Role of the Per/Arnt/Sim domains in ligand-dependent transformation of the aryl hydrocarbon receptor

Anatoly Soshilov, Michael S. Denison

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


The aryl hydrocarbon receptor (AhR) mediates the toxic and biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. In a process termed transformation, ligand binding converts the AhR into its high affinity DNA binding form that represents a dimer of the AhR and Arnt, a closely related nuclear protein. During transformation, protein chaperone Hsp90 is thought to be replaced by Arnt in overlapping binding sites in the basic helix loop helix and PASB domains of the AhR. Here, analysis of AhR variants containing a modified PASB domain and AhR PASA-PASB fragments of various lengths revealed (i) an inhibitory effect on transformation concomitant with Hsp90 binding in the PASB domain, (ii) an ability of the PASA-PASB fragment of the AhR to reproduce key steps in the transformation process, and (iii) a ligand-dependent conformational change in the PASA domain consistent with increased PASA exposure during AhR transformation. Based on these results, we propose a new mechanism of AhR transformation through initiation of Arnt dimerization and Hsp90 displacement in AhR PASA/B domains. This study provides insights into mechanisms of AhR transformation, dimerization of PAS domain proteins, and Hsp90 dissociation in activation of its client proteins.

Original languageEnglish (US)
Pages (from-to)32995-33005
Number of pages11
JournalJournal of Biological Chemistry
Issue number47
StatePublished - Nov 21 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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