Aryl hydrocarbon receptor

The aryl hydrocarbon receptor (AhR or AHR or ahr or ahR) is a is_associated_with::protein that in humans is encoded by the AHR is_associated_with::gene. The aryl hydrocarbon receptor is a ligand-activated is_associated_with::transcription factor involved in the regulation of biological responses to planar is_associated_with::aromatic hydrocarbons. This receptor has been shown to regulate is_associated_with::xenobiotic-metabolizing enzymes such as is_associated_with::cytochrome P450.

The aryl hydrocarbon receptor is a member of the family of is_associated_with::basic helix-loop-helix is_associated_with::transcription factors. AHR binds several exogenous ligands such as natural plant flavonoids, 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 is_associated_with::co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in is_associated_with::gene transcription.

Protein functional domains
The AhR is_associated_with::protein 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 is_associated_with::transcription factors. The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of is_associated_with::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 is_associated_with::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 is_associated_with::amino acids that exhibit a high sequence homology to the protein domains that were originally found in the is_associated_with::Drosophila genes period (Per) and single-minded (Sim) and in AhR’s dimerization partner the is_associated_with::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 heterozygous and homozygous 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 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 (is_associated_with::polychlorinated dibenzodioxins, dibenzofurans and biphenyls) and is_associated_with::polycyclic aromatic hydrocarbons (is_associated_with::3-methylcholanthrene, is_associated_with::benzo(a)pyrene, benzanthracenes and benzoflavones).

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 is_associated_with::tryptophan such as is_associated_with::indigo dye and indirubin, tetrapyrroles such as is_associated_with::bilirubin, the is_associated_with::arachidonic acid metabolites lipoxin A4 and prostaglandin G, modified low-density lipoprotein and several dietary carotenoids. One assumption made in the search for an endogenous ligand is that the ligand will be a receptor is_associated_with::agonist. 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.

Cytosolic complex
Non-ligand bound Ahr is retained in the is_associated_with::cytoplasm as an inactive is_associated_with::protein complex consisting of a dimer of is_associated_with::Hsp90, prostaglandin E synthase 3 (Ptges3, p23)    and a single molecule of the immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2), which was previously identified as AhR interacting protein (AIP)(base on HUGO http://www.genenames.org AIP is the accepted symbol for this gene and XAP2 is old name) and AhR-activated 9 (ARA9). The dimer of Hsp90, along with 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. XAP2 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, XAP2 is released resulting in exposure of the NLS, which is located in the bHLH region, leading to importation 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 and 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 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[T/A]TG-3’, is capable of indirectly acting with the AhR/ARNT complex. Regardless of the response element, the end result is a variety of differential changes in gene expression.

Role in development
In terms of evolution, the oldest physiological role of Ahr is in development. Ahr is presumed to have evolved from is_associated_with::invertebrates where it served a ligand-independent role in normal development processes. The Ahr homolog in is_associated_with::Drosophila, 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. is_associated_with::Evolution of the receptor in is_associated_with::vertebrates resulted in the ability to bind ligand. 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.

Adaptive 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 is_associated_with::CYP1A1, is_associated_with::CYP1A2, is_associated_with::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 is_associated_with::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 is_associated_with::interleukin 22 and downregulation of is_associated_with::Th17 response.

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 is_associated_with::benzo(a)pyrene (BaP), a ligand for Ahr, induces its own metabolism and bioactivation to a toxic metabolite via the induction of is_associated_with::CYP1A1 and is_associated_with::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 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 with:


 * is_associated_with::ARNTL,
 * CCNT1,
 * ESR1,
 * NCOA1,
 * is_associated_with::NEDD8
 * is_associated_with::NRIP1,
 * is_associated_with::RELA, and
 * RP.