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Published in final edited form as: J Mol Biol. 2023 Nov 20;436(3):168370. doi: 10.1016/j.jmb.2023.168370

Per-ARNT-Sim (PAS) Domains in Basic Helix-Loop-Helix (bHLH)-PAS Transcription Factors and Coactivators: Structures and Mechanisms

Nicolas Daffern 1,1, Ishwar Radhakrishnan 1,*
PMCID: PMC10922228  NIHMSID: NIHMS1949306  PMID: 37992889

Abstract

PAS domains are ubiquitous in biology. They perform critically important roles in sensing and transducing a wide variety of environmental signals, and through their ability to bind small-molecule ligands, have emerged as targets for therapeutic intervention. Here, we discuss our current understanding of PAS domain structure and function in the context of basic helix-loop-helix (bHLH)-PAS transcription factors and coactivators. Unlike the bHLH-PAS domains of transcription factors, those of the steroid receptor coactivator (SRC) family are poorly characterized. Recent progress for this family and for the broader bHLH-PAS proteins suggest that these domains are ripe for deeper structural and functional studies.

Graphical abstract

graphic file with name nihms-1949306-f0001.jpg

Background and Overview

PAS domains were first identified through sequence comparisons of basic helix-loop-helix (bHLH) transcription factors and were named after two Drosophila proteins, period (Per) and single-minded (Sim), and a human protein, the aryl hydrocarbon receptor nuclear translocator (ARNT).1,2 The domains were subsequently found to be far more widespread, being found in all three principal domains of life. They occur in a wide variety of proteins but particularly those involved in signal transduction. They display extraordinary functional diversity as protein-protein interaction modules, and through their ability to bind diverse ligands and cofactors, as molecular sensors, transducing environmental cues. The three-dimensional structures of a broad range of PAS domains have provided important insights into how they bind and sense ligands directly (or indirectly via bound cofactors) and effect chemical and physical transformations.3,4

PAS domains span a vast sequence space sharing low levels of pairwise sequence identity with homologs that are often deemed to be in the twilight or midnight zones of sequence homology.5 Nonetheless, a defining structural feature of the PAS fold is the presence of a five-stranded anti-parallel β-sheet with β-strands topologically arranged in the order 2-1-5-4-3 (βB-βA-βI-βH-βG; Fig. 1a). Linking the strands on either end of the β-sheet are typically two or more α-helices (designated αC, αD, αE, and αF; Fig. 1a) that engage with the inner surface of the sheet. The length and orientation of the helices with respect to the sheet are variable, but ligands and cofactors are typically bound in clefts between the helices and the sheet (Fig. 1b).3

Figure 1.

Figure 1.

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Structural features of a canonical PAS domain in bHLH-PAS transcriptional activators, domain maps of bHLH-PAS transcription factors and coactivators, and two distinct inter-domain architectures for ARNT and BMAL-bearing bHLH-PAS heterodimers. (a) Structure of the PAS-B domain belonging to the Drosophila homologue of the human aryl hydrocarbon receptor (AHR) and (b) close-up views of the AHR ligand-binding pocket occupied by α-naphthoflavone (rendered in green; PDB ID: 7VNH).27 The view in panel b is slightly rotated to facilitate cross-eyed stereo viewing of the backbone structure. Protein domains and sequence motifs in bHLH-PAS transcription factors including activators and repressors (c) and steroid receptor coactivators (SRCs; d). The aryl hydrocarbon receptor repressor (AHRR) lacks the PAS-B domain while an isoform of HIF-3α lacks the C-terminal transactivation/transrepression domain (TAD/TRD). The domains and motifs are drawn approximately to scale although boundaries for the TAD/TRD domain, when present, in the case of bHLH-PAS factors are highly variable. Previously designated TADs are indicated. Sites of biochemically characterized protein-protein interactions are indicated below each domain/motif. Note that while some of the interactors have been shown to interact specifically only with certain bHLH-PAS family members and not others, the specificity of these interactions remains to be characterized, and therefore, interaction with one member should not be assumed to extend automatically to all the other family members. Abbreviations: ANKRA2: ankyrin repeat protein 2; Brg-1: brahma related gene 1 protein; CARM1: coactivator associated arginine methyltransferase 1; CBP: CREB binding protein; CID: CBP/p300 interaction domain; CALCOCO1: calcium-binding and coiled-coil containing protein 1; ZNT9: zinc transporter 9; MEF-2C: myocyte enhancer factor 2C; PRMT1: protein arginine N-methyltransferase 1; RID: nuclear receptor interaction domain; STAT: signal transducer and activator of transcription factor; TACC3: transforming acidic coiled-coil 3; TRIP11: thyroid receptor interacting protein 230. Protein interactors are colored as follows: chromatin-modifiers: magenta; chromatin-remodelers: green; activators and coactivators: black; corepressors: blue. (e) Crystal structures of bHLH-PAS domains of transcriptional activators superimposed on the respective bHLH domains (PDB IDs: 4ZPK, 4H10, 4F3L, 5SY7, 7XI3, and 7XI4).9–11,15,87 For CLOCK:BMAL1, the bHLH domain of the apo and DNA-bound structures were superimposed (PDB IDs: 4F3L and 4H10). Protein backbones are color ramped according to the key at the bottom.

