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Nucleic Acids Research, 2000, Vol. 28, No. 12 2286-2291
© 2000 Oxford University Press

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

Sven Kronenberg1,2, Charlotte Esser1 and Carsten Carlberg2,*

1Abteilung Immunologie des Medizinischen Instituts für Umwelthygiene and 2Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany

DNA-complexed heterodimers of the aryl hydrocarbon receptor (AhR) with the Ah receptor nuclear translocator (Arnt) are the molecular switches for nuclear signaling of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AhR–Arnt heterodimers regulate genes involved in the metabolism of xenobiotics or fatty acids and various genes important for growth and differentiation. In this report several potent methods, such as the limited protease digestion, gel shift and gel shift clipping assays, allowed the investigation of ligand-stabilized conformations of AhR monomers in comparison to that of AhR–Arnt heterodimers. Interestingly, the ligand sensitivity of monomeric AhR was found to be very low at 25 nM, whereas DNA-dependent methods consistently provided EC50 values between 0.12 and 0.6 nM for AhR in a heterodimeric complex, i.e. an approximate 100-fold higher ligand sensitivity. This indicates that complex formation of AhR with Arnt on DNA is an important and critical step in transforming AhR into a high affinity receptor for TCDD. A comparison of wild-type AhR with different C-terminal receptor truncations suggests that the PAS-B subregion of its PAS domain is of central importance for stabilization of a functional, i.e. ligand-sensitive, AhR–Arnt confor­mation, whereas the PAS-A subregion appears to be critical for dimerization of AhR and Arnt. In conclusion, the results of this study provide important information on the ligand sensitivity of AhR and AhR–Arnt heterodimer conformations.

* To whom correspondence should be addressed. Tel: +49 211 811 5358; Fax: +49 211 208 399; Email: carlberg@uni-duesseldorf.de


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