Ecdysone receptor

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Ecdysone receptor protein
EcdysoneReceptor.pdb.png
Crystallographic structure of the ligand binding domain of the ecdysone receptor (rainbow color, N-terminus = blue, C-terminus = red) from Heliothis virescens complexed with ponasterone A (space-filling model, carbon = white, oxygen = red). [1]
Identifiers
Organism Drosophila melanogaster
SymbolEcR
Alt. symbolsEcRH, NR1H1
Entrez 35540
PDB 1R0O More structures
RefSeq (mRNA) NM_165461
RefSeq (Prot) NP_724456
UniProt P34021
Other data
Chromosome 2R: 1.97 - 2.07 Mb
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Structures Swiss-model
Domains InterPro
Ultraspiracle protein
1hg4.png
Ultraspiracle ligand binding domain. PDB 1hg4 [2]
Identifiers
Organism Drosophila melanogaster
SymbolUSP
Alt. symbolsCf1, NR2B4
Entrez 31165
PDB 1HG4 More structures
RefSeq (mRNA) NM_057433
RefSeq (Prot) NP_476781
UniProt P20153
Other data
Chromosome X: 1.93 - 1.94 Mb
Search for
Structures Swiss-model
Domains InterPro

The ecdysone receptor is a nuclear receptor found in arthropods, where it controls development and contributes to other processes such as reproduction. The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). It binds to and is activated by ecdysteroids. Insect ecdysone receptors are currently better characterized than those from other arthropods, and mimics of ecdysteroids are used commercially as caterpillar-selective insecticides.

Contents

Function

Pulses of 20-hydroxyecdysone occur during insect development, whereupon this hormone binds to the ecdysone receptor, a ligand-activated transcription factor found in the nuclei of insect cells. [3] This in turn leads to the activation of many other genes, as evidenced by puffing of polytene chromosomes at over a hundred sites. Ultimately the activation cascade causes physiological changes that result in ecdysis (moulting). The temporal expression of ecdysone receptor within neural stem cells mediates temporal patterning and neural diversity. [4] [5]

Structure

The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). These nuclear hormone receptor proteins are the insect orthologs of the mammalian farnesoid X receptor (FXR) and retinoid X receptor (RXR) proteins, respectively. Based on sequence homology considerations, [6] some researchers reserve the term USP for the EcR partner from lepidopteran and dipteran insects, and use RXR in all other instances.

EcR and USP share the multi-domain architecture common to all nuclear hormone receptors, namely an N-terminal transcriptional activation domain (A/B domain), a DNA-binding domain (C domain, highly conserved between receptors), a linker region (D region), a ligand-binding domain (E domain, moderately conserved), and in some cases a distinct C-terminal extension (F-domain). [7] The DNA-binding domains of EcR and USP recognise specific short sequences in DNA, and mediate the binding of the heterodimer to these ecdysone response elements (ECREs) in the promoters of ecdysone-responsive genes.

The ecdysteroid-binding pocket is located in the ligand binding domain of the EcR subunit, but EcR must be dimerised with a USP (or with an RXR) for high-affinity ligand binding to occur. In such circumstances, the binding of an agonist ligand triggers a conformational change in the C-terminal part of the EcR ligand-binding domain that leads to transcriptional activation of genes under ECRE control. [8] There is also a ligand-binding pocket in the corresponding domain of USP. Its natural ligand remains uncertain, and USPs appear to be locked permanently in an inactive conformation. [9]

X-ray crystal structures have been determined for several heterodimeric DNA-binding domains [10] and ligand-binding domains from ecdysone receptors.

Commercial applications

Ecdysone receptors have two main fields of application:

Related Research Articles

<span class="mw-page-title-main">Ecdysone</span> Precursor of an insect hormone

Ecdysone is a prohormone of the major insect molting hormone 20-hydroxyecdysone, secreted from the prothoracic glands. It is of steroidal structure. Insect molting hormones are generally called ecdysteroids. Ecdysteroids act as moulting hormones of arthropods but also occur in other related phyla where they can play different roles. In Drosophila melanogaster, an increase in ecdysone concentration induces the expression of genes coding for proteins that the larva requires. It causes chromosome puffs to form in polytene chromosomes. Recent findings in the laboratory of Chris Q. Doe have found a novel role of this hormone in regulating temporal gene transitions within neural stem cells of the fruit fly.

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

<span class="mw-page-title-main">20-Hydroxyecdysone</span> Chemical compound

20-Hydroxyecdysone is a naturally occurring ecdysteroid hormone which controls the ecdysis (moulting) and metamorphosis of arthropods. It is therefore one of the most common moulting hormones in insects, crabs, etc. A phytoecdysteroid produced by various plants, including Cyanotis vaga, Ajuga turkestanica and Rhaponticum carthamoides, its purpose is presumably to disrupt the development and reproduction of insect pests. In arthropods, 20-hydroxyecdysone acts through the ecdysone receptor. Although mammals lack this receptor, 20-hydroxyecdysone affects mammalian biological systems. 20-Hydroxyecdysone is an ingredient of some supplements that aim to enhance physical performance. In humans, it is hypothesized to bind to the estrogen receptor beta (ERβ) protein-coding gene.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. RAR receptors are also known to exhibit many retinoid-independent effects as they bind to and regulate other nuclear receptor pathways, such as the estrogen receptor.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist. Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">Constitutive androstane receptor</span> Protein-coding gene in humans

The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene. CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated. Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Nuclear receptor 4A1</span> Mammalian protein found in Homo sapiens

The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.

