Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Wang, Zixi; Wu, Yaling; Li, Lanfen; Su, Xiao Dong

doi:10.1038/cr.2012.170

Cited by 92 publications

(96 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6a, b). The ARNT residues forming DNA contacts (R102, E98 and H94) were identically positioned in BMAL1 to recognize the GTG half site, as revealed by the crystal structure of isolated CLOCK-BMAL1 bHLH domain with E-box (59-CACGTG-39) DNA 39 . We further verified the importance of these residues in HIF-2a-ARNT by introducing mutations and detecting reduced DNA binding as a result (Extended Data Fig.…”

Section: Binding To Hypoxia Response Elementsmentioning

confidence: 97%

Structural integration in hypoxia-inducible factors

Potluri

et al. 2015

Nature

267

345

View full text Add to dashboard Cite

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

show abstract

Section: Binding To Hypoxia Response Elementsmentioning

confidence: 97%

Structural integration in hypoxia-inducible factors

Potluri

et al. 2015

Nature

267

345

View full text Add to dashboard Cite

show abstract

“…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 overall architecture of the heterodimer will be similar to NPAS1/3-ARNT and HIF1/2-α-ARNT complexes (2-4).…”

mentioning

confidence: 99%

Assembly and function of bHLH–PAS complexes

Fribourgh

Partch

2017

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

View full text Add to dashboard Cite

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...

show abstract

“…BMAL1 binds with a second bHLH-PAS protein via the PAS domain, CLOCK to form a heterodimer in the nucleus (Huang et al 2012). Via its bHLH domain, this heterodimer binds to E-box response elements in the promoter regions of Per (Per1 and Per2) and Cry genes (Cry1 and Cry2) (Buhr and Takahashi 2013;Wang et al 2013). This binding upregulates the transcription and translation of PER1, PER2, CRY1 and CRY2 proteins.…”

Section: Combined and Non-hormonal Actions Of Srcsmentioning

confidence: 97%

Multiple functions and essential roles of nuclear receptor coactivators of bHLH-PAS family

Pecenova

Farkas

2016

Endocrine Regulations

View full text Add to dashboard Cite

Classical non-peptide hormones, such as steroids, retinoids, thyroid hormones, vitamin D3 and their derivatives including prostaglandins, benzoates, oxysterols, and bile acids, are collectively designated as small lipophilic ligands, acting via binding to the nuclear receptors (NRs). The NRs form a large superfamily of transcription factors that participate virtually in every key biological process. They control various aspects of animal development, fertility, gametogenesis, and numerous metabolic pathways, and can be misregulated in many types of cancers. Their enormous functional plasticity, as transcription factors, relates in part to NR-mediated interactions with plethora of coregulatory proteins upon ligand binding to their ligand binding domains (LBD), or following covalent modification. Here, we review some general views of a specific group of NR coregulators, so-called nuclear receptor coactivators (NRCs) or steroid receptor coactivators (SRCs) and highlight some of their unique functions/roles, which are less extensively mentioned and discussed in other reviews. We also try to pinpoint few neglected moments in the cooperative action of SRCs, which may also indicate their variable roles in the hormone-independent signaling pathways.

show abstract

Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domains with E-box DNA

Cited by 92 publications

References 55 publications

Structural integration in hypoxia-inducible factors

Structural integration in hypoxia-inducible factors

Assembly and function of bHLH–PAS complexes

Multiple functions and essential roles of nuclear receptor coactivators of bHLH-PAS family

Contact Info

Product

Resources

About