This review will focus on some recent progress for members of the bHLH-PAS family of transcription factors and coactivators, the largest family of PAS domain-containing proteins in eukaryotes. Unlike bHLH-PAS transcription factors, the coactivators are considerably less well characterized, and in this review, the key lessons learned from studies of the former will be used to contrast the latter. More comprehensive reviews exploring the structure and mechanism of bHLH-PAS transcription factors are discussed elsewhere in this issue. The bHLH-PAS family comprises 16 transcriptional activators and repressors and 3 transcriptional coactivators.6 Members of the family play critical regulatory and protective roles in sensing and responding to environmental toxins, oxygen levels in cells and tissues, besides regulating circadian rhythms as well as growth and development programs of a broad range of cell types and organs. All bHLH-PAS proteins, barring one, share a common domain organization comprising a bHLH DNA-binding domain followed by two PAS domains (designated PAS-A and PAS-B; Fig. 1c). The transcription factors exhibit considerable sequence diversity in their C-terminal halves,7 which in certain factors harbor transactivation or transrepression domains (TADs/TRDs) for engagement with coactivators and corepressors with chromatin-modifying and chromatin-remodeling activities. The bHLH-PAS coactivators also exhibit substantial sequence diversity in the region C-terminal to the PAS domains that comprise almost three-fourths of the total protein length (Fig. 1d). However, these regions harbor short, conserved sequence motifs and domains for engagement with nuclear receptors and other coactivators with chromatin-modifying activities.

PAS Domains in bHLH-PAS Transcription Factors – Lessons from Structural Biology

The structure and function of PAS domains in the context of the bHLH domain or in isolation have been described for several bHLH-PAS transcriptional activators.8–15 These factors assort into two classes with 12 members in Class I and four members in Class II. Class I factors specifically heterodimerize with Class II factors and bind with high affinity to specific DNA response elements through the bHLH domains (Fig. 1c). The PAS-A and PAS-B domains serve to provide additional surfaces for heterodimerization that are critical for the stability of these assemblies. Through these interactions, the bHLH, PAS-A, and PAS-B domains form a variety of inter- and intra-molecular interfaces, producing diverse quaternary structures. Broadly, two types of structural architectures have been described that correlate with the identity of the Class II factors (this class is further divided into two groups of two closely related proteins with ARNT and the brain and muscle ARNT-like 1 or BMAL1 serving as prototypes for each group; Fig. 1e).8–15 These differences likely have important implications in DNA target site selection because the PAS domains of the Circadian Locomotor Output Cycles Kaput (CLOCK)-BMAL1 heterodimer appear to have a role in engaging with the disc-like histone body of the nucleosome.16 However, some of the largest heterodimeric interfaces between corresponding domains including bHLH/bHLH, PAS-A/PAS-A, and PAS-B/PAS-B share similarities across the two types of architectures.8–15

