Structural characterization of mammalian bHLH-PAS transcription factors
Open accessAbstract
The mammalian basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factors share common architectural features that include a bHLH DNA-binding domain and tandemly positioned PAS domains. The sixteen members of this family include the hypoxia-inducible factors (HIF-1α and HIF-2α), ARNT (also known as HIF-1β), CLOCK and BMAL1. Most bHLH-PAS proteins have been genetically linked to variety of diseases in humans, including cancers, metabolic syndromes and psychiatric conditions. To function as transcription factors, the bHLH-PAS proteins must form heterodimeric complexes. Recent crystallographic studies of HIF-α-ARNT and CLOCK-BMAL1 complexes have unveiled the organization of their multi-domain bHLH-PAS-A-PAS-B segments, revealing how these architectures can give rise to unique patterns of heterodimerization. As our structural understanding becomes better integrated with ligand-discovery and target gene identification, a more comprehensive picture of their architectural and functional properties will emerge.
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The reliability of the homology model derived from the HIF-2α template is supported by the high conservation of the PAS fold, especially among bHLH-PAS proteins, with RMSD on Cα lower than 2 Å even between PAS domain pairs with 20-30% identity.
“The reliability of the model derived from this template is supported by the observation that the PAS fold is highly conserved, especially among the bHLH-PAS proteins which also share functional similarities2,33 (RMSD on Cα lower than 2 Å even between PAS domain pairs with 20–30% identity).”
From Modeling the binding of diverse ligands within the Ah receptor ligand binding domain (2019) · cites this paper as [33]
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“AHR belongs to the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family of transcription factors, characterized by a conserved bHLH DNA binding domain at its N-terminus, followed by tandem PAS domains (PAS-A and PAS-B), and an unstructured transactivation domain 13 – 15 .”
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- Authors
- Wu, D., & Rastinejad, F.
- Affiliations
- Shandong University (CN)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Rastinejad, Fraydoon
- Venue
- Current Opinion in Structural Biology
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 43
- Pages
- 1-9
- ISSN
- 0959-440X (ISSN-L)
- PMC
- PMC5382129
- OpenAlex
- W2528294899
- Cited by
- 122
- References
- 55
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 7 · 2023: 20 · 2022: 15 · 2021: 15 · 2020: 9 · 2019: 15 · 2018: 6 · 2017: 6 · 2016: 1
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- bHLH-PAS transcription factors, basic helix-loop-helix domain, PAS domain, hypoxia-inducible factor, HIF-1α, HIF-2α, ARNT, clocks, Bmal1, heterodimerization, protein structure, crystallography, transcriptional regulation
- MeSH terms
- Protein Domains, Animals, Humans, Protein Structure, Quaternary, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Protein Multimerization
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