Archives of Toxicology

, Volume 92, Issue 3, pp 1151–1160 | Cite as

Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291

  • A. Tkachenko
  • M. Bermudez
  • S. Irmer-Stooff
  • D. Genkinger
  • F. Henkler-Stephani
  • G. Wolber
  • A. Luch
Molecular Toxicology
  • 191 Downloads

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in the metabolism of physiological substances and xenobiotics, representing an interesting target in both toxicology and pharmacology. In this study, we investigated the ligand-dependent conjunction of nuclear import of the human AHR in living cells and target gene induction. Our findings strengthen the theory that the AHR triggers a precisely defined and rapid reaction upon binding to endogenous ligands, while the xenobiotic β-naphthoflavone only induces rather unspecific and slow effects. To better illuminate the ligand-mediated responses of the human AHR, we applied site-directed mutagenesis and identified histidine 291 as key residue for AHR functionality, essential for both nuclear import and target gene induction. Contrary, replacing histidine at position 291 by alanine did not affect nucleo-cytoplasmic shuttling, showing that permanent endogenous import and ligand-induced import of the AHR into the nucleus are two independent and differently regulated processes. Combining these observations with our structural investigations using a homology model of the AHR-PAS B domain, we suggest a dual role of histidine 291: (1) a major role for shaping the ligand binding site including direct interactions with ligands and, (2) an essential role for the conformational dynamics of a PAS B loop, which most likely influences the association of the AHR with the AHR nuclear translocator through interference with their protein–protein interface.

Keywords

AHR Ligand binding LBD PAS B ARNT interaction 

Notes

Acknowledgements

We thank the computing center of the Freie Universität Berlin (ZEDAT) for providing the compute cluster SOROBAN for molecular dynamics calculations.

Compliance with ethical standards

Funding sources

We acknowledge intramural funding at the German Federal Institute for Risk Assessment (BfR) Grant #1322-338.

Supplementary material

204_2017_2129_MOESM1_ESM.pdf (689 kb)
Supplementary material 1 (PDF 688 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Chemical and Product SafetyGerman Federal Institute for Risk Assessment (BfR)BerlinGermany
  2. 2.Institute of PharmacyFreie Universität BerlinBerlinGermany

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