The differences in overall quaternary structures notwithstanding, the PAS-A and PAS-B domains are sufficiently exposed to solvent to engage in additional interactions with other proteins. Besides histones, this was demonstrated for the ARNT PAS-B domain that engaged with coiled-coil coactivators including TRIP230, CALCOCO1, and TACC3.17–19 Intriguingly, both ARNT and the hypoxia inducible factor 2 α (HIF-2α) cooperatively engage with both sides of the TACC3 coiled-coil dimer via their respective β-sheets, structurally bolstering the ternary activator-coactivator complex (Fig. 1c & 1e). The recruitment of coactivators via the PAS-B domain is interesting because certain bHLH-PAS transcription factors such as HIF-1/2/3α can independently recruit coactivators including cyclic AMP response element binding protein (CREB)-binding protein (CBP) and its paralog p300 through the C-terminal TADs (Fig. 1c).20 These multi-valent interactions likely play a key role in building and structurally bolstering protein-protein interaction networks in addition to recruiting chromatin-modifying activities at gene promoters/enhancers.

Unlike canonical transcription factors with independent DNA-binding and transactivation/transrepression domains that typically regulate transcription via an active mechanism involving coregulator recruitment, bHLH-PAS transcription factors regulate transcription via both active and passive mechanisms. For example, the repressor AHRR competes with AHR for ARNT heterodimerization via the bHLH-PAS domains to repress AHR-mediated transcription passively, but also actively through the recruitment of corepressors and histone deacetylases.21–23 Cryptochrome represses transcription mediated by CLOCK-BMAL1 complexes by engaging in multi-valent interactions with the PAS-B domain of CLOCK and the TAD of BMAL1, thereby blocking CBP/p300 recruitment.24,25 Thus, bHLH-PAS transcription factors have evolved agile regulatory mechanisms that permit rapid, dynamic transitions between transcriptionally active and repressed states in response to environmental cues.

Both PAS-A and PAS-B domains in bHLH-PAS factors harbor internal pockets, providing another avenue for these factors to sense and respond to environmental signals.11 Small-molecule ligands for several of these domains, including AHR, HIF-3α, NPAS2, and CLOCK have been described and in some cases structurally characterized (Fig. 1b).14,26–30 Sharing features in common with certain ligand-dependent nuclear receptors, ligand binding to AHR dissociates the protein from its complex with heat shock factor 90, allowing it to subsequently translocate to the nucleus.31,32 A variety of synthetic ligands have also been described for PAS domains of bHLH-PAS factors that similarly cause dissociation of the corresponding heterodimeric complexes.33–37 Thus, even when the natural ligands are unknown, the presence of internal pockets in these PAS domains provide an opportunity to alter its normal activity. This is best exemplified in the case of HIF2-α for which several antagonists were successfully developed and one of which called Belzutifan recently gained FDA approval as treatment for renal cell carcinoma.38–41 An AHR agonist designated Tapinarof was also approved recently by the FDA for the treatment of psoriasis and atopic dermatitis.42–44 Comprehensive reviews of ligand-binding by PAS domains are discussed elsewhere in this issue.

PAS Domains in bHLH-PAS Transcriptional Coactivators

The steroid receptor coactivator family of bHLH-PAS proteins comprises three members including SRC1, SRC2/GRIP1/TIF2, and SRC3/AIB1/pCIP (also known as nuclear coactivators, NCoA1, NCoA2, and NCoA3, respectively; Fig. 1d).45–48 SRCs were discovered as critical mediators of transactivation effected by the 5-member steroid receptor family that each play fundamentally important roles in human reproductive biology and physiology; consequently, they are frequently implicated in a variety of NR-associated pathologies and prominently cancer.49 Like the steroid receptors, SRCs emerged late in evolution and are found only in vertebrates.50 SRCs were subsequently shown to function as coactivators for most of the 48-member nuclear receptor (NR) superfamily. These coactivators function as interaction hubs engaging in numerous protein-protein interactions involving DNA-bound activators, other coactivators, chromatin-modifying and chromatin-remodeling enzymes, forming interaction networks with components of the transcription machinery (Fig. 1d).45,49 At the molecular level, SRCs are recruited via short LxxLL sequence motifs located in the central region of the proteins by the ligand-binding domains of NRs. This has been extensively studied and structurally well characterized.51–56 Another well characterized interaction is the high affinity interaction with the histone acetyltransferase (HAT) activity-bearing CBP and p300 coactivators (Fig. 1d).57,58 SRCs also recruit other chromatin modifiers including CARM1, PRMT1, and PCAF via the domains at the C-terminus of the proteins.59–61 SRCs have been proposed to function as HATs themselves with the putative catalytic domain residing near the C-terminus of the protein;61,62 however, no high-resolution structures corresponding to these regions have yet been described and these regions appear to be devoid of significant secondary or tertiary structure in predicted models, suggesting that the detection of HAT activity in early studies could be due to associated factors.

