**5. Conclusions**

The available structure characterization of bHLH–PAS proteins is limited to the relatively well-conserved domains bHLH, PAS-A, and PAS-B. Importantly, all structures deposited in the Protein Data Bank are obtained for mammalian family members, the majority of them being heterodimers. On the other hand, the important parts of bHLH–PAS factors, which comprise their long C-termini, have not yet been structurally characterized. These fragments perform important functions in the specific modulation of protein action and for the recognition of interacting partners.

Performed in silico analysis revealed that the C-termini of representatives of the class I bHLH–PAS protein family members (SIM, SIM1, SIM2, AHR, HIF1-α, and Clock), and also class II (ARNT, BMAL1, and MET), are predicted as intrinsically disordered regions (IDRs) and are not homologous to any described domains. We discussed the known functions of the presented C-termini proteins according to their disorder character. Moreover, we proposed NMR techniques for intrinsically disordered C-termini characterization [94]. We believe that the structural properties of subsequent IDRs predicted in the sequences of bHLH–PAS transcription factors (mainly C-termini) need to be resolved for a full understanding of the way of bHLH–PAS family transcription factors function.

**Funding:** The work was supported by The National Science Centre (NCN): PRELUDIUM predoctoral grant UMO-2017/27/N/NZ1/01783 and ETIUDA doctoral scholarship UMO-2018/28/T/NZ1/00337, and partially supported by a statutory activity subsidy 0401/0143/18 from the Polish Ministry of Science and Higher Education for the Faculty of Chemistry of Wroclaw University of Science and Technology.

**Acknowledgments:** We would like to thank Andrzej O ˙zyhar (Department of Biochemistry, Faculty of Chemistry, Wroclaw University of Science and Technology) for all valuable comments and suggestions.

**Conflicts of Interest:** The authors declare no conflict of interest.
