The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, or dioxin receptor) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the AHR
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. The aryl hydrocarbon receptor is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that regulates gene expression. It was originally thought to function primarily as a sensor of
xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
chemicals and also as the regulator of enzymes such as
cytochrome P450s that metabolize these chemicals. The most notable of these xenobiotic chemicals are
aromatic (aryl) hydrocarbons from which the receptor derives its name.
More recently, it has been discovered that AhR is activated (or deactivated) by a number of
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
indole derivatives such as
kynurenine. In addition to regulating metabolism enzymes, the AhR has roles in regulating immunity,
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
maintenance, and
cellular differentiation
Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
.
The aryl hydrocarbon receptor is a member of the family of
basic helix-loop-helix transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s. AHR binds several exogenous ligands such as natural plant
flavonoid
Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.
Chemically, flavonoids ...
s,
polyphenolics and
indoles, as well as synthetic polycyclic aromatic hydrocarbons and
dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several
co-chaperone
Co-chaperones are proteins that assist chaperone (protein), chaperones in protein folding and other functions. Co-chaperones are the non-client binding molecules that assist in protein folding mediated by Hsp70 and Hsp90. They are particularly esse ...
s. Upon
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
binding to chemicals such as
2,3,7,8-tetrachlorodibenzo-''p''-dioxin (TCDD), the chaperones
dissociate resulting in AhR translocating into the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
and
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
izing with ARNT
(''AhR nuclear translocator''), leading to changes in
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
.
Protein functional domains
![AHR functional domains](https://upload.wikimedia.org/wikipedia/commons/e/e2/AHR_functional_domains.svg)
The AhR
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
contains several domains critical for function and is classified as a member of the
basic helix-loop-helix/
Per-Arnt-Sim (bHLH/PAS) family of
transcription factors.
The bHLH motif is located in the
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
of the protein and is a common entity in a variety of
transcription factors.
Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to
DNA. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
that exhibit a high sequence homology to the protein domains that were originally found in the
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
genes period (Per) and single-minded (Sim) and in AhR's dimerization partner the
aryl hydrocarbon receptor nuclear translocator (ARNT).
The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that dimeric and heteromeric protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain
and contains several conserved residues critical for ligand binding.
Finally, a
glutamine-rich (Q-rich) domain is located in the
C-terminal region of the protein and is involved in co-activator recruitment and transactivation.
Ligands
AhR ligands have been generally classified into two categories, synthetic or naturally occurring. The first ligands to be discovered were synthetic and members of the halogenated aromatic hydrocarbons (
polychlorinated dibenzodioxin
Polychlorinated dibenzodioxins (PCDDs), or simply dioxins, are a group of long-lived polyhalogenated organic compounds that are primarily anthropogenic, and contribute toxic, persistent organic pollution in the environment.
They are commonly ...
s,
dibenzofurans and
biphenyls) and
polycyclic aromatic hydrocarbons (
3-methylcholanthrene,
benzo yrene">'a''yrene,
benzanthracenes and
benzoflavones).
A range of synthetic ligands have been designed to target the possible future treatment of breast cancer.
Research has focused on naturally occurring compounds with the hope of identifying an endogenous ligand. Naturally occurring compounds that have been identified as ligands of Ahr include derivatives of
tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α- carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
such as
indigo dye
Indigo dye is an organic compound with a distinctive blue color. Historically, indigo was a natural dye extracted from the leaves of some plants of the ''Indigofera'' genus, in particular ''Indigofera tinctoria''; dye-bearing ''Indigofera'' pla ...
and
indirubin
Indirubin is a chemical compound most often produced as a byproduct of bacterial metabolism. For instance, it is one of the compounds responsible for the generally benign condition purple urine bag syndrome, resulting from bacteria metabolizing in ...
,
tetrapyrroles such as
bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
,
the
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
metabolites
lipoxin A4 and
prostaglandin G,
modified
low-density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
and several dietary
carotenoid
Carotenoids (), also called tetraterpenoids, are yellow, orange, and red organic compound, organic pigments that are produced by plants and algae, as well as several bacteria, and Fungus, fungi. Carotenoids give the characteristic color to pumpki ...
s.
One assumption made in the search for an endogenous ligand is that the ligand will be a receptor
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
. However, work by Savouret ''et al.'' has shown this may not be the case since their findings demonstrate that 7-ketocholesterol competitively inhibits Ahr signal transduction.
Carbidopa is a selective aryl hydrocarbon receptor modulator (SAhRM). Other SAhRMs include microbial-derived 1,4-dihydroxy-2-napthoic acid and plant-derived 3,3-diindolylmethane.
Indolocarbazole
Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range o ...
(ICZ) is one of the strongest non-halogenated agonists for AHR in vitro reported.
Signaling pathway
Cytosolic complex
Non-ligand bound Ahr is retained in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
as an inactive
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
complex consisting of a dimer of
Hsp90,
prostaglandin E synthase 3 (PTGES3, p23)
and a single molecule of the
immunophilin-like
AH receptor-interacting protein, also known as hepatitis B virus X-associated protein 2 (XAP2),
AhR interacting protein (
AIP),
and AhR-activated 9 (ARA9).
The dimer of Hsp90, along with PTGES3 (p23), has a multifunctional role in the protection of the receptor from proteolysis, constraining the receptor in a conformation receptive to ligand binding and preventing the premature binding of
ARNT.
AIP interacts with carboxyl-terminal of Hsp90 and binds to the AhR
nuclear localization sequence (NLS) preventing the inappropriate trafficking of the receptor into the nucleus.