SRCs harbor the bHLH DNA-binding motif, but there are no reports of these proteins directly binding to DNA (see below). SRC bHLH-PAS domains appear to serve as sites for interaction with transcription factors and other coactivators (Fig. 1d). Unlike the bHLH-PAS transcription factors, none of the bHLH or PAS domains of the coactivators, apart from SRC1 PAS-B, have been structurally characterized. The SRC1 PAS-B domain itself is somewhat unique in that a single longer helix (αD) replaces two short helices (αD and αE), exposing a hydrophobic cleft on the surface of the domain (Fig. 2a). In early studies, the SRC1 PAS-B domain was implicated in interactions with the TAD of the signal transducer and activator of transcription 6 (STAT6), a transcription factor that is activated by the binding of certain cytokines to receptor tyrosine kinases.63,64 Structural studies of the activator-coactivator interaction established the cleft as the docking site for two TAD helices of STAT6, one of which coincidentally also harbors an LxxLL motif (Fig 2a).65,66 Interestingly, in early studies STAT6 was shown to specifically interact only with SRC1 but not with SRC2 or SRC3,63 likely reflecting the sequence divergence of SRCs in the PAS-B domain (Fig. 3a). Members of the STAT family also show poor sequence conservation across paralogs in their C-terminal TADs. Although STAT5 has been implicated in interactions with the SRC1 bHLH-PAS region,67 it is likely that it interacts differently than STAT6. STAT3 has also been shown to recruit SRC1, again through a mechanism distinct from the other STATs; in this regard, STAT3 targets a completely different region of SRC1, C-terminal to the bHLH-PAS domains (Fig. 1d).

Figure 2.

Figure 2.

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SRC1 PAS-B domain as a coactivator recruitment site for transcriptional activators and as a site for ligand-binding to internal and solvent-exposed pockets harboring conserved cysteine residues. (a) NMR structure of SRC1 PAS-B bound to STAT6 TAD with the polypeptide backbones depicted as ribbons (left) and with PAS-B depicted as a molecular surface and the TAD backbone as a ribbon along with the side chains of selected residues at the protein-protein interface (right; PDB ID: 5NWM).66 (b) An experimentally validated AlphaFold2-multimer model of SRC1 PAS-B bound to the AF1 TAD of Nurr1.68 (c) Crystal structure of a STAT6 TAD inspired stapled peptide bound to SRC1 PAS-B (PDB ID: 5Y7W).86 The PAS-B surface in panels a, b and c is color-coded according to hydrophobicity in ChimeraX (polar: blue-green; hydrophobic: orange; neutral: white).88 (d) An internal pocket in the SRC1 PAS-B domain (PDB ID: 5Y7W) computed using CASTp.86,89 The side chains of residues lining the pocket are shown, all of which are essentially invariant in SRC1 orthologs. The location of a cysteine residue is indicated. (e) A solvent-exposed pocket on the opposite side of the domain that serves as a binding site for a prostaglandin, 15d-PGJ2. The small-molecule ligand is covalently bound to a cysteine residue (C347) near the pocket. An experimentally consistent structural model derived from molecular dynamics simulations featuring hydrophobic and salt bridging interactions between the domain and 15d-PGJ2. The side chains of residues lining the pocket, all of which are conserved in SRC1 orthologs, are rendered in stick representation within the semi-transparent molecular surface, which is rendered to accentuate the surface pocket.

Figure 3.

Figure 3.

