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> Chemical compound

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.

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<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.

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<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

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<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

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

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

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

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

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

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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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