Receptor activation
Upon ligand binding to AhR, AIP is released resulting in exposure of the NLS, which is located in the bHLH region,
leading to import into the nucleus.
It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of ARNT.
The activated AhR/ARNT heterodimer complex is then capable of either directly or indirectly interacting with DNA by binding to recognition sequences located in the 5’- regulatory region of dioxin-responsive genes.
DNA binding (xenobiotic response element – XRE)
The classical recognition motif of the AhR/ARNT complex, referred to as either the AhR-, dioxin- or xenobiotic- responsive element (AHRE, DRE or XRE), contains the core sequence 5'-GCGTG-3'
within the consensus sequence 5'-T/GNGCGTGA/CG/CA-3'
in the
promoter region
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...
of AhR responsive genes. The AhR/ARNT heterodimer directly binds the AHRE/DRE/XRE core sequence in an asymmetric manner such that ARNT binds to 5'-GTG-3' and AhR binding 5'-TC/TGC-3'.
Recent research suggests that a second type of element termed AHRE-II, 5'-CATG(N6)C
/AG-3', is capable of indirectly acting with the AhR/ARNT complex.
Regardless of the response element, the result is a variety of differential changes in gene expression.
Functional role in physiology and toxicology
Role in development
In terms of evolution, the oldest physiological role of AhR is in development. AhR is presumed to have evolved from
invertebrates
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
where it served a ligand-independent role in normal development processes.
The AhR homolog in ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
, spineless ''(ss) is necessary for development of the distal segments of the antenna and leg.
''Ss'' dimerizes with ''tango ''(tgo), which is the homolog to the mammalian Arnt, to initiate gene transcription.
Evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
of the receptor in
vertebrates
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
resulted in the ability to bind ligand and might have helped humans evolve to tolerate smoke of fires. In developing vertebrates, AhR seemingly plays a role in cellular proliferation and differentiation.
Despite lacking a clear endogenous ligand, AhR appears to play a role in the differentiation of many developmental pathways, including hematopoiesis,
lymphoid systems,
T-cells,
neurons,
and hepatocytes.
AhR has also been found to have an important function in hematopoietic stem cells: AhR antagonism promotes their self-renewal and ex-vivo expansion
and is involved in megakaryocyte differentiation.
In adulthood, signaling is associated with the stress response and mutations in AhR are associated with major depressive disorder.
Adaptive and innate response
The adaptive response is manifested as the induction of xenobiotic metabolizing enzymes. Evidence of this response was first observed from the induction of cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1a1) resultant from TCDD exposure, which was determined to be directly related to activation of the Ahr signaling pathway.
The search for other metabolizing genes induced by AhR ligands, due to the presence of DREs, has led to the identification of an "AhR gene battery" of Phase I and Phase II metabolizing enzymes consisting of
CYP1A1
Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein
that in humans is encoded by the ''CYP1A1'' gene.
The protein is a member of the cytochrome P450 superfamily of enzymes.
Function
Metabolism of xenobiotics and drugs
CYP1A1 ...
,
CYP1A2,
CYP1B1, NQO1, ALDH3A1, UGT1A2 and GSTA1.
Presumably, vertebrates have this function to be able to detect a wide range of chemicals, indicated by the wide range of substrates AhR is able to bind and facilitate their
biotransformation and elimination. The AhR may also signal the presence of toxic chemicals in food and cause aversion of such foods.
AhR activation seems to be also important for immunological responses and inhibiting inflammation
through upregulation of
interleukin 22
Interleukin-22 (IL-22) is protein that in humans is encoded by the ''IL22'' gene.
Structure
IL-22 is an α-helical cytokine. IL-22 binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1 subunits. IL-22R is expressed o ...
and downregulation of
Th17
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...
response.
The Knockdown of AHR mostly downregulates the expression of innate immunity genes in
THP-1 cells.
Toxic response
Extensions of the adaptive response are the toxic responses elicited by AhR activation. Toxicity results from two different ways of AhR signaling. The first is a side effect of the adaptive response in which the induction of metabolizing enzymes results in the production of toxic metabolites. For example, the polycyclic aromatic hydrocarbon
benzo yrene">'a''yrene (BaP), a ligand for AhR, induces its own metabolism and bioactivation to a toxic metabolite via the induction of
CYP1A1
Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein
that in humans is encoded by the ''CYP1A1'' gene.
The protein is a member of the cytochrome P450 superfamily of enzymes.
Function
Metabolism of xenobiotics and drugs
CYP1A1 ...
and
CYP1B1 in several tissues.
The second approach to toxicity is the result of aberrant changes in global gene transcription beyond those observed in the "AhR gene battery." These global changes in gene expression lead to adverse changes in cellular processes and function.
Microarray analysis
A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon t ...
has proved most beneficial in understanding and characterizing this response.
Protein-protein interactions
In addition to the protein interactions mentioned above, AhR has also been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with the following:
*
AIP
*
ARNTL
*
CCNT1
*
ESR1
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex h ...
*
NCOA1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
*
NEDD8
*
NRIP1
*
RELA
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene.
RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tran ...
*
RELB
Transcription factor RelB is a protein that in humans is encoded by the ''RELB'' gene.
Interactions
RELB has been shown to interact with NFKB2, NFKB1, and C22orf25.
Activation and function
In resting cells, RelB is sequestered by the NF-κ ...
*
RP
References
External links
*
*
*
{{Aryl hydrocarbon receptor modulators
Receptors
Transcription factors
PAS-domain-containing proteins