Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules

Background: Coiled-coil coactivators can enhance HIF-dependent gene transcription via direct interaction with the HIF/ ARNT heterodimer. Results: ARNT uses the ␤-sheet of the PAS-B domain to recruit coiled-coil coactivators. Conclusion: Coiled-coil coactivators bridge HIF and ARNT via the PAS-B domain ␤-sheet contacts to both proteins to form a ternary structure. Significance: This work reveals the mechanism for assembling a coiled-coil coactivator complex with the HIF-2 transcription factor heterodimer.

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“…2a, PDB code 4LPZ) (17). As anticipated, GCN4-TACC3-CT D622A/E629A crystallized as a parallel coiled-coil dimer.…”

Section: Gnc4 Fusion Protein Is Well Folded In Solutionsupporting

confidence: 60%

Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization

Guo

Scheuermann

Partch

et al. 2015

Journal of Biological Chemistry

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“…Does AHR-like ligand binding by PAS domains regulate other members of this protein family? Leveraging the existence of buried, hydrophilic cavities in PAS-B domains, Gardner and colleagues identified a series of small molecules that selectively target the HIF2-α or ARNT PAS-B domain to regulate heterodimer formation (12)(13)(14) or recruitment of coactivator proteins (15,16). A careful analysis of PAS domains in CLOCK, BMAL1, NPAS1, NPAS3, ARNT, HIF1-α, and HIF2-α identified potential ligand-binding pockets in both PAS-A and PAS-B domains, suggesting the broad potential for ligand binding in these transcription factors (4).…”

Section: O M M E N T a R Ymentioning

confidence: 99%

Assembly and function of bHLH–PAS complexes

Fribourgh

Partch

2017

Proc. Natl. Acad. Sci. U.S.A.

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The basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family of transcription factors coordinates the expression of distinct transcriptional programs to control processes from development to the hypoxia response and beyond. Despite differences in their target genes and modes of regulation, these transcription factors share a common domain architecture, consisting of a bHLH DNA-binding domain followed by tandem PAS domains and intrinsically disordered C-terminal regulatory domains. In PNAS, Seok et al. present the structure of the core bHLH-PAS dimer of the aryl hydrocarbon receptor (AHR)-aryl hydrocarbon nuclear receptor translocator (ARNT) transcription factor bound to DNA (1). This study provides a foundation for understanding how AHR-ARNT specifically recognizes its consensus DNA motif and highlights how changes in interdomain contacts may communicate information about ligand binding to regulate subcellular localization and transcriptional activation.The bHLH-PAS family is defined by formation of heterodimers comprising class I and class II subunits. Class I proteins are typically regulated by tissue or environmental-specific factors, whereas class II proteins are expressed ubiquitously. Examples of class I proteins include AHR (regulated by xenobiotics), hypoxiainducible factor-α (HIF-α, regulated by hypoxia), neuronal PAS domain proteins (NPAS, developmentally regulated), and circadian locomotor output cycles protein kaput (CLOCK, circadian rhythms). ARNT is the predominant class II subunit found in bHLH-PAS complexes, whereas the related protein brain and muscle ARNTlike 1 (BMAL1) appears to be primarily dedicated to CLOCK to regulate circadian rhythms. Although cellular studies have largely outlined the different regulatory mechanisms that control heterodimerization, subcellular localization, and activity of these complexes, the structural basis for their assembly and diverse functions has been unclear.The structure of AHR-ARNT by Seok et al.(1) adds to a recent bounty of bHLH-PAS structures, providing several key insights that address these fundamental questions. As the newest representative of ARNTcontaining bHLH-PAS complexes (2-4), this structure solidifies earlier observations noting a similar global architecture among heterodimers that share an ARNT subunit (Fig. 1). Notably, the PAS-A domains of AHR, NPAS3, and HIF1-α all make direct contacts with their own bHLH domains that tether the N-terminal PAS domain in close proximity to DNA. It appears that ARNT and BMAL1 confer distinct differences in the global architecture of the bHLH-PAS heterodimers via the spatial arrangement of their PAS domains (Fig. 1). Specifically, the PAS-A and PAS-B domains of ARNT are completely separated in space from one other, whereas the PAS domains of BMAL1 make numerous interdomain contacts that orient the CLOCK-BMAL1 heterodimer more linearly away from DNA (2, 5). Although the structure of AHR-ARNT by Seok et al. (1) lacks the PAS-B domains, its similarity in packing of the AHR and ARNT PAS-A domains suggests that the ove...

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“…Although members of the family share a relatively high degree of sequence similarity within the bHLH and PAS domains, a sequence alignment clearly segregates genes together into clusters that regulate the same pathway ( Figure 1). These findings highlight the importance of letting conservation guide identification of functional subclasses within bHLH-PAS proteins and ing of PAS domains from HIF-2α and its obligate heterodimeric partner ARNT, has led to the discovery of selective, high affinity exogenous small molecules that bind within the PAS domains to regulate protein interaction, suggesting that they may have potential applications for therapeutic modulation of bHLH-PAS function 12,14 . The ability to target specific bHLH-PAS transcription factors with PAS-binding small molecules and elicit tight control over gene expression pathways highlights the importance of gaining additional mechanistic information into this family of proteins.…”

Section: Modularity Within the Bhlh-pas Familymentioning

confidence: 96%

bHLH-PAS proteins: Functional specification through modular domain architecture

Michael¹,

Cl²

2013

OA Biochemistry

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IntroductionThe basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family of transcription factors respond to a wide range of external stimuli to regulate diverse biological processes ranging from development to circadian rhythms. These proteins selectively heterodimerize through relatively well-conserved bHLH and PAS domains, while differences in C-terminal regulatory domains confer opposing activities to either stimulate or repress transcription. The evolution of modular regulatory domains and the ability to selectively dimerize with different subunits within the family allows fine-tuning of gene expression through temporal and tissue-specific expression of bHLH-PAS subunits. The aim of this critical review is to discuss the functional specification through modular domain architecture of bHLH-PAS proteins. ConclusionThe modular domain architecture of bHLH-PAS transcription factors plays an integral role in their ability to keep mammals healthy and in tune with their environment.

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Regulating the ARNT/TACC3 Axis: Multiple Approaches to Manipulating Protein/Protein Interactions with Small Molecules

Cited by 43 publications

References 45 publications

Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization

Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia-inducible Factor Heterodimerization

Assembly and function of bHLH–PAS complexes

bHLH-PAS proteins: Functional specification through modular domain architecture

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