Abstract
The basic helix–loop–helix/Per-ARNT-SIM (bHLH–PAS) proteins are a class of transcriptional regulators, commonly occurring in living organisms and highly conserved among vertebrates and invertebrates. These proteins exhibit a relatively well-conserved domain structure: the bHLH domain located at the N-terminus, followed by PAS-A and PAS-B domains. In contrast, their C-terminal fragments present significant variability in their primary structure and are unique for individual proteins. C-termini were shown to be responsible for the specific modulation of protein action. In this review, we present the current state of knowledge, based on NMR and X-ray analysis, concerning the structural properties of bHLH–PAS proteins. It is worth noting that all determined structures comprise only selected domains (bHLH and/or PAS). At the same time, substantial parts of proteins, comprising their long C-termini, have not been structurally characterized to date. Interestingly, these regions appear to be intrinsically disordered (IDRs) and are still a challenge to research. We aim to emphasize the significance of IDRs for the flexibility and function of bHLH–PAS proteins. Finally, we propose modern NMR methods for the structural characterization of the IDRs of bHLH–PAS proteins.
Highlights
Introduction to bHLHPAS ProteinsThe basic helix–loop–helix/Per-ARNT-single-minded protein (SIM) proteins are a class of transcriptional regulators that commonly occur in living organisms
The basic helix–loop–helix/Per-ARNT-SIM proteins are a class of transcriptional regulators that commonly occur in living organisms
The structure predicted for class I proteins (Figure 5A,B) is undeniably more ordered, while class II proteins show a marked structure relaxation in their middle part (Figure 5C), which is C-terminally linked to the PAS-A domain responsible for specificity of gene activation by bHLH–PAS proteins [63]
Summary
The basic helix–loop–helix/Per-ARNT-SIM (bHLH–PAS) proteins are a class of transcriptional regulators that commonly occur in living organisms. The AHR has been described as a critical modulator of host–environment interactions, especially for immune and inflammatory responses [6] Another interesting example of a bHLH–PAS family member is the single-minded protein (SIM), which plays a significant role during central nerve cord [7] and genital imaginal disc development [8]. As AHR was shown to modulate the immune response in the respiratory tract, this protein can be potentially used as a therapeutic object for the treatment of various inflammatory lung diseases [13,14] Another member of the family, expressed mainly in the brain, neuronal PAS domain-containing protein 4 (NPAS4) has been proposed as a novel therapeutic target for depression and neurodegenerative diseases [15] and as a component of new stroke therapies [16]. The MET2 protein function in B. mori is not yet defined [40]
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