Assembly and function of bHLH–PAS complexes

Abstract

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), hypoxia-inducible 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 ARNT-like 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 … [↵][1]1To whom correspondence should be addressed. Email: cpartch{at}ucsc.edu. [1]: #xref-corresp-1-1