An aryl hydrocarbon receptor conformation acts as the functional core of nuclear dioxin signaling

Kronenberg, Sven

doi:10.1093/nar/28.12.2286

Cited by 39 publications

(17 citation statements)

References 27 publications

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“…It is reasonable to assume that the binding of TCDD to AhR must also elicit some initial conformational change to enable the release of associated proteins (e.g., hsp90, AIP) that are known to comprise the nonligand-occupied AhR complex) and subsequent dimerization with Arnt. Kronenberg et al (2000) reported detection of a ϳ35-kDa fragment of […”

Section: Discussionmentioning

confidence: 99%

Agonist but Not Antagonist Ligands Induce Conformational Change in the Mouse Aryl Hydrocarbon Receptor as Detected by Partial Proteolysis

Henry

Gasiewicz²

2003

Mol Pharmacol

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The cytosolic transcription factor known as the aryl hydrocarbon receptor (AhR) undergoes transformation to a DNA-binding form by a series of processes initiated by binding of ligand. Subsequent steps include dissociation of several proteins that are complexed with the inactive receptor, nuclear translocation, and dimerization with Arnt. We have used limited proteolysis of the in vitro-translated mouse AhR to determine whether this technique can detect conformational change(s) associated with AhR transformation and whether the effect of agonist and antagonist ligands can be distinguished by this assay. Limited digestion of [35 S]AhR/AhR nuclear translocator (Arnt) by trypsin produced a peptide of approximately 40 kDa that was more resistant to proteolysis in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) than vehicle and was also Arnt-dependent. This trypsin-resistant peptide was also elicited in the presence of other agonist ligands, but not with antagonist ligands that do not form the DNA-binding AhR/Arnt complex. Immunoblot of trypsin-treated AhR/Arnt Ϯ TCDD indicated that the trypsin-resistant peptide did not include the N-terminal portion of the AhR against which the antibody was made. Truncated AhRs were also subjected to limited trypsinization. From AhR(1-399), a TCDD-dependent peptide of approximately 35 kDa was observed; from the constitutively active AhR(1-348), a band of approximately 30 kDa was produced from vehicle-and TCDD-treated protein. From these observations, we hypothesize that the trypsin-resistant peptide from full-length AhR spans approximately from amino acid 80 to 440. We conclude that agonist ligands initiate structural alteration in AhR that is Arnt-dependent and at least partially involves the ligand-binding/Per-Arnt-Sim domain.

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Section: Discussionmentioning

confidence: 99%

Agonist but Not Antagonist Ligands Induce Conformational Change in the Mouse Aryl Hydrocarbon Receptor as Detected by Partial Proteolysis

Henry

Gasiewicz²

2003

Mol Pharmacol

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“…The structural diversity of endogenous ligands may induce differential conformations of the ligand-bound receptor that ultimately dictate varying biologic activities (Lees and Whitelaw, 1999;Kronenberg et al, 2000;Patel et al, 2009;Murray et al, 2010a,b;Jin et al, 2012). Synthesis or accumulation of distinct endogenous ligands within certain cell types or tissues could mediate the tissue/cell selective activity of AHR.…”

Section: Possible Mechanism Of Ahr Activation By Low-molecularweight mentioning

confidence: 99%

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

477

432

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligandmediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

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“…However, the biological significance of ARNT-bHLH tetramerization is unclear since the cellular concentration of ARNT has not been established. Furthermore, the PAS-A domain, which is critical for the heterodimerization of AHR and ARNT and is not present in the bHLH peptide, could play a significant negative or positive role in ARNT homodimerization (44). Comparison of the sensitivity to ionic strength or other solution parameters of ARNT homodimers with ARNT heterodimers (e.g.…”

Section: Effects Of Poly(d[i⅐c]) On Equilibrium Binding-asmentioning

confidence: 99%

The Basic Helix-Loop-Helix Domain of the Aryl Hydrocarbon Receptor Nuclear Transporter (ARNT) Can Oligomerize and Bind E-box DNA Specifically

Huffman¹,

Mokashi²,

Bächinger³

et al. 2001

Journal of Biological Chemistry

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The aryl hydrocarbon receptor nuclear transporter (ARNT) is a basic helix-loop-helix (bHLH) protein that contains a Per-Arnt-Sim (PAS) domain. ARNT heterodimerizes in vivo with other bHLH PAS proteins to regulate a number of cellular activities, but a physiological role for ARNT homodimers has not yet been established. Moreover, no rigorous studies have been done to characterize the biochemical properties of the bHLH domain of ARNT that would address this issue. To begin this characterization, we chemically synthesized a 56-residue peptide encompassing the bHLH domain of ARNT (residues 90 -145). In the absence of DNA, the ARNT-bHLH peptide can form homodimers in lower ionic strength, as evidenced by dynamic light scattering analysis, and can bind E-box DNA (CACGTG) with high specificity and affinity, as determined by fluorescence anisotropy. Dimers and tetramers of ARNT-bHLH are observed bound to DNA in equilibrium sedimentation and dynamic light scattering experiments. The homodimeric peptide also undergoes a coil-to-helix transition upon E-box DNA binding. Peptide oligomerization and DNA affinity are strongly influenced by ionic strength. These biochemical and biophysical studies on the ARNT-bHLH reveal its inherent ability to form homodimers at concentrations supporting a physiological function and underscore the significant biochemical differences among the bHLH superfamily.

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An aryl hydrocarbon receptor conformation acts as the functional core of nuclear dioxin signaling

Cited by 39 publications

References 27 publications

Agonist but Not Antagonist Ligands Induce Conformational Change in the Mouse Aryl Hydrocarbon Receptor as Detected by Partial Proteolysis

Agonist but Not Antagonist Ligands Induce Conformational Change in the Mouse Aryl Hydrocarbon Receptor as Detected by Partial Proteolysis

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

The Basic Helix-Loop-Helix Domain of the Aryl Hydrocarbon Receptor Nuclear Transporter (ARNT) Can Oligomerize and Bind E-box DNA Specifically

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