla of early-and nonmetazoan organisms suggests that NR are specific to metazoans and also reveals that the NR genes in Hydra or Anemonia appear to be limited to homoiogues of orphan receptors. Taken together these data suggest that the first members of the superfamily were probably orphan receptors that later on gained the ability to bind a ligand. Finally, we observed that SmFTZ-Fl and SmRXR are expressed at different levels along the life cycle of the parasitic flatworm Schistosoma mansoni.
Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR
Molecular and Cellular Endocrinology, 2011
Nuclear hormone receptors (NHRs) are transcription factors that work in concert with coactivators and co-repressors to regulate gene expression. Some examples of ligands for NHRs include endogenous compounds such as bile acids, retinoids, steroid hormones, thyroid hormone, and vitamin D. This review describes the evolution of liver X receptors α and β (NR1H3 and 1H2, respectively), farnesoid X receptor (NR1H4), vitamin D receptor (NR1I1), pregnane X receptor (NR1I2), and constitutive androstane receptor (NR1I3). These NHRs participate in complex, overlapping transcriptional regulation networks involving cholesterol homeostasis and energy metabolism. Some of these receptors, particularly PXR and CAR, are promiscuous with respect to the structurally wide range of ligands that act as agonists. A combination of functional and computational analyses has shed light on the evolutionary changes of NR1H and NR1I receptors across vertebrates, and how these receptors may have diverged from ancestral receptors that first appeared in invertebrates.
A Mollusk Retinoic Acid Receptor (RAR) Ortholog Sheds Light on the Evolution of Ligand Binding
Endocrinology, 2014
Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms.
Evolutionary genomics of nuclear receptors: from 25 ancestral genes to derived endocrine
2014
Bilaterian animals are notably characterized by complex endocrine systems. The receptors for many steroids, retinoids, and other hormones belong to the superfamily of nuclear receptors, which are transcription factors regulating many aspects of development and homeostasis. Despite a diversity of regulatory mechanisms and physiological roles, nuclear receptors share a common protein organization. To obtain the broad picture of bilaterian nuclear hormone receptor evolution, we have characterized the complete set of nuclear receptor genes from nine animal genome sequences and analyzed it in a phylogenetic framework. In addition, expressed sequence tags from key lineages with no available genome sequence were also searched. This allows us to date the evolutionary events that led from an ancestral nuclear receptor gene, in an early metazoan, to present day diversity. We show that there were ;25 nuclear receptor genes in Urbilateria, the ancestor of bilaterians, at which point the fundamental diversity of the subfamily was already established. Surprisingly, differential gene loss played an important role in the evolution of different nuclear receptor sets in bilaterian lineages. The nuclear receptor distribution was also shaped by periods of gene duplication, essentially in vertebrates, as well as a lineage-specific duplication burst in nematodes. Our results imply that the genes for major receptors such as steroid receptors or thyroid hormone receptors were present in Urbilateria.
Evolutionary genomics of nuclear receptors: from 25 ancestral genes to derived endocrine systems
2000
Bilaterian animals are notably characterized by complex endocrine systems. The receptors for many steroids, retinoids, and other hormones, belong to the superfamily of nuclear receptors, which are transcription factors regulating many aspects of development and homeostasis. Despite a diversity of regulatory mechanisms and of physiological roles, nuclear receptors share a common protein organization. To obtain the broad picture of bilaterian nuclear hormone receptor evolution, we have characterized the complete set of nuclear receptor genes from nine animal genome sequences, and analyzed it in a phylogenetic framework. In addition, Expressed Sequence Tags from key lineages with no available genome sequence were also searched. This allows us to date the evolutionary events which led from an ancestral nuclear receptor gene, in an early metazoan, to present day diversity. We show that there were ca. 25 nuclear receptor genes in Urbilateria, the ancestor of bilaterians, at which point the fundamental diversity of the subfamily was already established.
Molecular Biology and Evolution, 2004
Bilaterian animals are notably characterized by complex endocrine systems. The receptors for many steroids, retinoids, and other hormones belong to the superfamily of nuclear receptors, which are transcription factors regulating many aspects of development and homeostasis. Despite a diversity of regulatory mechanisms and physiological roles, nuclear receptors share a common protein organization. To obtain the broad picture of bilaterian nuclear hormone receptor evolution, we have characterized the complete set of nuclear receptor genes from nine animal genome sequences and analyzed it in a phylogenetic framework. In addition, expressed sequence tags from key lineages with no available genome sequence were also searched. This allows us to date the evolutionary events that led from an ancestral nuclear receptor gene, in an early metazoan, to present day diversity. We show that there were ;25 nuclear receptor genes in Urbilateria, the ancestor of bilaterians, at which point the fundamental diversity of the subfamily was already established. Surprisingly, differential gene loss played an important role in the evolution of different nuclear receptor sets in bilaterian lineages. The nuclear
Minireview: Structural and Functional Evolution of the Thyrotropin Receptor
Endocrinology, 2004
TSH receptor (TSHR) is a member of the leucine-rich repeatcontaining G protein-coupled receptors. Both TSHR and its ligand TSH have evolved to acquire specificity, minimize cross-reaction to other glycoprotein hormone receptors, and modulate cognate interaction (and thereby thyrotropic activity). TSHR sequences available from two life orders, teleost and mammals, were analyzed. Teleost TSHRs with low affinity are expressed in many nonthyroidal tissues and show a tendency to gene duplication. In some teleosts, TSHR has limited specificity, and in others extremely high constitutive activity, suggesting the possibility of ligand-independent receptor function. Although mammalian TSHR, in contrast to other glycoprotein hormone receptors, maintains relatively high constitutive activity, the thyrotropic activity of TSH appears to decline in hominoids including humans, probably as part of metabolic adaptation to the changing environment. Critical TSHR residues that determine hormone specificity have been identified in the leucine-rich repeats, and others within the cysteine-rich C-flanking region that determines hormonal activation as well as receptor silencing. Transmembrane (TM) helices, particularly the TM5 and TM6, are likely involved in receptor homodimerization and a unique motif in TM7 appears essential to receptor silencing and internalization. Surprisingly, ternary structures in the intracellular domain as opposed to specific sequence motifs are critical for intracellular TSHR trafficking. It is evident that progress in understanding structure-function relationships of TSHR and its ligand can be further stimulated by inclusion of evolutionary analysis of their primary, secondary and tertiary structure. Such an integrated approach should also contribute to the rational design of highly efficacious therapeutics with either agonistic or antagonistic properties. (Endocrinology 145: 4048 -4057, 2004)
Steroid/thyroid hormone receptor genes in Caenorhabditis elegans
Proceedings of the National Academy of Sciences of the United States of America, 1995
The large family of steroid/thyroid hormone receptor (STR) genes has been extensively studied in vertebrates and insects but little information is available on it in more primitive organisms. All members possess a DNA binding domain of zinc fingers of the C2, C2 type. We have used the polymerase chain reaction with degenerate oligonucleotide primers covering this region to clone three distinct members of this family from the nematode Caenorhabditis elegans. All three belong to the retinoic acid receptor (RAR), thyroid hormone receptor subfamily of genes. The cDNA of one of these clones shows such a high homology to DHR3, an early ecdysone response gene found in Drosophila, and MHR3, identified in Manduca sexta, that we have termed it CHR3. Furthermore, the C-terminal portion of the deduced protein sequence shows a box containing eight identical amino acids among CHR3, DHR3, and MHR3 suggesting an identical specific ligand for these proteins. CNR8 shows homology to NAK1, and CNR14 ha...