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EspañolARYL HYDROCARBON RECEPTOR
The 'Aryl hydrocarbon receptor' ('AhR') is member of the family of basic-helix-loop-helix transcription factors. AhR is a cytosolic transcription factor that is normally inactive, bound to several 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 gene transcription.
Protein Functional Domains
'AhR Functional Domains' - Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O (1995). "Identification of functional domains of the aryl hydrocarbon receptor". J. Biol. Chem. 270 (49): 29270-8.
★ Reprinted, with permission, from the Journal of Biological Chemistry, Volume 270 (c)1995[1].
★ Reprinted, with permission, from the Journal of Biological Chemistry, Volume 270 (c)1995[1].
The AhR 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 transcription factors [2] [1]. The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors [4]. 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 that exhibit a high sequence homology to the protein domains that were originally found in the Drosophila genes period (Per) and single minded (Sim) and in AhR’s dimerization partner the aryl hydrocarbon receptor nuclear translocator(ARNT) [5]. 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 [6] and contains several conserved residues critical for ligand binding [7]. Finally, a Q-rich domain is located in the C-terminal region of the protein and is involved in co-activator recruitment and transactivation [8].
Ligands
Signaling pathway
'AhR Signaling Pathway' - Denison MS, Nagy SR (2003). "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals". Annu. Rev. Pharmacol. Toxicol. 43: 309-34.
★ Reprinted, with permission, from the Annual Review of Pharmacology and Toxicology, Volume 43 (c)2003 by Annual Reviews[9].
★ Reprinted, with permission, from the Annual Review of Pharmacology and Toxicology, Volume 43 (c)2003 by Annual Reviews[9].
Cytosolic complex
Non-ligand bound Ahr is retained in the cytoplasm as an inactive protein complex consisting of a dimer of Hsp90 [10] [11], prostaglandin E synthase 3 (Ptges3, p23) [12] [13] [14] [15] and a single molecule of the immunophilin-like protein hepatitis B virus X-associated protein 2 (XAP2) [16] which was previously identified as AhR interacting protein (AIP) [17] and AhR-activated 9 (ARA9) [18]. 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 [19] [6] [13] [22] [15] [24]. 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 [25] [26] [27].
Receptor activation
Upon ligand binding to AhR, XAP2 is released resulting in exposure of the NLS, which is located in the bHLH region [28], leading to importation into the nucleus [29]. It is presumed that once in the nucleus, Hsp90 dissociates exposing the two PAS domains allowing the binding of AhR’s dimerization partner, the AhR Nuclear Transporter (ARNT) [30] [31] [32] [24]. 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 [34] [31] [24].
DNA binding (Xenobiotic Response Element)
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’ [37] within the consensus sequence 5’-T/GNGCGTGA/CG/CA-3’ [38] [39] in the promoter region of AhR responsive genes. The AhR/ARNT entity directly binds the AHRE/DRE/XRE core sequence in a manner such that ARNT binds to 5’-CGTG-3’ and AhR binding 5’-AGC-3’ [40] [41]. Recent research suggests that a second type of response element termed AHRE-II, 5’-CATG(N6)C[T/A]TG-3’, is capable of indirectly acting with the AhR/ARNT complex [42] [43]. Regardless of the response element, the end result is a variety of differential changes in gene expression.
