Ecdysone receptor
Encyclopedia
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.
occur during insect
development
, whereupon this hormone
binds to the ecdysone
receptor
, a ligand
-activated transcription factor
found in the nuclei
of insect cells
. This in turn leads to the activation of many other genes
, as evidenced by chromosomal puffing
at over a hundred sites. Ultimately the activation cascade causes physiological changes that result in ecdysis
(moulting).
(FXR) and retinoid X receptor
(RXR) proteins, respectively. Based on sequence homology
considerations, 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). 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 element
s (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. 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
.
X-ray crystal structures
have been determined for several heterodimeric DNA-binding domains and ligand-binding domains from ecdysone receptors.
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
found in arthropods, where it controls development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
and contributes to other processes such as reproduction
Sexual reproduction
Sexual reproduction is the creation of a new organism by combining the genetic material of two organisms. There are two main processes during sexual reproduction; they are: meiosis, involving the halving of the number of chromosomes; and fertilization, involving the fusion of two gametes and the...
. The receptor is a non-covalent heterodimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
of two proteins, the EcR protein and ultraspiracle protein (USP). It binds
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
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
Caterpillar
Caterpillars are the larval form of members of the order Lepidoptera . They are mostly herbivorous in food habit, although some species are insectivorous. Caterpillars are voracious feeders and many of them are considered to be pests in agriculture...
-selective insecticides.
Function
Pulses of 20-hydroxyecdysone20-hydroxyecdysone
20-Hydroxyecdysone is a naturally occurring ecdysteroid hormone which controls the ecdysis and metamorphosis of arthropods. It is therefore one of the most common moulting hormones in insects, crabs, etc...
occur during insect
Insect
Insects are a class of living creatures within the arthropods that have a chitinous exoskeleton, a three-part body , three pairs of jointed legs, compound eyes, and two antennae...
development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
, whereupon this hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
binds to the ecdysone
Ecdysone
Ecdysone is a steroidal prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. Insect molting hormones are generally called ecdysteroids. Ecdysteroids act as moulting hormones of arthropods but also occur in other related phyla where they...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, a ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
-activated transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
found in the nuclei
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of insect cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. This in turn leads to the activation of many other genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
, as evidenced by chromosomal puffing
Michael Ashburner
Michael Ashburner FRS is a biologist and emeritus Professor in the Department of Genetics at University of Cambridge. He is also the former joint-head of the European Bioinformatics Institute of the European Molecular Biology Laboratory .Born in Sussex, England, Ashburner attended High Wycombe...
at over a hundred sites. Ultimately the activation cascade causes physiological changes that result in ecdysis
Ecdysis
Ecdysis is the moulting of the cuticula in many invertebrates. This process of moulting is the defining feature of the clade Ecdysozoa, comprising the arthropods, nematodes, velvet worms, horsehair worms, rotifers, tardigrades and Cephalorhyncha...
(moulting).
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 receptorFarnesoid X receptor
The bile acid receptor , also known as farnesoid X receptor or NR1H4 is a nuclear receptor that is encoded by the NR1H4 gene in humans.- Function :...
(FXR) and retinoid X receptor
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
(RXR) proteins, respectively. Based on sequence homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
considerations, 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
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
architecture common to all nuclear hormone receptors, namely an N-terminal transcriptional
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
activation domain (A/B domain), a DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
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). 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 element
Response element
Response elements are short sequences of DNA within a gene promoter region that are able to bind a specific transcription factor and regulate transcription of genes.-Examples:Examples of response elements include:*Hormone response element...
s (ECREs) in the promoters of ecdysone-responsive genes.
The ecdysteroid-binding pocket is located in the ligand binding domain of the EcR subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
, but EcR must be dimerised with a USP (or with an RXR) for high-affinity
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
ligand binding to occur. In such circumstances, the binding of an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
ligand triggers a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in the C-terminal part of the EcR ligand-binding domain that leads to transcriptional
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
activation of genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
under ECRE control. 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
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
.
X-ray crystal structures
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
have been determined for several heterodimeric DNA-binding domains and ligand-binding domains from ecdysone receptors.
Commercial applications
Ecdysone receptors have two main fields of application:- Gene switches - ecdysoneEcdysoneEcdysone is a steroidal prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. Insect molting hormones are generally called ecdysteroids. Ecdysteroids act as moulting hormones of arthropods but also occur in other related phyla where they...
receptor-controlled transgenes for controlled gene expressionGene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
in scientific research, agricultureAgricultureAgriculture is the cultivation of animals, plants, fungi and other life forms for food, fiber, and other products used to sustain life. Agriculture was the key implement in the rise of sedentary human civilization, whereby farming of domesticated species created food surpluses that nurtured the...
, and medicineMedicineMedicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
. The last category includes potential use in gene therapyGene therapyGene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
. - Insecticides - the development of selective insect growth regulators for use as environmentally benignEnvironmentalismEnvironmentalism is a broad philosophy, ideology and social movement regarding concerns for environmental conservation and improvement of the health of the environment, particularly as the measure for this health seeks to incorporate the concerns of non-human elements...
insecticides. Although dibenzoylhydrazine compounds are not ecdysteroids, many are agonists of lepidopteran ecdysone receptors and are used as caterpillarCaterpillarCaterpillars are the larval form of members of the order Lepidoptera . They are mostly herbivorous in food habit, although some species are insectivorous. Caterpillars are voracious feeders and many of them are considered to be pests in agriculture...
-selective larvicidesLarvicideA larvicide is an insecticide that is specifically targeted against the larval life stage of an insect. Their most common use is against mosquitoes...
.
External links
- PDBProtein Data BankThe Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
representative structures of ecdysone receptor ligand binding domains: - 1R1K, ligand-binding domain heterodimer of HeliothisHeliothisHeliothis is a genus of moths, whose larvae are agricultural pests on crop species such as tobacco, cotton, soybean and pigeon pea. Several of the species formerly placed in this genus are now in the genus Helicoverpa.-Species:...
viresecens in complex with an ecdysteroid; 1R20, the same heterodimer in complex with a dibenzoylhydrazine agonist. - Mimic insecticide, and associated regulatory information (for Australia).