<span class="mw-page-title-main">Small heterodimer partner</span> Protein found in humans

The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein found in humans

Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">Liver X receptor beta</span> Protein-coding gene in the species Homo sapiens

Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.

<span class="mw-page-title-main">BRD8</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 8 is a protein that in humans is encoded by the BRD8 gene.

Vitamin D response element (VDRE) is a type of DNA sequence that is found in the promoter region of vitamin D regulated genes. This sequence binds the vitamin D receptor (VDR), when complexed with calcitriol (1,25(OH)2D), the active form of vitamin D, and so regulates the expression of many genes.

Dino Moras, born on 23 November 1944, is a French biochemist, research director at the CNRS and co-director of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Illkirch-Graffenstaden until 2010.

References

  1. ↑ PDB: 1R1K ​; Billas IM, Iwema T, Garnier JM, Mitschler A, Rochel N, Moras D (November 2003). "Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor". Nature. 426 (6962): 91–6. Bibcode:2003Natur.426...91B. doi:10.1038/nature02112. PMID   14595375. S2CID   4413300.
  2. ↑ Clayton GM, Peak-Chew SY, Evans RM, Schwabe JW (February 2001). "The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation". Proceedings of the National Academy of Sciences of the United States of America. 98 (4): 1549–54. doi: 10.1073/pnas.041611298 . PMC   29294 . PMID   11171988.
  3. ↑ Riddiford LM, Cherbas P, Truman JW (2000). "Ecdysone receptors and their biological actions". Vitam. Horm. Vitamins & Hormones. 60: 1–73. doi:10.1016/S0083-6729(00)60016-X. ISBN   978-0-12-709860-9. PMID   11037621.
  4. ↑ Syed MH, Mark B, Doe CQ (April 2017). "Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity". eLife. 6: e26287. doi: 10.7554/eLife.26287 . PMC   5403213 . PMID   28394252.
  5. ↑ Henrich VC (2005). "The ecdysteroid receptor". In Gill SS, Gilbert LI, Iatrou K (eds.). Comprehensive molecular insect science . Amsterdam: Elsevier. pp.  243–285. ISBN   978-0-444-51516-2.
  6. ↑ Hayward DC, Bastiani MJ, Trueman JW, Truman JW, Riddiford LM, Ball EE (September 1999). "The sequence of Locusta RXR, homologous to Drosophila Ultraspiracle, and its evolutionary implications". Dev. Genes Evol. 209 (9): 564–71. doi:10.1007/s004270050290. PMID   10502114. S2CID   8703952.
  7. ↑ Koelle MR, Talbot WS, Segraves WA, Bender MT, Cherbas P, Hogness DS (October 1991). "The Drosophila EcR gene encodes an ecdysone receptor, a new member of the steroid receptor superfamily". Cell. 67 (1): 59–77. doi:10.1016/0092-8674(91)90572-G. PMID   1913820. S2CID   6805386.
  8. ↑ Bourguet W, Germain P, Gronemeyer H (October 2000). "Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications". Trends Pharmacol. Sci. 21 (10): 381–8. doi:10.1016/S0165-6147(00)01548-0. PMID   11050318.
  9. ↑ Clayton GM, Peak-Chew SY, Evans RM, Schwabe JW (February 2001). "The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1549–54. doi: 10.1073/pnas.041611298 . PMC   29294 . PMID   11171988.
  10. ↑ Devarakonda S, Harp JM, Kim Y, Ozyhar A, Rastinejad F (November 2003). "Structure of the heterodimeric ecdysone receptor DNA-binding complex". EMBO J. 22 (21): 5827–40. doi:10.1093/emboj/cdg569. PMC   275426 . PMID   14592980.
  11. ↑ Palli SR, Hormann RE, Schlattner U, Lezzi M (2005). "Ecdysteroid receptors and their applications in agriculture and medicine". Vitam. Horm. Vitamins & Hormones. 73: 59–100. doi:10.1016/S0083-6729(05)73003-X. ISBN   0-12-709873-9. PMID   16399408.
  12. ↑ Dhadialla TS, Carlson GR, Le DP (1998). "New insecticides with ecdysteroidal and juvenile hormone activity". Annu. Rev. Entomol. 43: 545–69. doi:10.1146/annurev.ento.43.1.545. PMID   9444757.
  13. ↑ Dhadialla TS, Retnakaran A, Smagghe G (2005). "Insect growth- and development-disrupting insecticides". In Sarjeet S. Gill, Gilbert, Lawrence I., Kostas Iatrou (eds.). Comprehensive molecular insect science . Amsterdam: Elsevier. pp.  55–115. ISBN   0-444-51516-X.
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