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Sequence conservation and an AlphaFold2 structural model for the SRC bHLH-PAS coactivator family. (a) A Clustal Ω-guided multiple sequence alignment of SRC orthologs from six representative vertebrate species with the sequences of each member clustered together.90 The bHLH and PAS domain boundaries are indicated at the top of the alignment. The stars denote conserved residues in the bHLH domain that are typically involved in engaging E-box DNA sequences. The filled circles correspond to conserved cysteine residues in SRC1 orthologs that could serve as sites for covalent modification by endogenous and synthetic ligands. The boxed region corresponds to a ~50 residue segment within PAS-A that exhibits significant sequence diversity. (b) Two views of an AlphaFold2 model of human SRC1 spanning the bHLH and PAS domains (UniProt accession: Q15788). The protein backbone is color ramped from blue to red (top view) following the scheme depicted in Figure 1e, whereas it is colored according to the predicted local difference test (pLDDT) metric (bottom view) according to the color key on the left. The arrows identify the locations of two long loops each spanning ~20 residues on either side of the βG strand in the PAS-A domain. (c) Molecular surfaces of the SRC1 bHLH and PAS-A domains color-coded according to hydrophobicity in ChimeraX (polar: blue-green; hydrophobic: orange; neutral: white).88 The surfaces are rendered semi-transparently so that backbone secondary structural elements are partially visible.

More recently, we showed that the nuclear receptor Nurr1 (aka NR4A2) also interacts with SRC1 by engaging its N-terminal TAD called activation function 1 (AF1) with the PAS-B domain through a similar mechanism as STAT6 (Fig. 2b).68 Unlike other well-characterized NRs, Nurr1 and its closely related paralogs, Nur77 and NOR1 (aka NR4A1 and NR4A3), harbor atypical ligand-binding domains and are unable to recruit SRCs by engaging LxxLL motifs, relying predominantly on the interaction mediated by the N-terminal AF1 region.69–71 Whether Nurr1 and its paralogs make additional contacts with SRCs remains to be established. The involvement of the cryptic AF1 TAD in engaging the SRC1 PAS-B domain raises the possibility that the AF1 regions of other NRs might also play a similar role, contributing to ligand-independent mechanisms of transactivation.

The bHLH-PAS domains of SRCs also serve as the interaction site for other transcription factors including myogenic enhancer factor 2C (MEF-2C), myogenin, and myocardin, all of which play essential roles in muscle development, as well as other coactivators including the calcium-binding coiled-coil coactivator, CALCOCO1, and the zinc transporter ZNT9, which moonlights as a transcriptional coactivator (Fig. 1d).17,72–75 Biochemical and structural characterizations are needed to establish whether these interactions involve solely the SRC PAS-B domain and/or the other domains. SRCs appear to share a few interaction partners, mostly coactivators, with the bHLH-PAS activators. Although recruitment of secondary coactivators by coactivators is not unprecedented (indeed, the recruitment of CBP/p300 by SRCs is well established), this could suggest competition between activators and coactivators for the same binding site or the formation of multi-valent protein-protein interaction networks. With regards to the latter, SRCs themselves appear to be recruited by certain bHLH-PAS activators.76,77 It is also plausible that SRCs are capable of binding DNA through the bHLH domains. Further biochemical and structural studies addressing this specific issue are needed to clarify the role of these domains, especially since they are not only well conserved across the SRC family in diverse species, but also harbor similar residues as bHLH-PAS transcription factors, especially at those positions known to engage DNA (Fig. 3a). In this regard, we note that SRCs are classified as likely sequence-specific DNA-binding transcription factors as obligate hetero-oligomers in the manually curated transcription factor database.78

The PAS-B domain of SRCs has been suggested to serve as a hetero- and homodimerization site for the CBP/p300-interaction domain (CID) found in these proteins (Fig. 1d).79 Since the affinity of the interaction is not known, it is not clear whether it could compete effectively with the high-affinity interaction between the CID and CBP/p300.58 Nevertheless, this interaction between effectively two transactivation domains might serve as a regulatory mechanism for inactivating coactivator(s) in the absence of cognate interactors.

