The crystal structure of the AhRR–ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription

Abstract

Tetrachlorodibenzo-p-dioxin and related compounds are extraordinarily potent environmental toxic pollutants. Most of the 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor belonging to the basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, because of the lack of structural information. Here, we determined the structure of the AhRR-ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR-ARNT and AhR-ARNT were similar in the bHLH-PAS-A region, whereas the PAS-B of ARNT in the AhRR-ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA and further suggested the existence of an AhRR-ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription. Aryl hydrocarbon receptor (AhR), 3 a ligand-dependent transcription factor, responds to diverse exogenous and endoge-The atomic coordinates and structure factors (code 5Y7Y) have been deposited in the Protein Data Bank (http://wwpdb.org/).

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…The N‐terminal bHLH domain consists of a sequence of four to six basic amino acids required for DNA binding and dimerization . Each PAS domains has approximately 110 amino acids, and in AhR, are both used for heterodimerization with ARNT .…”

“…This enhances the AhR‐ARNT complex stability and strengthens DNA binding . The PAS‐B domains of AhR and ARNT both contribute to heterodimerization; however, more importantly for the AhR, the PAS‐B region contains the LBD …”

“…The binding of the AhR to XRE on DNA upregulates the expression of the CYPs, as well as AhRR; the expressed AhRR then competitively binds ARNT, inhibiting the function of the AHR in a negative feedback loop . The AhR/ARNT complex exhibits similar domain arrangements to the AhRR/ARNT heterodimer, as the residues involved in the interactions with ARNT are highly conserved between the two . A recent study has demonstrated that while AhR expression is associated with age, ER and HR negative status, as well as the ER subtype, expression of the AhRR is unrelated to these factors.…”

Light‐induced complex formation of bacteriophytochrome RpBphP1 and gene repressor RpPpsR2 probed by SAXS

“…In these structures, HTH domains serve as dimerization domains, while PAS domains provide stability and specificity to the dimer . Heterodimers are well‐documented, such as the ARNT protein heterodimer with AHR and mammalian hypoxia‐inducible factor or dioxin receptor, which makes homo dimers as well as heterodimers with ARNT . A feature of the proposed complex model is that it can work with pure Pr dimers and mixed Pfr/Pr Rp BphP1 dimers.…”

Acute Exposure to TCDD Increases Liver Disease Progression in Mice With Carbon Tetrachloride-Induced Liver Injury

“…AhR activity can be repressed by a protein called the AhR repressor (AhRR). The gene encoding this protein contains an XRE and is expressed in response to AhR activation (Sakurai et al, 2017). The AhRR functions as a repressor by competing with AhR to form a heterodimer complex with ARNT, which prevents formation of the transcriptionally active AhR/ARNT complex (Mimura et al, 1999;Vogel et al, 2016).…”