title: Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex.
abstract: The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors.forename: Seung-Hyeon
authors.identifier: 0000-0002-2396-8810
authors.initials: SH
authors.lastname: Seok
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|The University of Wisconsin School of Veterinary Medicine's Comparative Biomedical Sciences, University of Wisconsin, Madison, WI 53706.
authors.forename: Woojong
authors.initials: W
authors.lastname: Lee
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Biophysics Program, University of Wisconsin, Madison, WI 53706.
authors.forename: Kaivalya
authors.initials: K
authors.lastname: Molugu
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zheng
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors.forename: Yitong
authors.initials: Y
authors.lastname: Li
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Park
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705.|Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705; xing@oncology.wisc.edu.|The University of Wisconsin School of Veterinary Medicine's Comparative Biomedical Sciences, University of Wisconsin, Madison, WI 53706.|Biophysics Program, University of Wisconsin, Madison, WI 53706.|Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706.
authors.forename: Yongna
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D020836:Protein Structure, Quaternary; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator
keywords: AHR; ARNT; DNA recognition; dimerization; transcriptional complex