Contrasting Features and Roles of SRC bHLH-PAS domains

The accurate prediction of protein tertiary structures using AlphaFold2 has provided an alternative avenue for gaining insights typically afforded only by experimentally determined structures.80 Since the oligomerization status of the SRCs is presently unknown, i.e., whether it is a monomer, a homo-oligomer or a hetero-oligomer, the monomeric structure of the bHLH-PAS domains of SRC1 predicted by AlphaFold2 was analyzed (Fig. 3b). In this model, all three domains appear to adopt a beads-on-a-string type architecture with no inter-domain interactions predicted. More precisely, the predicted aligned errors between individual domains are large, indicative of low confidence for inter-domain interactions. This would suggest that the individual domains are poised to engage in interactions with other proteins. In this regard, the solvent-exposed surfaces of both SRC1 bHLH and PAS-A exhibit significant hydrophobic character; comparable surfaces in bHLH-PAS transcription factors are involved in heterodimeric interactions.8–15 Further biochemical and structural studies are needed to test these predictions and establish the precise molecular roles of the individual domains.

Sequence analysis reveals a high degree of conservation in the bHLH and PAS-A regions across all three SRC family members (Fig. 3a), suggesting that these domains likely perform similar functions in paralogous proteins, perhaps by engaging with the same heterodimeric partner protein. Note that there is a ~50 residue segment in PAS-A that is predicted to encompass a β-strand at one edge of the β-sheet that features two long, poorly conserved loops (Fig. 3a & 3b). In contrast, the SRC PAS-B regions show the greatest sequence variation across family members although these regions are highly conserved within each member (Fig. 3a). This suggests functional divergence that might be manifest in the form of preferential engagement with specific interactors.

Like the PAS domains of bHLH-PAS transcription factors, the SRC1 PAS-B domain harbors an internal pocket surrounded by highly conserved (essentially invariant) residues and adjacent to the STAT6/Nurr1 binding site (Fig. 2d). Like many PAS domains, the identity of the cognate ligand(s) for this PAS domain remains to be established. Although in silico docking suggested binding by fatty acids, somewhat akin to the modes in previously described structures,81 our studies serendipitously identified a second solvent-exposed pocket on the opposite side of the domain, but not far from the binding site used to engage transcriptional activators (Fig. 2e).82 This pocket appears to be potentially targeted by a prostaglandin, a signaling molecule and fatty acid derivative, that reacts specifically and covalently with a cysteine residue in the vicinity. Although the physiological relevance of this observation remains to be established and the binding mode is novel compared with those described previously,83–85 it nevertheless opens new lines of inquiry for both pockets and their role in potentially modulating protein-protein interactions. Even though no small-molecule inhibitors of SRC1 PAS-B have yet been described, a STAT6 TAD inspired stapled peptide has shown promise in blocking the association between SRC1 and STAT6 that could also be useful in other settings (Fig. 2c).86

Summary and Prospectus

The past decade has witnessed considerable progress in our understanding of the mechanisms by which bHLH-PAS transcription factors exert their effects by binding DNA, small-molecule ligands and other proteins, including bHLH-PAS factors. By contrast, our understanding of the structural and mechanistic biology of bHLH-PAS transcriptional coactivators is still in its infancy. But recent progress raises many fundamental questions about these proteins, making them ripe for these types of characterizations. An especially critical gap in our knowledge relates to the role of the conserved pockets in most bHLH-PAS proteins. Therefore, an important goal for the near future will be to identify endogenous small-molecule ligands that bind to these pockets and assess their impact on biology, especially in light of recent successes in exploiting these pockets for developing novel, effective molecular therapeutics. Another important goal would be to characterize the bHLH-PAS domains in the context of full-length proteins to gain an understanding of how these domains cooperate with other domains within these proteins as well as with other proteins to effect transcriptional outcomes. With cryogenic electron microscopy and artificial intelligence-based approaches such as AlphaFold transforming contemporary structural biology, these goals seem both plausible and timely.

Highlights.

  • The bHLH-PAS transcription factor family functions as sensors and transducers of environmental signals

  • Compared to bHLH-PAS activators/repressors, little is known about the structure and mechanism of bHLH-PAS coactivators

  • Recent progress suggests interesting parallels but also important differences between the functionally-distinct groups

  • Intensive structural studies are needed to understand bHLH-PAS coactivators function and their modulation by small-molecules

Acknowledgements:

This work was supported by a grant from the Sherman Fairchild Foundation to I.R. N.D. was supported by a Molecular Biophysics Training Program traineeship (T32 GM008382).

Footnotes

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Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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