Gene expression
Functional role in physiology and toxicology
Physiological processes
Carcinogenesis and teratogenesis
References
1. Identification of functional domains of the aryl hydrocarbon receptor, Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O, , , J. Biol. Chem., 1995
2. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor, Burbach KM, Poland A, Bradfield CA, , , Proc. Natl. Acad. Sci. U.S.A., 1992
3. Identification of functional domains of the aryl hydrocarbon receptor, Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O, , , J. Biol. Chem., 1995
4. An overview of the basic helix-loop-helix proteins, Jones S, , , Genome Biol., 2004
5. cDNA cloning and structure of mouse putative Ah receptor, Ema M, Sogawa K, Watanabe N, Chujoh Y, Matsushita N, Gotoh O, Funae Y, Fujii-Kuriyama Y, , , Biochem. Biophys. Res. Commun., 1992
6. Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity, Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML, , , J. Biol. Chem., 1995
7. Identification of amino acid residues in the Ah receptor involved in ligand binding, Goryo K, Suzuki A, Del Carpio CA, Siizaki K, Kuriyama E, Mikami Y, Kinoshita K, Yasumoto K, Rannug A, Miyamoto A, Fujii-Kuriyama Y, Sogawa K, , , Biochem. Biophys. Res. Commun., 2007
8. The Q-rich subdomain of the human Ah receptor transactivation domain is required for dioxin-mediated transcriptional activity, Kumar MB, Ramadoss P, Reen RK, Vanden Heuvel JP, Perdew GH, , , J. Biol. Chem., 2001
9. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals, Denison MS, Nagy SR, , , Annu. Rev. Pharmacol. Toxicol., 2003
10. Association of the dioxin receptor with the Mr 90,000 heat shock protein: a structural kinship with the glucocorticoid receptor, Denis M, Cuthill S, Wikström AC, Poellinger L, Gustafsson JA, , , Biochem. Biophys. Res. Commun., 1988
11. Association of the Ah receptor with the 90-kDa heat shock protein, Perdew GH, , , J. Biol. Chem., 1988
12. Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling, Cox MB, Miller CA, , , Cell Stress Chaperones, 2004
13. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor, Kazlauskas A, Poellinger L, Pongratz I, , , J. Biol. Chem., 1999
14. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor, Kazlauskas A, Sundström S, Poellinger L, Pongratz I, , , Mol. Cell. Biol., 2001
15. P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex, Shetty PV, Bhagwat BY, Chan WK, , , Biochem. Pharmacol., 2003
16. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity, Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH, , , Mol. Cell. Biol., 1998
17. A novel cytoplasmic protein that interacts with the Ah receptor, contains tetratricopeptide repeat motifs, and augments the transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, Ma Q, Whitlock JP, , , J. Biol. Chem., 1997
18. Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo, Carver LA, Bradfield CA, , , J. Biol. Chem., 1997
19. The 90-kDa heat shock protein is essential for Ah receptor signaling in a yeast expression system, Carver LA, Jackiw V, Bradfield CA, , , J. Biol. Chem., 1994
20. Definition of a minimal domain of the dioxin receptor that is associated with Hsp90 and maintains wild type ligand binding affinity and specificity, Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML, , , J. Biol. Chem., 1995
21. Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor, Kazlauskas A, Poellinger L, Pongratz I, , , J. Biol. Chem., 1999
22. Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity, Pongratz I, Mason GG, Poellinger L, , , J. Biol. Chem., 1992
23. P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex, Shetty PV, Bhagwat BY, Chan WK, , , Biochem. Pharmacol., 2003
24. Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor, Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L, , , Mol. Cell. Biol., 1993
25. Characterization of the Ah receptor-associated protein, ARA9, Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA, , , J. Biol. Chem., 1998
26. Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2, Petrulis JR, Hord NG, Perdew GH, , , J. Biol. Chem., 2000
27. The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity, Petrulis JR, Kusnadi A, Ramadoss P, Hollingshead B, Perdew GH, , , J. Biol. Chem., 2003
28. Nuclear localization and export signals of the human aryl hydrocarbon receptor, Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K, , , J. Biol. Chem., 1998
29. Analysis of the complex relationship between nuclear export and aryl hydrocarbon receptor-mediated gene regulation, Pollenz RS, Barbour ER, , , Mol. Cell. Biol., 2000
30. Cloning of a factor required for activity of the Ah (dioxin) receptor, Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O, , , Science, 1991
31. Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action, Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O, , , Mol. Pharmacol., 1993
32. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor, Reyes H, Reisz-Porszasz S, Hankinson O, , , Science, 1992
33. Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor, Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L, , , Mol. Cell. Biol., 1993
34. In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition, Dolwick KM, Swanson HI, Bradfield CA, , , Proc. Natl. Acad. Sci. U.S.A., 1993
35. Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action, Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O, , , Mol. Pharmacol., 1993
36. Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor, Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA, Poellinger L, , , Mol. Cell. Biol., 1993
37. Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor, Shen ES, Whitlock JP, , , J. Biol. Chem., 1992
38. Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor, Lusska A, Shen E, Whitlock JP, , , J. Biol. Chem., 1993
39. DNA sequence determinants for binding of transformed Ah receptor to a dioxin-responsive enhancer, Yao EF, Denison MS, , , Biochemistry, 1992
40. Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence, Bacsi SG, Reisz-Porszasz S, Hankinson O, , , Mol. Pharmacol., 1995
41. DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins, Swanson HI, Chan WK, Bradfield CA, , , J. Biol. Chem., 1995
42. Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting, Boutros PC, Moffat ID, Franc MA, Tijet N, Tuomisto J, Pohjanvirta R, Okey AB, , , Biochem. Biophys. Res. Commun., 2004
43. A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer, Sogawa K, Numayama-Tsuruta K, Takahashi T, Matsushita N, Miura C, Nikawa J, Gotoh O, Kikuchi Y, Fujii-Kuriyama Y, , , Biochem. Biophys. Res. Commun., 2004
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