Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

Seok, Seung-Hyeon; Lee, Woojong; Jiang, Li; Molugu, Kaivalya; Zheng, Aiping; Li, Yitong; Park, Sanghyun; Bradfield, Christopher A.; Xing, Yongna

doi:10.1073/pnas.1617035114

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

Journal Article · Mon Apr 10 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1617035114· OSTI ID:1372922

^[1]; Lee, Woojong ^[1]; Jiang, Li ^[2]; Molugu, Kaivalya ^[1]; Zheng, Aiping ^[1]; Li, Yitong ^[1]; Park, Sanghyun ^[1]; Bradfield, Christopher A. ^[1]; Xing, Yongna ^[1]

Univ. of Wisconsin, Madison, WI (United States)
Univ. of Wisconsin, Madison, WI (United States); Chinese Academy of Agricultural Sciences, Harbin (China)

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. Furthermore, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: McArdle; Univ. of Wisconsin

OSTI ID:: 1372922

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 21 Vol. 114; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
AHR
ARNT
DNA recognition
dimerization
transcriptional complex

Structural hierarchy controlling dimerization and target DNA recognition in the AHR transcriptional complex

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