Abstract
Per-Arnt-Sim (PAS) domains are evolutionarily-conserved regions found in proteins in all living systems, involved in transcriptional regulation and the response to hypoxic and xenobiotic stress. Despite having low primary sequence similarity, they show an impressively high structural conservation. Nonetheless, understanding the underlying mechanisms that drive the biological function of the PAS domains remains elusive. In this work, we used molecular dynamics simulations and bioinformatics tools in order the investigate the molecular characteristics that govern the intrinsic dynamics of five PAS-B domains (human AhR receptor, NCOA1, HIF1α, and HIF2α transcription factors, and Drosophila Suzukii (D. Suzukii) juvenile hormone receptor JHR). First, we investigated the effects of different length of N and C terminal regions of the AhR PAS-B domain, showing that truncation of those segments directly affects structural stability and aggregation propensity of the domain. Secondly, using the recently annotated PAS-B located in the methoprene-tolerant protein/juvenile hormone receptor (JHR) from D. Suzukii, we have shown that the mutation of the highly conserved “gatekeeper” tyrosine to phenylalanine (Y322F) does not affect the stability of the domain. Finally, we investigated possible redox-regulation of the AhR PAS-B domain by focusing on the cysteinome residues within PAS-B domains. The cysteines in AhR PAS-B are directly regulating the dynamics of the small molecule ligand-gating loop (residues 305 to 326). In conclusion, we comprehensibly described several molecular features governing the behaviour of PAS-B domains in solution, which may lead to a better understanding of the forces driving their biological functions.
Highlights
Per-ARNT-Sim (PAS) domains can be found in proteins from all kingdoms of life
PAS domains are found in the basic helix-loop-helix-PAS transcription factors
We found that the replacement of the “gatekeeper” tyrosine Y322 of aryl hydrocarbon receptor (AhR), by a phenylalanine
Summary
Per-ARNT-Sim (PAS) domains can be found in proteins from all kingdoms of life. Proteins containing PAS domains in the animal kingdom are involved in cellular responses to hypoxia [1,2], hormonal signalling cascades [3], circadian cycles [2,4,5], synaptic plasticity [6]and xenobiotic responses [7]. Proteins containing PAS domains in the animal kingdom are involved in cellular responses to hypoxia [1,2], hormonal signalling cascades [3], circadian cycles [2,4,5], synaptic plasticity [6]. Proteins containing PAS domains are involved in pathologies, such as tumourigenesis [10], excessive inflammatory responses [11] and neurodegeneration [12,13]. PAS domains are found in the basic helix-loop-helix (bHLH)-PAS transcription factors. Class I includes aryl hydrocarbon receptor (AhR), AhR repressor (AhRR), and two single-minded proteins (SIM1 and SIM2). Class II includes two aryl hydrocarbon receptor nuclear translocators (ARNT1 and ARNT2) and two interrelated brain and muscle
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
