title: The Q-rich/PST domain of the AHR regulates both ligand-induced nuclear transport and nucleocytoplasmic shuttling.
abstract: The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. Concomitantly mutants lacking this residue are exclusively localised in the nucleus. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650-661. Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding.
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Tkachenko
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Henkler
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Joep
authors.initials: J
authors.lastname: Brinkmann
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Sowada
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Genkinger
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kern
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Tewes
authors.initials: T
authors.lastname: Tralau
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Luch
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D049790:Nuclear Export Signals; D000072417:Protein Domains; D021381:Protein Transport; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008024:Ligands; D049790:Nuclear Export Signals; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human