Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation
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The Aryl hydrocarbon Receptor (AhR) is a transcription factor that mediates the biochemical response to xenobiotics and the toxic effects of a number of environmental contaminants, including dioxins. Recently, endogenous regulatory roles for the AhR in normal physiology and development have also been reported, thus extending the interest in understanding its molecular mechanisms of activation. Since dimerization with the AhR Nuclear Translocator (ARNT) protein, occurring through the Helix-Loop-Helix (HLH) and PER-ARNT-SIM (PAS) domains, is needed to convert the AhR into its transcriptionally active form, deciphering the AhR:ARNT dimerization mode would provide insights into the mechanisms of AhR transformation. Here we present homology models of the murine AhR:ARNT PAS domain dimer developed using recently available X-ray structures of other bHLH-PAS protein dimers. Due to the different reciprocal orientation and interaction surfaces in the different template dimers, two alternative models were developed for both the PAS-A and PAS-B dimers and they were characterized by combining a number of computational evaluations. Both well-established hot spot prediction methods and new approaches to analyze individual residue and residue-pairwise contributions to the MM-GBSA binding free energies were adopted to predict residues critical for dimer stabilization. On this basis, a mutagenesis strategy for both the murine AhR and ARNT proteins was designed and ligand-dependent DNA binding ability of the AhR:ARNT heterodimer mutants was evaluated. While functional analysis disfavored the HIF2α:ARNT heterodimer-based PAS-B model, most mutants derived from the CLOCK:BMAL1-based AhR:ARNT dimer models of both the PAS-A and the PAS-B dramatically decreased the levels of DNA binding, suggesting this latter model as the most suitable for describing AhR:ARNT dimerization. These novel results open new research directions focused at elucidating basic molecular mechanisms underlying the functional activity of the AhR.
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Modeling studies on the AhR:ARNT dimer, based on the HIF-2α:ARNT template, predicted that the Fα/Gβ site may be involved in the dimerization interface.
“our modeling studies on the AhR:ARNT dimer, based on the HIF-2α:ARNT template, predicted that the Fα/Gβ site may be involved in the dimerization interface47,48.”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [47]
The Results (Template selection and modeling strategies; Characterization of the dimerization interfaces, page unavailable) describe an AhR:ARNT model based on the HIF-2α:ARNT structure and place its proposed interface at the β-sheets of both domains. They do not identify an Fα/Gβ site as part of that interface. The Discussion further says the authors’ data refute the HIF-2α:ARNT-based model. (LLM, conf=0.84)
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Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450910
Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450916
Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450913
Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450901
Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450907
Jiang, C., Lv, G., Ge, J., He, B., Zhang, Z., Hu, Z., & Zeng, B. (2021) · Figshare · doi:10.6084/m9.figshare.14450904
- Authors
- Corrada, D., Soshilov, A. A., Denison, M. S., & Bonati, L.
- Affiliations
- University of Milano-Bicocca (IT)
- University of California, Davis (US)
- Corresponding author
- Bonati, Laura
- Venue
- PLOS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-06-13
- Volume
- 12
- Issue
- 6
- Pages
- e1004981
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC4905635
- OpenAlex
- W2437960705
- Cited by
- 43
- References
- 61
- Citations by year
- 2025: 6 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 13 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 2
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Environmental Health Sciences (R01ES07685)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- aryl hydrocarbon receptor, ARNT, PAS domain, protein dimerization, helix-loop-helix, bHLH-PAS proteins, homology modeling, binding free energy, MM-GBSA, hot spot prediction, mutagenesis, DNA binding, Clock/BMAL1, transcription factor activation
- MeSH terms
- Protein Domains, Humans, Models, Molecular, Mutation, Receptors, Aryl Hydrocarbon, Computational Biology, Aryl Hydrocarbon Receptor Nuclear Translocator
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